HIV-1 Nnrtis: Structural Diversity, Pharmacophore Similarity, and Implications for Drug Design

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HIV-1 NNRTIs: Structural Diversity, Pharmacophore Similarity, and Implications for Drug Design

Peng Zhan,1 Xuwang Chen,1 Dongyue Li,1 Zengjun Fang,1 Erik De Clercq,2 and Xinyong Liu1

1Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, P.R. China 2Rega Institute for Medical Research, Katholieke Universiteit Leuven, Leuven, Belgium

Published online in Wiley Online Library (wileyonlinelibrary.com). DOI 10.1002/med.20241 .

Abstract: Nonnucleoside reverse transcriptase inhibitors (NNRTIs) nowadays represent very potent and most promising anti-AIDS agents that specifically target the HIV-1 reverse transcriptase (RT). However, the effectiveness of NNRTI drugs can be hampered by rapid emergence of drug-resistant viruses and severe side effects upon long-term use. Therefore, there is anurgentneedtodevelopnovel,highlypotentNNRTIs with broad spectrum antiviral activity and improved pharmacokinetic properties, and more efficient strategies that facilitate and shorten the drug discovery process would be extremely beneficial. Fortunately, the structural diversity of NNRTIs provided a wide space for novel lead discovery, and the pharmacophore similarity of NNRTIs gave valuable hints for lead discovery and optimization. More importantly, with the continued efforts in the development of computational tools and increased crystallographic information on RT/NNRTI complexes, structure-based approaches using a combination of traditional medicinal chemistry, structural biology, and computational chemistry are being used increasingly in the design of NNRTIs. First, this review covers two decades of research and development for various NNRTI families based on their chemical scaffolds, and then describes the structural similarity of NNRTIs. We have attempted to assemble a comprehensive overview of the general approaches in NNRTI lead discovery and optimization reported in the literature during the last decade. The successful applications of medicinal chemistry strategies, crystallography, and computational tools for designing novel NNRTIs are highlighted. Future directions for research are also outlined. & 2011 Wiley Periodicals, Inc. Med Res Rev

Key words: HIV-1; RT; NNRTIs; drug resistance; drug design; medicinal chemistry; crystallography; computational chemistry Contract grant sponsor: National Natural Science Foundation of China (NSFC); Contract grant numbers: 30873133; 30772629; 30371686; Contract grant sponsor: Key Project of NSFC for International Cooperation; Contract grant number: 30910103908; Con- tract grant sponsor: Research Fund for the Doctoral Program of Higher Education of China; Contract grant number: 070422083; Contract grant sponsor: Independent Innovation Foundation of Shandong University (IIFSDU); Contract grant number: 2010GN044; Contract grant sponsor: Shangdong Postdoctoral Innovation Science Research Special Program; Contract grant number: 201002023; Contract grant sponsor: China Postdoctoral Science Foundation; Contract grant number: 20100481282. Correspondence to: Xinyong Liu, Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, 44, West Culture Road, 250012, Jinan, Shandong, P.R. China, E-mail: [email protected]

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1. INTRODUCTION

Human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is a primary target for antiretroviral chemotherapy. HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs) are important in the drug combination therapies (namely, highly active antiretroviral therapy) currently used to treat HIV infection and AIDS due to their unique antiviral activity, high specificity, and low toxicity.1–3 Nevertheless, drug resistance is still the main reason of failure for their anti-HIV infection efficacy. Three NNRTIs clinically used (efavirenz, nevirapine, and delavirdine) could effectively inhibit proliferation of the wild-type (WT) HIV, but they are less effective against clinically important RT mutant viruses, such as Y188C, Y181C, K103N, and L100I, which are involved in high-level resistance to most current NNRTIs.2 Although the newly approved etravirine (Fig. 1) shows improved potency against many drug resistance mutations, it lacks the convenience of once-daily dosing and is also involved in cutaneous and hypersensitivity.4 In addition, efavirenz, as the most pre- scribed NNRTI, is associated with side effects including dysfunction of central nervous system and teratogenicity.5 Therefore, there is compelling need for the discovery of next generation NNRTIs that possess an improved safety property with the convenience of once- daily administration and high activity against drug-resistant mutant viruses.6 NNRTIs are targeted at a specific and allosteric binding site (an especially flexible pocket formed upon binding the inhibitor) situated about 10 A˚from the polymerase catalytic site within the HIV-1 RT. One of the main issues in computational NNRTIs drug design is incorporation of the inherent flexibility of the NNRTIs binding pocket (NNIBP). This is especially crucial in ligand binding process, when induced fit can lead to structural re- arrangement of RT. Although current computational methods (such as docking) deal with flexible ligands, it is very challenging to manage receptor flexibility.7–9 To date, the advances in the medicinal chemistry of HIV-1 NNRTIs have relied mostly on ligand-based design. The flexibility of the binding pocket in RT resulted in the structural and chemical diversity of NNRTIs, providing a wide opportunity for novel scaffold discovery. Although they are structurally quite diverse, all NNRTIs bind in the NNIBP in a similar conformation and in identical fashion, providing valuable information on NNRTI lead discovery and optimization. Furthermore, with the continued efforts in the development of computational tools and increased structural information on RT, coordinated multidisciplinary effort involving traditional medicinal chemistry (SAR analysis, bioisosteric replacement, molecular hybridization, scaffold hopping, multi-target/multivalent drug design, etc.), structural biology (crystallography), and computational chemistry (molecular modeling) have proven to be powerful strategies to handle flexibility of the NNIBP and to identify novel NNRTIs with high antiviral activity against WT and mutant viruses, and improved pharmacokinetic profiles (Fig. 2).

Me CN CN Me HN N N Me Me N O N N F3C O N NH H Cl Me S N N O N O Br N N O N O H O CH SO H H NH Me H 3 3 2

1, Nevirapine 2, Delavirdine 3, Efavirenz 4, Etravirine/TMC-125

Figure 1. Chemical structures of NNRTIs approved by the FDA for HIV-1 treatment.

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HIV-1 NNRTIs K 3

RT Mutations in NNIBP Flexibility of NNIBP

NNRTIs Pharmacophore Drug Resisitance Structural Diversity Similarity

Necessity Feasibility Inspiration

NNRTIs Leads Discovery and Optimization

Medicinal Chemistry Crystallography Computational Chemistry

Bioisosterism Principle The Explanation of QSAR Molecular Docking RT/NNRTI Interaction Database Searching Molecular Hybridization Concept The Identification of Pharmacophore Modeling Scaffold Hopping Tolerate Region in NNRTI De Novo Methodologies Prodrug Approach Structural Basis Free Energy Perturbation Multiple Ligands Design QM/MM calculations Multivalency Theory Strategies To ols

Multidisciplinary Coordination

Figure 2. The paradigm for NNRTI lead discovery and optimization. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

In this review article, we will first describe the structural diversity and the pharmacophore similarity of NNRTIs, as well as the implications for drug design. Then, the following sections will emphasize recent research approaches in NNRTIs lead discovery and modifications. Especially, the application of the medicinal chemistry strategies in the structural modifications will be discussed with the aid of illustrative examples.

2. STRUCTURAL DIVERSITY OF NNRTIS

Currently, more than 50 structurally diverse classes of compounds have been identified as genuine NNRTIs (Table I), which specifically suppress HIV-1 replication and are targeted at the NNIBP.10–17 These compounds can be divided into two classes: the first generation NNRTIs (exemplified by HEPT and TIBO), originally obtained by fortuitous discovery (HEPT) or targeted screening, and showed a dramatic decrease of activity against single point mutations in the NNIBP, and the second generation NNRTIs, discovered as a result of comprehensive strategies involving computational chemistry (molecular modeling), structure-based rational drug design and synthesis, and biological and pharmacokinetic assays. Generally, second generation NNRTIs tend to be more active against WT and broad- spectrum HIV-1 drug-resistant strains than the first generation compounds. Based on the types of the chemical scaffolds, the structural classes of NNRTIs can be devided into: multicyclic scaffolds, benzo-fused heterocyclic scaffolds, six-membered

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Table I. Overview of the Structural Classes of NNRTIs

Chemical General Representative scaffolds NNRTIs families abbreviation compounds References

Multicyclic Tetrahydromidazo [4,5,1-jk][1,4] TIBO 5a, Tivirapine 18a,b scaffolds benzodizepin-2(1H)-one Dipyridodiazepinone 1, Nevirapine 19 Indolyldipyridodiazepinone 6 20 Thiazolobenzimidazole TBZ 7, NSC 625487 21a,b Thiazolo-iso-indolinone 8,BM151.0836 22 Pyrrolobenzodiazepinone 9 23 Imidazodipyridodiazepine 10, UK-129,485 24 Arylpyrido(thio)diazepine 11, MEN 10979 25 Pyrrolobenzoxazepinone 12 26a,b Indolobenzothiazepine 13 27 Imidazopyridazine 14 28 Trioxothienothiadiazine TTD 15, QM96521 29 Imidazoquinazoline 16 30 Pyrido[1,2a]indole 17, BCH-4989 31 Tricyclic benzothiophene 18, NSC-380292 32 Coumarin 19, Calanolide A 33a,b 20a, DCK 33b–d 5H-Pyrrolo[1,2-b] PBTD 21 34 [1,2,5]benzothiadiazepine Pyranoquinazolinones 22 35 Dihydro-1H-pyrido[3,2-b]indole 23, VRX-329747 36 Benzo-fused Bisheteroarylpiperazine BHAP 2, Delavirdine 37a,b heterocycles Quinoxaline 24a, HBY 097 38 Indole carboxamide 25, L-737,126 39a,b Benzothiadiazine 26, 40 Quinazolinone 27a 41 Benzoxazinone 3, Efavirenz 42 Benzothiadiazepine 28 43 Oxindoles 29a 44 Quinolones 30 45a 31 45b 32 45c Benzimidazolones 33a 46 1-(2,6-Diﬂuorobenzyl)-2-(2, BPBIs 34 47 6-diﬂuorophenyl)benzimidazoles Six-membered Diaryltriazine DATA 35 48 heterocycles Diarylpyrimidine DAPY 4a, TMC125 49a,b core Diarylpyrazinone 36 50 Diarylpyridine 37 51 Diarylaniline 38 52 1-[(2-Hydroxyethoxy)methyl]-6- HEPT 39a, HEPT 53 (phenylthio)thymine derivatives Alkoxy(arylthio)uracil 39b 54 Dihydroalkoxybenzyloxypyrimidine DABO 40a–c 55a,b Pyridinone 41a, L-697,661 56a–c Benzylthiopyrimidine 42a, U-31355 57a,b (Pyrimidinethioethers) Furopyridinylthiopyrimidinamine 42d, PNU-142721 58 Diarylamines (Het–NH–Ph–U) 43 59a–c

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HIV-1 NNRTIs K 5

Table I. Continued

Chemical General Representative scaffolds NNRTIs families abbreviation compounds References

Five-membered Thiadiazolyl dialkylcarbamate TDA 44, RD-4-2024 60 heterocycles Highly substituted pyrrole 45a, 45b 61a,b core Azoles 46 62a–c Imidazole 47, S-1153 63a–c 1,5-Diphenylpyrazole 48, PNU-32945 64 Diarylthiazolidinone 49a 65 N-Aryl pyrrolidinone 50 66a,b Sulfanyltriazole/tetrazole 51a, VRX-480773 67a–h 51b, RDEA806 Thiazolidenebenzenesulfonamide 52a–c 68a,b (Thio)amide a-Anilinophenylacetamido a-APA 53, Loviride 69 linker (a-APA, R89439) containing Imidoyl thiourea ITU 54 70 scaffolds Thiocarboxanilide 55, UC-781 71 Phenethylthiazolylthiourea PETT 56a, Trovirdine 72a–c (LY 300046) Quinoxalinylethylpyridylthiourea QXPT 56b, 6-FQXPT 73 Urea-PETT analogues 56c, MSC-204; 74a–d 56d, MSC-372 (PETT-5) O-Phthalimidoethyl- TC 57a–c 75 N-arylthiocarbamate Diphenyl Alkenyldiarylmethane ADAM 58a 76 scaffolds Tetrahydronaphthalene lignan 59a 77 Sulfonylbenzonitrile 60 78 Indazole 61a, 61b 79 Benzophenone 62a 80 Diaryl ether 63a 81 1-[2-(Diphenylmethoxy)ethyl]-2- DAMNI 64 82 methyl-5-nitroimidazole Others Hexahydroxybiphenyl derivatives 65a, 65b 83 20,50-Bis-O-(tert-butyldimethylsilyl)- TSAO 66, TSAO-m3T 84a–c 30-spiro-500-(400-amino-100,200- oxathiole-200,20- dioxide)pyrimidine

heterocyclic core scaffolds, ﬁve-membered heterocyclic core scaffolds, (thio)amide linker containing scaffolds, diphenyl scaffold, and so on. As shown in Table I, the prototype leads or the promising candidates are selected as representatives in each class of NNRTIs (Figs. 3–9). As is well known, the current anti-AIDS drug research priorities are looking actively for new drugs from the original leads and complex prescription for management of HIV infection effectively, as well as against various mutant viral strains. In addition to the four approved NNRTIs, a few more candidates are in clinical stage. Ideally, in order to be considered a bona ﬁde candidate drug, a compound of interest must meet all the following criteria.10d (1) High level of activity against key mutants (i.e. K103N and Y181C) resistant to other NNRTIs without allowing breakthrough; (2) excellent oral bioavailability, and prolonged duration

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H Me Me N Me F N Me N N N N N N F Cl N S N S N N N H O O H Me Me N

5a, Tivirapine (R 86183) 1, (Nevirapine, BI-RG-587) 6 7, NSC 625487

Me Me Me N N Me O MeO N N N N S N S

N N N N S N Me H O Me O 8, BM +51.0836 9 10, UK-129,485 11, MEN 10979

O N Me N S N O O Cl N N NH N

O N O H Me O 12 13 14

OO N Me Me Cl S N N O N S 7b N O O OMe N O 2a O O S CN HO MeO 15, QM96521 16 17, BCH-4989 18, NSC-380292

O O Me N Me Me Cl S N O

N O O Me CF3 Cl O O O 21 NH O2N O O O Me OH Me N O H Me Me O Me Me 22 19, (+)-Calanolide A OO O Me O O N Me O CN Me O N Me O H 20a, DCK 23, VRX-329747

Figure 3. Chemical structures of NNRTIs with multicyclic scaffolds. of potency; (3) signiﬁcantly decreased toxicity; and (4) easy of synthesis and formulation. Obviously, the more requirements a selected drug meets, the more success it will have in the clinical setting and in the global market as the ‘‘miracle’’ drug for the treatment of AIDS.

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HIV-1 NNRTIs K 7

Me Me Me Me HN N O O N O O S O MeO N O S H SMe Cl N Me S N N NH O N S N S N O H N O H CH SO H H H 2, Delavirdine (U-90152) 24a, HBY 097 25, L-737,126 26, NSC 287474

OEt Me O N O Me F C O Cl Cl Cl S N Br NH O Me O N Ο N Ο N N H H H O H 27a 3, Efavirenz 28 29a

R Me Me Cl CO R O S O X N O O S Me Cl R MeO OH Cl N O N H O R = (CH ) CHCH , nPent N O Ν O N Η R = Et, Me, Allyl H H 30 31 32 33a

F F F

F F F F N N Cl N F O N Me N N F F H Me O O 33b 34a 34b

Figure 4. Chemical structures of NNRTIs with benzo-fused heterocyclic scaffolds.

3. COMMON FEATURES OF NNRTIs

NNRTIs, although belonging to a wide range of structurally diverse scaffolds, contain many ubiquitous fragments in their structures and possess a common pharmacophore model, including an aromatic ring able to participate in p-p stacking interactions, amide or thioamide moieties capable of hydrogen bonding, and one or more hydrocarbon-rich domain that participate in hydrophobic interactions. In addition, the interactions with RT show similar binding mode which is considered reminiscent of a ‘‘butterﬂy’’ with one ‘‘body’’ and two hydrophobic ‘‘wings’’.

A. Ubiquitous Fragments (Motifs) in NNRTI Scaffolds The existence of ubiquitous motifs in NNRTIs is very similar with the concept of privileged structures85,86 in medicinal chemistry. For instance, para-substituted aniline motif exists in multicyclic-typed NNRTIs (i.e. tivirapine) and many second generation NNRTIs with

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N N N N N N N N N Me

Me Me Me Me Me Me ONNH O N NH Me Me Me Me N NH O N NH O NH N Br Me N O NN NH Me NH O N NH 35 4a, TMC 125 36 37 38

O O Me O Cl Me R' HN HN Me HN R'' R N O N S O N S X N H N Me O HO O Cl O Me 40a, DABO (X = O) Me N O Me Me 40b, S-DABO (X = S) H 39a, HEPT 39b 40c, N-DABO (X = N) 41a, L-697,661 Me Cl Cl Me N N Me H O N H N N S H N N S R Het O 42d, PNU-142721 N N H 42a, U-31355 (S)-(-)-enantiomer 43

Figure 5. Chemical structures of NNRTIs with six-membered heterocycles core scaffolds.

benzo-fused heterocyclic scaffolds (i.e. efavirenz, HBY 097), and (thio)amide linker containing scaffolds (i.e. UC-781, trovirdine) (Fig. 10A). A diphenyl, substituted thiourea functional group, a (thio)acetamide linker, and a nitrile-containing aromatic (not shown), are also ubiquitous motifs in many NNRTI families (Fig. 10B–D). Structural similarity is remarkable among the NNRTIs with different chemical scaffolds (Fig. 10E–G). Otherwise, the usage of three different drug design strategies, bioisosteric principle, de novo design approach, and pharmacophore-based virtual screening, resulted in the same quinolone scaffold NNRTIs 30–32, respectively, illustrating the structural similarity of NNRTIs. Based on the fragment-based ligand discovery strategy,87 the ubiquitous motifs derived from databases of known NNRTIs with high potency against WT and drug-resistant variants of HIV-1 RT, high oral bioavailability and favorable pharmacokinetics, can be used as basic fragments for the generation of ‘‘privileged scaffolds’’ libraries that are capable of providing high-quality NNRTI hits. In fact, the computational tools of understanding bioactive molecular similarity has been employed in the ‘‘colonization’’ of the existing chemistry space for each molecular scaffold and in association with de novo drug design45b,59a and classical medicinal chemistry concepts (such as molecular hybridization) has assisted the rational design of new drug-candidate prototypes against WT and key mutant viruses. The method can be easy to put in place, and is fast enough to be iteratively applied to different sources of drug-like molecules.

B. Molecular Modeling (From ‘‘Butterﬂy’’ to ‘‘Horseshoe’’) On the basis of molecular modeling and X-ray crystallography investigations on nevirapine (1), TIBO (5b) and 8b, Scha¨fer et al. proposed a three-dimensional (3D) model describing the

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HIV-1 NNRTIs K 9

Me Me Me Me N SN N OMe O N O S O Me O N NH Me O Cl Cl N OMe Me N Me H O O O

44, RD4-2024 45a 45b

Cl Cl

N Cl Me R R S N N NH N Cl O NH O N Me N N O S XN Me Me CN O X = CH, N 46 47, Capravirine (AG1549) 48, PNU-32945 49a

O NH NN Cl H O Me N N S R S N Br N S O O N Me R MeO CN Me Me O 52a: R = Cl. EC = 1.7 nM, SI > 15000 51a, VRX-480773, (R = SO NH ) 52b: R = Br. EC = 2.1 nM, SI > 12000 50 51b, RDEA806, (R = COOH) 52c: R = CN. EC = 1.8 nM, SI = 6100

Figure 6. Chemical structures of NNRTIs with five-membered heterocycles core scaffolds.

N Me N Cl Me O Me

H O N O Br Cl Cl HN Cl N H Me S Cl N NH H N O N H Me N S NH S H 53, Loviride (α-APA, R89439) 54 55, UC-781 56a, Trovirdine (LY 300046)

Me Me O O

N O OH O N N O X F F F O

Br HN Br HN NC HN N N N N S S O O H N N N H H H 57a, TC-1, X = Cl, EC = 40 nM 56b, 6-FQXPT 56c, MSC-204 56d,MSC-372 57b, TC-2, X = Br, EC = 30 nM (Active metabolite of PETT-4) (PETT-5) 57c, TC-3, X = I, EC = 20 nM

Figure 7. Chemical structures of NNRTIs with (thio)amide linker containing scaffolds.

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COOMe COOMe MeO Br NC CN MeO OMe S MeO F O Br Br OMe O S Me O CN MeO OMe R

OMe NH N NH a85 59a 06 61a: R = Me, RT IC = 50 nM 61b: R = Et, RT IC = 25 nM MeO O

H Cl CN Me N O O O C O N N Ο AB O O NH N O N MeO

Me NMeCl 62a 63a 64, RS1478

Figure 8. Chemical structures of NNRTIs with diphenyl scaffolds.

OMe O Br Me O HN

O COOMe O N COOMe O Me2(t-Bu)SiO O H2N O R O OSi(t-Bu)Me2 OMe S O O 65a: R = H 65b: R = Br 66, TSAO-m3T

Figure 9. Chemical structures of NNRTIs with other scaffolds.

structural elements that were critical determinants for anti-HIV-1 activity (Fig. 11)88:a central lipophilic domain (‘‘body’’) to which are attached two hydrophobic (normally a benzene ring and an extended p system) moieties (‘‘wings’’), as in a ‘‘butterfly-like’’ orientation. Moreover, an additional lipophilic region, such as a carbonyl or thiocarbonyl group, should be adjacent to the benzene ring. Other NNRTIs, such as a-APA, DABO, TBZ, and TTD, are examples of agents conformationally related to nevirapine and TIBO. Taking account the ‘‘butterfly-like’’ conformation as determinant for anti-HIV-1 activity, many novel families of NNRTIs were initially designed, such as 1-[2-(diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs). Another butterfly-like model was derived utilizing eight well-known NNRTIs, i.e. nevirapine (1), delavirdine (2), efavirenz (3), indole carboxamide (25), benzothiadiazine-1-oxide (26), thiocarboxanilide (44), loviride (53), and trovirdine (56a).89 As shown in Figure 12, the 3D-pharmacophoric distance model proposed may be considered reminiscent of a ‘‘butterfly’’ with a hydrophilic center (‘‘body’’: amide or thioamide groups) and two hydrophobic outskirts (‘‘wings’’), one of which is usually substituted by a halogen atom.

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HIV-1 NNRTIs K 11

AC NH N R Br N HN N O(S) Cl N S H N N S H PETT (LY 300046) U-31355 B Me R R Me N O X Me S X = C, O, SO N Cl N S N S H N H R 86183 NSC 287474

D Me Me N Cl O NH Me Me N N N S N S Cl

N N N MeO S S Me O O O 8, BM +51.0836 11, MEN 10979 49a 50

NN Cl H H N N Br N S O O C O O SO NH Ο AB MeO Me NMe 51a, VRX-480773 62a

E Me Me Me Me Me O N Me O O S Me O Cl N Cl N Cl Me O S N N N S H H H R 86183 33 55, UC-781

F O Me CN Me NC

R R F Me Me N O N NH NH HN NH X N N N X = CH, N O 35 46 56d, MSC-372

Me G Me Me Br Me Me Me N O O O O S O S S N O S Me O Me O O O S Me Cl NH NH MeO OH Cl N CN N O Me N N O H O N H Ν O O Η H NH 25, L-737,126 45b 32 33a 60

Figure 10. Some ubiquitous fragments (motifs) and structural similarity in different NNRTI scaffolds: (A) para-substituted aniline motif; (B) diphenyl scaffold; (C) substituted thiourea; (D) (thio)acetamide. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Me Me

Me N N N N Lipophilic S region Benzene ring Extended π-system N or aromatic ring N N H O S Me N 4.5--5A H O O 108--115 CH (Thio) carbonyl Methyl or other group 1, Nevirapine 5b, TIBO 8b or sulphonyl Linked at π-system

Figure 11. The commonthree-dimensional model derived from the comparison of 1, 5 b,and8b (see text). [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

It must be pointed out that these two butterfly-like molecular models were derived from ligand-based pharmaphore modeling. As a wealth of crystal structures of RT-NNRTI complexes were reported,90–92 the ‘‘butterfly-like’’ conformation of NNRTIs with different structural classes has been confirmed by crystallographic analysis. For instance, the first- generation NNRTI nevirapine and the recently approved etravirine can be superimposed in a ‘‘two-wing’’ binding mode (compare the superposition figure of nevirapine with etravirine).12 Comparing the conformation of ten NNRTIs (nevirapine, delavirdine, efavirenz, a-APA, BM121.1326, 9-Cl-TIBO, PETT-2, UC-781, MKC-442, and capravirine (S-1153)) when bound with RT also disclosed a high degree of inhibitor overlap causing a ‘‘butterfly-like’’ configuration separated by a linker (‘‘body’’), where planes of the ‘‘wings’’ are separated by 1201 (compare two orthogonal views of ten NNRTIs in NNIBP).93 The RT-bound conformation of the ITU/DATA/DAPY NNRTIs resembles a ‘‘U’’ or ‘‘horseshoe’’, in contrast to the above-mentioned ‘‘butterfly-like’’ shape.49b There are important differences in the conformations of these two models (‘‘butterfly’’ and ‘‘horseshoe’’) and specific positioning within the NNIBP. For instance, the ‘‘horseshoe’’ model could adapt to the plasticity and changes of the NNIBP better, which appear to be critical for potency against WT and a wide range of drug-resistant mutant HIV-1 RTs.

C. 3D Pharmacophore Model of NNRTIs Based on the crystallographic structures of RT-NNRTI complexes and computational studies, it has been demonstrated that the ‘‘butterfly-like’’ or ‘‘horseshoe’’ NNRTIs also share the common binding mode with NNIBP (the key interactions involved in binding sum- marized in Table II)94,95 and 3D pharmacophore model (illustrated in Fig. 14),96,97 which is the spatial arrangement of key chemical features: hydrophobic domain, hydrogen bond acceptor, and donor. The hydrophobic domain fills the hydrophobic subpocket consisted of the residues Y181, Y188, F227, and W229 (Fig. 13). The hydrogen bond acceptor and donor form a key hydrogen bond with the backbone imino and carbonyl groups of K101 (or K103) residue (directly or via a structural water molecule). The derived pharmacophore model can facilitate insight into the detailed interactions between NNRTIs and RT, and to design the next generaction of NNRTIs. As is well known, perceiving a pharmacophore is the first essential step towards understanding the receptor–ligand interaction. Other similar pharmacophore models for NNRTIs were also obtained.45c,46,98–100 As the pharmacophore-based virtual screening has evolved into one of the well-established computational tools in rational drug design, this technology could be used for obtaining new potentially active NNRTIs, lead optimization, as well as combinatorial library focusing (will be described in detail in the following section).

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HIV-1 NNRTIs K 13

Me Me HN N N N O O N N F C S H Cl O Me S N N O Cl NH O N N O N O N O H O CH SO H H Me H H

enipariveN,1 enidrivaleD,2 znerivafE,3 25, L-737,126

Me Me N N S N Cl Me O O N O H S O N N Br HN N Cl Cl Cl S N S H H N O N H Me

26, NSC 287474 44, RD4-2024 53, Loviride 56a, Trovirdine

Molecular mechanics calculations

Geometrical optimization

Uniform sampling of low energy conformers

Mapping the essential structural components

Hydrophilic site A

4.2 - 6.7 A 9.12 - 9.44 A

114-119˚

B C 4.25 - 7.6 A Lipophilic site Lipophilic site

Figure 12. Schematic representation of the pharmacophoric distance map derived from eight well-known NNRTIs.89 In general, NNRTIs consist of two hydrophobic moieties (wing I and wing II) connected by a polar central body. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

D. General Types of NNIBP There are subtle differences in the conformation of the NNIBP which mainly rely on the NNRTI itself. The size and volume of the NNIBP are remarkably affected by the re- positioning of b10 strand (residues 232–234) and b11 strand (residues 239–241) and the moving of the P236 ‘‘hairpin loop’’, as veriﬁed by crystallographic studies.101 Consequently, it is commonly accepted that various NNRTI pockets can be divided into two discrete binding modes. The ﬁrst mode is a small NNRTI (such as nevirapine)-type binding pocket (PDB code 1VRT) in which there is a main chain hydrogen bond between the carbonyl

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Table II. The Key Interactions Involved in Binding to HIV RT and Deﬁnition of Pharmacophore Points94,95

Pharmacophore points Groups Interaction

Hydrogen bond O–H, S–H, N–H Donor to K103 (1EP4, 1KLM) donors or K101 Hydrogen bond (Thio)carbonyl, ester, sulfone O in ether, Acceptor to K103 (1EP4, 1KLM) acceptors Pyridine N atom, N, O in aromatic or K101 5/6-membered rings Hydrophobic Aliphatic or aromatic rings, Double and Hydrophobic interaction with Y188, domains triple C–C bonds, CF3, Aliphatic chains Y181, W229, F227, L100, L234, V106, Y318

W229 Wing I Wing II CN CN

Y188 HN

OH Me Me Y181 Hydrophobic domain O N N OH Me H Cl N Me Br

NH2 N TMC125 (4) Me N N H Hydrogen bond donor 9-Cl-TIBO (5b) S Hydrogen bond acceptor O H N K101

Figure 13. Positioning of NNRTI binding into NNIBP by mapping of the pharmacophore points (exemplified by 9-Cl-TIBO and TMC125).96,97 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.] oxygen of P236 and the nitrogen of K103. The second mode is a larger NNRTI [such as delavirdine (PDB code 1KLM) or 1-(2-hydroxyethoxymethyl)-6-(phenylthio) thymine (HEPT)]-type NNIBP in which there is no hydrogen bond between P236 and K103.101,102 These bulkier NNRTIs bind with the RT in an expanded volume relative to smaller inhibitors and contain members that extend from the common NNIBP toward a ﬂexible protein/solvent interface (Fig. 14), providing a valuable clue for drug design (will be described in detail in the following section).103

4. THE NNRTI LEAD DISCOVERY APPROACHES

Lead discovery is one of the most considerable components in rational drug design, and represents a major research area of medicinal chemistry today. There are two basic

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Figure 14. Positioning of delavirdine in the NNIBP (PBD code: 1KLM).101 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

approaches to obtain original leads, namely, de novo design and database screening. Although de novo design is conceptually more attractive, high-throughput screening (HTS) of compound collections is still the predominant approach in drug lead exploration, including NNRTI lead discovery.

A. HTS In the pharmaceutical industry, database HTS is frequently applied at the beginning of a drug discovery program to detect novel hits.104,105 The combinatorial chemistry strategy together with the HTS approach has permitted the discovery and optimization of novel anti- HIV lead compounds.106 Some novel and diverse NNRTI leads discovered through HTS using the cell-based HIV replication or enzymatic assay (presented in Fig. 15), such as benzophenone (62),80 sulfanyltriazole (51c and 51d),67b,c sulfanyltetrazole (51e and 51f),67d oxindole (29),44 tricyclic benzothiophene (18),32 N-aryl pyrrolidinone (50),66a and thiazolidenebenzenesulfonamide (52d and 52e),68a are of great value for the discovery of the next generation NNRTI candidates.

B. Natural Products Nature has always provided a wealth of drugs for various disease.107 Natural products with promising anti-HIV properties have been revealed.108–110 Over the past decade, significant progress has been made in the investigation of the medicinal plants as novel NNRTIs. These plant-derived naturally occurring compounds belong to a broad range of diverse structural families, e.g. flavonoids, coumarins, terpenes, tannins, lignans, alkaloids, polysaccharides, and naphtha(anthrax)quinones.107–110 Most of them can serve as leads for developing novel RT inhibitors that may be developed into anti-HIV candidates. This section described representative examples of the successful use of chemical modification or molecular simplification strategy in the discovery of new leads from bioactive natural products.

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16 K ZHAN ET AL.

H NN NN Br N H H O O N N Me N S Me N S O Ο O O Me

MeO 62a Me NMe 51c 51d Me Me

OEt NN Cl NN NO N H H O N N O N N 7b N S N S Br OMe Me Me O O 2a O O S N H MeO 51e 51f 29 18, NSC-380292 Me IC (WT RT Pol) = 5 nM 2aS,7bS- and 2aR,7bR enantiomers IC (WT RT Pol) = 5 nM EC = 75 nM IC (K103N) = 20 nM EC = 1.24 M, SI > 800 IC (K103N) = 15 nM IC (K103N/Y181C) = 849 nM

O NH

N Me O Me O S N S N Me S NO S NO MeO Me N O Me N O O Me Me Me Cl 50 52d 52e EC = 125 nM EC Mn58= CE = 48 nM

Figure 15. Examples of representative NNRTIs discovered from HTS.

OH HO O OMe HO O O Br OH O O O COOMe HO O OH O COOMe OH OH O HO O O R OH HO O OMe Hexahydroxybiphenyl O HO 65a: R = H, EC50 = 0.52 ug/mL, SI > 190 67, Ellagitannin punicalin OH 65b: R = Br, EC50 = 0.23 ug/mL, SI > 480

Figure 16. The discovery of hexahydroxybiphenyl NNRTIs.

As early as in 1990s, the hexahydroxybiphenyl compounds 65a and 65b (Fig. 16), derived from tannins ellagitannin punicalin (67), were identiﬁed as a unique NNRTI family.83,111 With biologically active lignans, phenylpropanoid dimer compounds of plant origin, as a starting point, synthetic tetrahydronaphthalene (THN) lignan derivatives 59a and 59b have demonstrated potent anti-HIV activity (Fig. 17).77 Naturally occurring Calanolides112a–d and Inophyllums (mainly isolated from Calophyllum lanigerum33a and the Malaysian tree, Calophyllum inophyllum,113 respectively),

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H H MeO O S S MeO O H H OMe OMe

MeO OMe OMe OMe OBz 59a 59b μ μ EC50 = 0.15 M, SI = 161.6 EC50 = 1.09 M, SI > 769

Figure 17. Lignans-based NNRTIs.

MeMe Me MeMe Me Me Me Me Me Me Me Me Me Me

O O O O O

O O O O O O O O O O O O O O O

Me OH Me OH Me OH Me OH Me OH Me Me Me Me Me

Me Me Me Me Me Me Me Me O O Me O O

O O O O O O O O O O O O Y Cl O Me X Me OH Me O Me Me Me

Figure 18. The structures of Calanolides and Inophyllums. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

as well as their structural analogs,114 represent novel coumarin-based NNRTIs (Fig. 18). In particular, (1)-calanolide A is unique in inhibiting HIV-1 Y181C isolates.112b The (1)-calanolide A also displays additive to synergistic anti-HIV activity with other antiviral agents to suppress mutant strains. Nevertheless, its low potency against HIV-1 is likely to account for the limitation in clinical trials although it was proved to be well tolerated in phase Ia/Ib trials.112c,d Thus, many structural modifications on (1)-calanolide A with the aim of improving inhibitory potency have been performed. Very recently, 10-chloromethyl-11-demethyl-12- oxo-calanolide A, 19f, was reported, which shows druggable properties with higher oral bioavailability (32.7% in the rat), tolerable toxicity upon a single oral dose administration in mice, and interesting resistance profiles (especially the feature of high inhibitory potency 115 against the WT and Y181C mutant HIV-1 at an EC50 5 7.4 and 0.46 nM, respectively). Taking the natural product, suksdorfin (68) (Fig. 19), which was isolated from the fruit of Lomatium suksdorfii,116 as a lead compound, further modifications led to the discovery of 3,4-di-O-(S)-camphanoyl-(1)-cis-khellactone (20a, DCK) and its analogs,117–130 such as

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O O O Me O O O Me O Me Me Me OO Me O Me Me O O 20a, R1 = R2 = H (DCK) 20b, R = H, R = Me OO Me O 1 2 O Me 20c, R = CH OH, R = Me (HMDCK) Me O 1 2 2 Me Me 20d, R1 = CH2CN, R2 = Me 68, Suksdorfin O

Figure 19. The novel suksdorfin derivatives as potent NNRTIs.

4-methyl-DCK (20b), 3-hydroxymethyl-4-methyl-DCK (20c, HMDCK), and (30R,40R)-3- cyanomethyl-4-methyl-DCK (20d), which belong to a novel NNRTI family (Fig. 19). The structural optimization of DCKs is still a research focus in the current anti-HIV drug discovery field.131 Especially, DCK derivative 20d, which contains a cyano group, not only exhibited promising potency against WT HIV-1 in H-9 lymphocytes assay but also showed improved drug resistance profiles. It also has mediocre oral bioavailability, mediocre cell permeability, and low systemic clearance.130 Its design was based upon the computational studies,132 coupled with the fact that a cyano group demonstrates good metabolic stability under most conditions. This cyano group is also a good H-bond acceptor and can favorably interact with key residues on the NNIBP, which are determinant requisites for the affinity of several NNRTIs.133 These results suggest that natural products combined with rational drug design- based modifications and analogs synthesis could provide promising lead molecules for the development as clinical trial candidates. In summary, structural modification (simplification) of a natural product has afforded a practical way in theory to find novel NNRTI leads with promising antiviral potency and less toxicity. However, identifying novel NNRTIs by random screening of natural product libraries and then optimizing them by systematic chemical modifications are highly time- and resource consuming. Therefore, faster and more efficient approaches that facilitate and shorten the novel NNRTI discovery process would be extremely beneficial.

C. Virtual Screening Virtual screening is becoming a major source in the discovery of hit- and lead-compounds.134–136 Several approaches of virtual screening, such as molecular docking and pharmacophore-based searching algorithms, are gaining acceptance and are applied to discover more potent NNRTIs. Numerous related software tools have been developed. In this section, we will describe several examples of different virtual screening approaches for NNRTI lead discovery.

1. Docking-Based Virtual Screening Docking-based virtual screening is a widely used computational tool in hit identiﬁcation and lead optimization, which ‘‘dock’’ small molecules into the binding sites of macromolecular targets and ‘‘score’’ the target–ligand binding afﬁnity.137 Sangma et al. used a docking and neural network combined approach to screen active compounds targeting HIV-1 RT and PR from the Thai medicinal plants database.138 The

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results show that this combined approach allows to execute the successive screening and to minimize the analyzing step from the docking and scoring procedure. In a recent report, virtual screening of the Maybridge library of 70,000 compounds was carried out using a similarity filter, docking, and molecular mechanics-generalized Born/ surface area postprocessing to search for novel NNRTIs. Although known NNRTIs were retrieved, purchase and evaluation of top-scoring representative compounds from the library failed to obtain any active HIV inhibitors.62a Hierarchical filters, from simple structural and PK lead filters (e.g. molecular weight, number of rotatable bonds, and number of hydrogen bond acceptors/donors) to high- throughput rigid docking were applied to seek the National Cancer Institute (NCI) database for HIV-1 RT hits. Finally, in vitro assay, a novel molecule NIC 14129 (69), was identified as the most efficient hit for HIV-1 RT inhibition (Fig. 20).139 To discover NNRTIs that are effective against both WT virus and Y181C mutations, docking-based virtual screening using standard-precision scoring and the more computational intensive extra-precision scoring with the Glide program was carried out using three RT proteins (PDB entries 1RT4, 2BE2, and 1JLA) and more than 2,000,000 commercially available compounds. The structures 1RT4 and 2BE2 are for WT RT with different conformations of Y181, while the protein 1JLA contains the Y181C mutant. Among the purchased compounds, 70 shows moderate inhibitory activity against both the WT and Y181C-mutant HIV-1 in low micromolar level, while 71 has 7.5 mM activity against the

O CN H N Me N N S N Me 4 NH O O N O N N O Me HO NH N 69, NIC 14129 μ Me O N O IC = 18.9 M H Nevirapine IC = 4.20 μM 70 71 72

S Br N OH N N S S MeO HN O N N HN H 73 S O EC = 374 nM MeO HN OMe 74a Me SI > 446 HN EC = 3.0 μM Me O S Cl OMe Me Me HN 74c Me Me HN EC = 168 nM O S SI > 345 N O O MeO OH Cl 74b Me EC = 2.6 μM Ν O Η 32

H S N NH O S O O 75, NAPETA

Figure 20. The structures of NNRTIs obtained using virtual screening.

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Y181C mutant, and 72 is a 4.8 mM NNRTI toward the WT virus. This research illustrates a viable protocol to uncover anti-HIV agents with improved resistance properties.140 The virtual screening by docking a large compounds library (Leadquest 3) into two RTs (PDB entries 1FK9 and 1DTQ) led to initial identification of several potential compounds (i.e. 73, 74a,and74b) with effects against the RT-associated DNA polymerase activities and the HIV-1 pseudovirus infection in susceptible cells. Moreover, combining functional groups of two structurally related inhibitors 74a and 74b resulted in a more potent inhibitor 74c that inhibited the RNA-dependent DNA polymerase activity of recombinant HIV-1 RT with an IC50 value of about 510 nM. This compound also suppressed the infection of HIV-1 pseu- 141 dovirus in human lymphocytes with an EC50 value of about 168 nM. It should be noticed that these structures have high similarity to the known PETT family. Through docking-based virtual screening of a large library of 50,000 compounds, N-f2-[4- (aminosulfonyl)phenyl]ethylg-2-(2-thienyl)acetamide (NAPETA, 75) was identified as novel HIV-1 RT inhibitor, which interfered with the formation of the RT-DNA complex. This mechanism is different from that of the classical NNRTIs used for treating HIV infection.142 2. Pharmacophore-Based 3D Database Searching Once a bona fide drug against a known target has been identified, computational approaches, such as 3D pharmacophore-based database searching, can play a pivotal role in the discovery of novel leads with different chemical scaffolds. The large number of successful applications of 3D pharmacophore-based searching in medicinal chemistry clearly demonstrate its utility in the modern drug discovery paradigm.143,144 As early as 1998, a 3D stereoelectronic pharmacophore derived from a 3D-QSAR investigation was reported as the foundation of the development of a two-phase data-mining methodology to seek novel NNRTI leads.145 In 2007, a 3D structure-based pharmacophore model for DAPY NNRTIs was used to screen large chemical databases (CAP Complete 2004 and Derwent-WDI2005). The obtained hits were further filtered by taking into account the fitness score and by using ‘‘Lipinski’s rule of five’’ in addition to molecular docking studies (Glide program). Finally, six compounds were selected for assaying of their inhibitory potency against HIV-1 RT. In particular, compound 32, which belongs to the quinolin-2(1H)-one scaffold, showed an IC50 value (200 nM) comparable to that of nevirapine (180 nM).45c It must be pointed out that pharmacophore-based virtual screening by itself may not always guarantee a successful identification of potent inhibitors against HIV-1 RT and may therefore require additional complementary approaches. The hierarchical multiple-filter database searching strategy combined many cheminformatic tools is an attractive strategy in drug lead exploration. Two efficient approaches by using hierarchical database screenings are presented in Figure 21.99,146 Although the applicability of virtual screening methodology has been well established, it seems that there are still no successful projects of NNRTIs drug discovery in which virtual screening has been the pivotal contributor.

D. De Novo Design of NNRTIs De novo drug design is an active area of structure-based rational design approach, which relies only on prior knowledge of the 3D structure of target to design entirely new lead compounds with desired properties.147 Two categories can be divided for de novo design: atom-based and fragment-based approaches. The fragment-based method shows more attractive as a virtual structure can be easily constructed from combinatorial building blocks. Since the discovery of NNRTIs, crystal structures of WT and mutated RT have been used extensively in the de novo design of novel NNRTIs.148 However, the considerable

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Figure 21. Flowchart representation of the hierarchical multiple-filter database searching strategy. (A) Hierarchical database screening combined sequentially a pharmacophore model, multiple-conformation rigid docking, solvation docking, and molecular mechanics-Poisson--Boltzmann/surface area (MM-PB/SA) sequentially.99 (B) Virtual screening by pre-filter pharmacophore hypotheses and docking.14 6 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Four RT crystal structures: WT, Y181C, K103N, L100I + K103N

Search in each structures for fragments that bind to NNRTIs binding site

Identified fragments that appears in all structures

Build a molucule by linking cross reacting fragments

Minimize and dock final molecule to each structure separately

Synthesize and test various derivatives based on the designed pharmacophore

I O 76

Figure 22. Outline of the design process of new NNRTIs.149 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

conformational ﬂexibility of RT has complicated the traditional structure-based de novo drug design approach for the discovery of novel NNRTIs, because no one would ever predict the formation of the allosteric binding pocket just looking for the unbound structure. In 2007, a successful de novo drug discovery of NNRTI was reported (Fig. 22).149 First, the authors searched small fragments capable of interacting with each one of four RT proteins (WT and Y181C, K103N, L100I1K103N mutations), using the Ludi module (Cerius2 LUDI user guide; San Diego, CA, 2003), a program widely used to dock small molecular

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fragments in target binding sites for the de novo design approach. Then, these fragments were combined to build a core scaffold. Out of 27 synthesized compounds, four had low micro- mole activity against the DNA polymerase activity of RT (IC50 value o10 mM). The most potent compound 76 shows high RT inhibitory activity with (IC50 value: about 3.5 mM), meanwhile, its potency against clinically relevant drug resistance mutants was more efficiently than that of nevirapine. Factors important for tight binding of inhibitors and resilience to mutations were elu- cidated based on the detailed analysis of a broad range of crystal structures of RT in complexing with various NNRTIs together with data on drug-resistant HIV-1 mutations. These information were used to the structure-based (fragment-based methods) discovery of a novel series of quinolone NNRTIs 31a–d. Several of them retain high activity against the Y181C and L100I mutated RT (Table III). Crystal structure analysis confirms the predicted binding modes.45b The ligand-growing program BOMB (Biochemical and Organic Model Builder, Jorgensen, W. L. BOMB, v 2.5; Yale University: New Haven, CT, 2004.) is used to construct molecules by adding layers of substituents to a scaffold that is isolated or that has been placed in a binding site. De novo design of NNRTIs with the program BOMB based on diarylamines (Het–NH–Ph–U) scaffold resulted in the identification of compound 77 (Het 5 2-thiazolyl and U 5 dimethylallyloxy) as a promising original hit (Fig. 23). As described below, this compound was further optimized to multiple highly potent NNRTIs.59a

Table III. Anti-RT (WT and Mutant) Activity (IC50, mM) and Antiviral Activity (EC50, mM) of Quinolone Derivatives

Cl X Cl R 31a: R = Pr, X = O 31b: R = i-Pr, X = O N O H 31c: R = Pr, X = S N O 31d: R = Pr, X = SO Popular fragment H Nevirapine-resistant Compd RTWT RTY181C RTL100I HIV-1IIIB HIV-1

31a 0.71 1.13 1.36 0.035 0.607 31b 0.63 2.50 1.96 0.051 0.710 31c 0.24 0.86 1.61 0.100 0.368 31d 0.38 1.26 2.38 0.242 2.210 Nevirapine 0.30 4100 4100

Me U Me O

BOMB S Het Ph N N N H H

Het-NH-Ph-U 77: EC50 = 10,000 nM

Figure 23. The discovery of diarylamine NNRTIs using BOMB. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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Because the Gordian knot of most de novo design methods may be synthetic in- accessibility, an advance de novo design program SYNOPSIS providing a synthesis route for each generated molecule has been developed.150 This novel program has been successfully applied to design several NNRTIs showing HIV inhibitory activity in vitro.150

5. OPTIMIZATION STRATEGIES OF NNRTI LEADS

In the NNRTI modiﬁcation process, the combination of traditional medicinal chemistry, computational chemistry, and crystallographic studies led to the identiﬁcation of numerous promising candidates, which were active against both WT and drug-resistant variants of RT.

A. Crystallographic Studies and Implication for Modification of NNRTIS Nowadays, the course of drug development for the treatment of AIDS is being revolutionized by high-resolution crystallographic structures of keyproteins in the HIV-l life cycle. Espe- cially, crystal structures of WT and drug-resistant mutants of HIV-1 RT have been used extensively in the design of novel NNRTIs. The structural information reveals the important interaction mode of inhibitor, indicating the essential aspects determining their binding affinity and generates new ideas about opportunities for improving drug efficacy.151 1. The Identification of Tolerant Region in NNRTIS or NNIBP The identification of the tolerated region in the lead compounds using the structure biology information of HIV-1 RT/NNRTI complexes is a premise that allows rational optimization. In view of the plasticity of NNIBP, a ‘‘composite binding pocket’’ model, integrating all available crystallographic information on the NNIBP of HIV-1 RT,152–154 was used to rationally design potent inhibitors with improved profiles against drug-resistance mutants of HIV-1 RT. This ‘‘composite binding pocket’’ was successfully demonstrated as a powerful tool to handle flexibility of the NNIBP and to identify specific domains (the potentially usable space) for structural optimization of the inhibitors. Based on the obtained results, several novel, highly potent NNRTIs with broad-spectrum antiviral activity were identified.155–159 On the basis of the crystallographic studies on binding of larger NNRTIs, the P236 ‘‘hairpin loop’’ in RT is closer to the apo conformation, forming a more open pocket; this represented a tolerant region for introducing additional groups to the binding NNRTIs (described in the earlier section).160 Additionally, two relatively inflexible residues at the pocket entrance, V179 and L100, manage the openness of the entrance and form the fortress of the inhibitor-unbinding channel, which therefore was regarded as another attracting tolerant region and could be exploited by diverse groups, giving an additional contribution to the generation of the allosteric NNIBP.161 For instance, the 5,6-positions in the central pyrimidine ring of DAPY NNRTIs162,163 and the 5-position in the pyrimidone ring of HEPT NNRTIs164 are well accommodated in a small cavity consisting of V179 side chain, respectively, which has been validated by crystallographic studies (Fig. 24) and further chemical modifications (Figs. 25 and 26). In summary, the plasticity of NNIBP resulted in the discovery and/or validation of the tolerated region in NNRTIs or NNIBP using crystallographic studies, which provides a broad space for the discovery of new generations of NNRTIs. It seems possible to exploit the tolerated region of NNIBP to gain specific protein–ligand interactions to accommodate substantial modifications of the NNRTI molecule which improve its pharmacokinetic properties or to construct multi-target ligand165,166 by incorporating another bioactive moiety without a significant deprivation of binding affinity.

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Figure 24. TMC125 (A) and TNK-6123 (compound 39e)(B) in the NNIBP (PDB code for TMC125 and TNK-6123: 3MEC, 1C1C).151,16 4 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

CN CN CN CN CN CN Me CN Me CN

Me Me Me Me Me Me Me Me Me Me O N NH O N NH O N NH O N NH O N NH

N N N N N Br HN N NH NH N NH HO V179 V179 V179 V179 V179 4d 4e 4f 4g 4c EC < 10 nM EC < 10 nM EC < 10 nM EC < 10 nM (WT) (WT, L100I+K103N) (WT, L100I+K103N) (WT, L100I+K103N) 10 nM < EC < 100 nM (100I+K103N)

Figure 25. Diverse bicyclic heterocycle DAPYanalogs.163 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

O V179 O Me V179 O Me V179 O Me V179 Me HN HN Me HN Me HN Me

O N S O N O N O N S

O O O O HO Me Me 39a, HEPT 39c, TNK-651 39d, MKC-442 39e, TNK-6123

Figure 26. HEPT and the second generation pyrimidine diones. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

2. Structural Biology Explanation of NNRTIs With Resilience to Mutations We gained a thorough understanding of the structural biology of HIV-1 RT/NNRTI complexes and the data on drug-resistance mutations, inherent conformational ﬂexibility, and positional adaptability of NNRTIs,72c,167–169 forming extensive hydrogen bonding170 or

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other key interactions171 with the main chain. This has allowed us to target highly conserved residues in the HIV-1 RT167,172 and to exploit unconventional mechanisms for NNRTI- mediated inhibition of RT.173–175 These are important factors for the design of inhibitors with improved resilience to mutations. Therefore, only using these information as a staring point would the application of the following described medicinal chemistry strategies be highly effective.

B. Medicinal Chemistry Strategies in the Modiﬁcation of NNRTIs In this section, successful applications of medicinal chemistry strategies (bioisosteric replacement, molecular hybridization, scaffold hopping, design of multiple ligands, and multivalent drug design) for NNRTI modiﬁcations are reviewed.

1. Bioisosterism Principle: Me-Too Bioisosteric replacement is an excellent tool for lead optimization to produce the desired potency, selectivity, and the required ADME profiles for a marketable drug.176a–c The use of bioisosteres in NNRTI lead optimization is illustrated by some recent examples from the literature. Case 1. Diarylazine-based NNRTIs Taking a-anilinophenylacetamido (a-APA) as the original lead compound,69a further optimization carried out by Janssen and his colleagues led to the discovery of the imino- 70 thiourea (ITU) analogs (i.e. 54,IC50(LAI) 5 3 nM) to the diaryltriazine (DATA) analogs (i.e. 48 35,IC50(LAI) 5 0.3 nM) and the diarylpyrimidine (DAPY) analogs (i.e. 4c, TMC120), successively.49 The first DAPY compound, dapivirine (TMC120), is being pursued for its microbicidal potential. The second DAPY compound etravirine (TMC125) (Fig. 27),177 which has been recently approved (Intelences) for clinical use, and the third DAPY compound (R278474) (35) corresponds to rilpivirine (TMC278) (Fig. 27),178 which is expected to be approved soon for clinical use. Thus, the structural modifications of the DAPY series are still a research hotspot.179–182 Recently, using the isosteric replacement strategy, pyrazinone,50 diarylpyridine,51 and diarylaniline compounds52 were discoveried as novel scaffolds of potent NNRTIs, active against both WT and drug-resistant HIV-1 strains. Especially, the diarylpyridine 37 showed low nanomolar EC50 values and high SI values (410,000) against HIV-1 IIIB, NL4-3, and RTMDR1.51 The diarylaniline 38 inhibited WT HIV-1 strains with low nanomolar EC50 values of 0.003–0.032 mM and inhibited several 52 drug-resistant strains with EC50 values in 0.005–0.604 mM range. In addition, the pyridine or substituted aniline ring replacement offers a more convenient and shorter synthetic route, using inexpensive commercial reagents, compared to the synthesis of DAPY derivatives TMC125 and TMC278. Case 2. Efavirenz analogs Efavirenz (DMP 266, L-743,726, SustivaTM) is one of the four approved NNRTI drugs for the treatment of HIV-1 infection, which belongs to the series of benzoxazinones, structurally related to the first subset of NNRTIs developed by Merck and based on a quinazolinone skeleton. The development of quinazolinone derivatives started from the lead L-608,788 (78), unstable under screening conditions (Fig. 28).41 Researchers have continued to develop additional potent NNRTIs with other ring systems, structurally related to efavirenz, such as dihydroquinazolinone skeleton (DPC 961, DPC 963, DPC 082, and DPC 083),183–187 cis-3-alkylbenzoxazepinone skeleton (79a, 79b),188 and benzothiadiazine skeleton (80).189 They showed antiviral activity in the nanomolar range. Based on the structural features of efavirenz (3), HBY-097 (24), and oxindole 29b, a quinolone scaffold (30b) was obtained as a good surrogate of efavirenz.45a

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N N N N Me Me

Cl Cl Cl Cl Me Me Me Me H H N NH N NH N NH HN N NH

NH S NH N NN N 54 N 35 4c, TMC 120 (1998)

N N N N N N N N

Me Me Me Me Me Me Me Me ONNH O N NH O N NH O NH

N Br Me N O NH O N NH NH Me 36 37 38 4a, TMC 125 Pyrazinones (2005) Diarylpyridine (2009) Diarylaniline (2010) (1999) IC (LAI) = 6 nM EC = 1.4 nM; SI = 22,700 IC (K103N + Y181C) = 63 nM (HIV-1 ,MT-2 cell) EC = 0.68 nM; SI = 13,206 N (HIV-1 , TZM-b1 cell) EC = 0.96 nM; SI = 9,354 N (HIV-1 ,TZM-b1 cell)

Me Me HN N NH

4b, TMC 278 (2001)

Figure 27. The chemical evolution of diarylazine-based NNRTIs (Arrows represent development timelines). [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Case 3. Capravirineanalogs Imidazole compound capravirine (47, formerly known as AG1549 and S-1153) displayed potency at subnanomolar concentrations in vitro against a broad-spectrum of HIV-1 strains 63a–c (EC50 values: 0.7–10.3 nM). Unfortunately, capravirine’s development was discontinued due to poor results in clinical trials and complex interactions with other anti-HIV therapies.63a–c In the continued modiﬁcation of capravirine, novel arylthio isopropyl pyr- idinylmethylpyrrolemethanol (AThP) derivatives were found to be active to block the replication of HIV-1 in infected cells in the concentration range of 0.008–53 mM.190a–b Com- pounds 81a and 81b were the most two active derivatives in cell-based assays with similar inhibitory effects and SI to that of capravirine (EC50 5 8, 7, and 3 nM; SI 5 6,250, 16,357, and 7,000, respectively).190a–b Compound 81b retained impressive activities against clinically important drug-resistant RT carrying K103N, Y181I, and L100I mutations.190b 5-Aryloxy imidazole 82, achieved by removing a metabolically vulnerable pyridine ring and replacing a vulnerable sulfur atom with oxygen, illustrates the impressive overall proﬁle against both WT RT and the clinically relevant mutations K103N and Y181C and remarkable improvement in potency and metabolic stability over capravirine.191,192 Recently, a new series of S-1153 analogs

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HIV-1 NNRTIs K 27

OEt H

Cl Cl Cl OEt NMe NMe NH H O N S N O N O Cl H H H O 78, L-608,788 27b 27a IC = 12 nM N H 29b Me Me

O O F C F C F C Cl NH NH O MeO N X X SMe N O N O N O H H N O H H 27c, DPC 961 (X = 6-Cl) 27e, DPC 083 (X = 6-Cl) 3, Efavirenz 24, HBY-097 27d, DPC 963 (X = 5,6-diF) 27f, DPC 082 (X = 5,6-diF)

Efavirenz: EC = 38 nM Me R DPC961: EC = 32 nM O DPC083: EC = 23 nM Cl Br NH OEt F C F C S O N N O Cl O Cl O H O H Me Me 80 30b EC = 182 nM N N H O H O 79a 79b EC = 82 nM EC = 46 nM

Figure 28. The discovery and development of Efavirenz. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

were studied, in which the imidazole ring is replaced by a pyrazole moiety. Several of these derivatives (such as compound 83a) displayed the excellent broad spectrum anti-HIV activity.193a,b Especially, compound 83b (UK-453,061, lersivirine) was selected for further clinical evaluation due to its very impresive potency against an interesting panel of key HIV-1 mutants, safety, pharmacokinetic, and pharmaceutical proﬁles (Fig. 29).193c–e Case 4. Sulfanyltriazole/tetrazolederivatives Sulfanyltriazole/tetrazole derivatives were newly emerging HIV-1 NNRTIs with low nanomolar intrinsic potency against the RT and anti-HIV activity cell-based assay.67a–g Currently, a number of compounds derived from this triazole/tetrazole scaffold are being considered for further clinical trials for the treatment of HIV infection.67h Molecular modeling indicated that the triazole/tetrazole moiety stays in the center of the NNIBP, anchoring the substituents in the scaffold into the optimal space for interactions with NNIBP, which are in agreement with the present insights of SAR and provide valuable avenues for the future optimization of novel analogs as promising candidates for the treatment of AIDS.67a Based on these analyses, additional and potentially more potent scaffolds have been designed and synthesized independently in our194 and other195 laboratories (Fig. 30). Some derivatives demonstrated high potency in inhibiting HIV-1 proliferation at nanomolar concentrations. Case 5. Diaryletherderivatives Taking advantage of the solvent exposed region (in the RT/solvent interface) of NNRTIs as a means to incorporate solubilizing groups and to further optimize physico-chemical properties and pharmacokinetics led to the discovery of novel structurally diverse diaryl ether derivatives, such as indazole 63a,81 pyrazolopyridine 93 (MK-4965),196 pyrazolopyridazine

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28 K ZHAN ET AL.

Pyrrole core Me Me O Me Me H N HO O N S S S O O N N N Cl Cl NH

Cl Me Cl N N N

47, Capravirine 81a 81b

Designed to improve metabolic stability Me Pyrazole core Me Me Me

N N N O O N N N HO HO HO CN Me Cl CN Me Me NC Cl NC 82 83a 83b, UK-453,061 (lersivirine) EC =10 nM EC =33 nM (WT) EC = 4 nM (WT) CC >100 μM

Figure 29. Optimization strategy for capravirine. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

94,197a pyridazinone 95,197b triazolinone 96,197c 97, 98,197d imidazolinone 99, 100, benzo- [d]imidazolinone 101, imidazopyridinone 102, 103, imidazo[4,5-c]pyridazine 104, pyridone 105, pyrimidones 106, 107,197d pyrazole 108,198 and oxadiazole 109,199 which were regarded as classic bioisosteres (Fig. 31). These analogs have high levels of activity against HIV-1 bearing WT strain and a panel of key mutations, and some of them show excellent oral bioavailability and favorable pharmacokinetics. Case 6. Modifications of other NNRTIs based on bioisosterismprinciple 1-[2-(Diarylmethoxy)ethyl]-2-methyl-5-nitroimidazoles (DAMNIs) is an unique and highly potent family of HIV-1 NNRTIs.82,200 Replacement of one phenyl group of lead compound RS1408 (64) with heterocycles, such as 3-pyridinyl (110) or 2-thienyl (111), led to novel DAMNIs with increased potency (Fig. 32). In HIV-1 WT cell-based assay, compounds 110 and 111 were found to be 2.5 and 6.7 times more active than compound 64. Compound 111 (IC50 5 8.25 mM) was also found more active than efavirenz (IC50 5 25 mM) against the K103N mutant RT, suggesting for this compound a potential addition in efavirenz-based anti-HIV regimens.201 A bioisosterism principle-based alteration, focusing on the replacement of the benzylthio group of pyrimidine thioether NNRTI 42a,57a by different heteroaromatic systems, led to the identification of PNU-142721 (42) as a clinical candidate (Fig. 33).57b,c,58 (7)-6-Ethyl-6-phenylpyrrolo[2,1-d][1,5]benzoxazepin-7(6H)-one (12) is the prototype of pyrrolobenzoxazepinone NNRTs.26a Structural modifications based on the bioisosterism principle, dictated by docking studies, prompted the discovery of pyrrolopyridooxazepinones (PPOs) analogs 112a–c featuring a meta-substituted phenyl or a 2-thienyl ring at C-6 and a pyridine system in place of the fused-benzene ring in the lead compound with a significantly improved pharmacological properties, in terms of efficacy, broad spectrum, and low cytotoxicity (Fig. 34). Compared with the lead 12 and nevirapine, PPOs 112a–c displayed higher inhibitory activity against WT RT and several key clinical RT mutations: L100I, K103N,

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HIV-1 NNRTIs K 29

N S X N X N Se X H H H N N R N N N S N S S

R2 O R2 O R2 O Y Y Y

84 85 86 R4 R4 R4 Novel scaffolds discovered in our lab

Bioisosterism Principle

NN NN Br H H N N Me N S Me N S O O Me 51c 51d μ μ EC50= 2.053 M (WT) EC50 = 0.1 M (WT) EC = 1.3 μM (K103N/Y181C) Me 50

NN Cl NN NO2 H H N N N N N S N S Me Me O O

51e 51f IC50 = 5 nM (WT) IC50 = 9.5 nM (WT) Me IC50 = 766 nM (K103N/Y181C)

Bioisosterism Principle

N X X N X H H H N N N N Me N N N S N S S

R2 O R2 O R2 O Y Y Y

87 88 89

R4 R4 R4

S X O X HN N X H H H N N N N Me N S S S

R2 O R2 O R2 O Y Y Y

90 19 29

R4 R4 R4

Novel scaffolds discovered in other labs

Figure 30. The structures of sulfanyltriazole/tetrazole derivatives. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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30 K ZHAN ET AL.

NC O O NC O O NC O N NH Cl N Cl N Cl Cl NH Cl NH Cl N 63a 93 94 N N H N EC (WT): 1 nM EC (wt): 4.7 nM EC (WT): 1.35 nM EC (K103N/Y181C): 5 nM EC (K103N/Y181C): 141 nM EC (K103N/Y181C): 84 nM

F F F O NC O N NC O N NC O NH N NH NH N N Cl O R Me Br Me O R 95 Me Cl 96 Cl O 97 R = F, OMe, CN R= Cl, Br, Me, Et, c-Pro IC (WT) = 7 nM, IC (K103N/Y181C) = 5 nM EC (WT): 1 nM EC (WT): 2-11 nM EC (WT) = 3 nM, EC (K103N/Y181C) = 28 nM EC (K103N/Y181C): 20-40 nM EC (K103N/Y181C): 4-40 nM

F 98a: F O O NC O IC (WT) = 45 nM, IC (K103N/Y181C) = 13 nM NC O N N NH EC (WT) = 14 nM, EC (K103N/Y181C) = 55 nM NH N Br Br R 98b: O Cl IC (WT) = 55 nM, IC (K103N/Y181C) = 12 nM Cl 98a, R = H 99 98b, R = Me EC (WT) = 11 nM, EC (K103N/Y181C) > 100 nM IC (WT) = 9 nM, IC (K103N/Y181C) = 11 nM EC (WT) = 4 nM, EC (K103N/Y181C) > 100 nM

F O F F NC O NC O N N NC O NH N N NH Br Me Br NH O Br O Cl O Cl 101 100 Cl 102 IC (WT) = 6 nM, IC (K103N/Y181C) = 7 nM IC (WT) = 13 nM, IC (K103N/Y181C) = 8 nM IC (WT) = 5 nM, IC (K103N/Y181C) = 4 nM EC (WT) = 4 nM, EC (K103N/Y181C) = 11 nM EC (WT) = 5 nM, EC (K103N/Y181C) = 46 nM EC (WT) = 0.4 nM, EC (K103N/Y181C) = 6 nM

F F F N NC O NC O NC O N N N N

NH NH Br Br O N Br O O H Cl 103 Cl 104 Cl 105

IC (WT) = 6 nM, IC (K103N/Y181C) = 5 nM IC (WT) = 5 nM, IC (K103N/Y181C) = 4 nM IC (WT) = 19 nM, IC (K103N/Y181C) = 18 nM EC (WT) = 3 nM, EC (K103N/Y181C) = 20 nM EC (WT) = 4 nM, EC (K103N/Y181C) = 38 nM EC (WT) = 25 nM, EC (K103N/Y181C) > 100 nM

F F 107a: NC O Me NC O R N N IC (WT) = 4 nM, IC (K103N/Y181C) = 4 nM EC (WT) = 1 nM, EC (K103N/Y181C) = 19 nM Br O N O Br O N O H H 107b: Cl 106 Cl 107a, R = H IC (WT) = 3 nM, IC (K103N/Y181C) = 3 nM 107b, R = Me IC (WT) = 6 nM, EC (WT) = 1 nM, EC (K103N/Y181C) = 11 nM 107c, R = Cl EC (WT) = 5 nM, EC (K103N/Y181C) = 66 nM 107c: IC (WT) = 4 nM, IC (K103N/Y181C) = 4 nM N EC (WT) = 2 nM, EC (K103N/Y181C) = 10 nM

F NH NC O O NC O O N R2

N N Cl Cl R Cl Cl 108 109

IC (WT) = 4.5 nM, IC (L100I) = 21.9 nM IC (WT) < 10 nM, IC (K103N) < 10 nM, IC (K103N) = 19.7 nM IC (V106A) < 10 nM,IC (Y181C) < 10 nM

Figure 31. Diaryl ether-based antivirals. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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HIV-1 NNRTIs K 31

Me Me Me O O O N N N N N N

O2N O2N S O2N N 64, RS1478 110 111

EC50 = 200 nM, SI >500 EC50 = 80 nM, SI >1250 EC50 = 30 nM, SI >3333

Figure 32. The strategy to the optimization of DAMNIs. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Cl Cl Cl

N N N Me H N H2N N S H2N N S R H2N N S

O 42a 42b: R = CONMe2, EC90 = 90 nM (WT) 42d, PNU-142721 42c: R = CONEt2, EC90 = 20 nM (WT) (S)-(-)-enantiomer Delavirdine: EC90 = 30 nM (WT) IC50 = 20 nM (WT) IC50 = 22 nM (P236L)

Figure 33. The strategy to the development of PNU-142721. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

N N N N N N N O O O O Me Me Me Me O O O O

S Me 12 112a 112b 112c

CEM-SS cells, EC50 = 470 nM, SI = 11 EC50 = 69 nM, SI = 56 EC50 = 150 nM, SI >13 EC50 = 27 nM, SI >75 C8166 cells, EC50 = 800 nM, SI = 12.5 EC50 = 54 nM, SI = 111 EC50 = 1200 nM, SI = 16.6 EC50 = 270 nM, SI = 26.7

Figure 34. Structural modification of pyrrolobenzoxazepinone NNRTIs. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Table IV. Inhibition of WT HIV-1 and Several Key RT Mutations

Ki (mM)

Compd WT L100I K103N V106A Y181I Y188L

12 0.19 0.75 7.7 3.9 410 410 112a 0.022 0.04 0.3 0.07 4 1.5 112b 0.093 0.09 0.045 0.09 0.43 0.475 112c 0.021 0.044 0.03 0.4 1.2 1.5 Nevirapine 0.4 9 7 10 36 18

V106A, Y181I, and Y188L (Table IV). The antiviral activity and the synergistic antiviral properties of 112a and 112b with AZT suggest a potential therapeutic usefulness in combination with NRTIs, against clinically signiﬁcant NNRTI-resistant HIV-1 strains.26b

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32 K ZHAN ET AL.

Table V. Anti-HIV Activities and Metabolic Stability of Cosalane Analogues

EC50 (mM) CC50 (mM)

HIV-1RF HIV-1IIIB IC50 CEM-SS MT-4 t1/2 Compd (CEM-SS cells) (MT-4 cells) (mM) cells cells (min) References

58b 0.013a 0.6b 0.3a 31.6a 160b 5.8b 202,203a 58c ND 1.8 ND ND 4224 55.3 204,205b 58d 2.7 ND ND 16.3 ND 22.1 206 58e 0.7 0.24 0.67 2.9 12.4 3,641 207 58f 0.36 0.42 0.39 2.8 6.4 331 207 58g 0.05 0.14 0.47 5.7 7.0 864 208 58h 0.04 0.02 0.91 0.5 1.09 3.46 209 58i 0.6 41.1 0.63 1.2 41.1 51.4 209 58j 0.03 0.09 0.02 5.1 16.86 1.3 210 ‘‘a’’ represents that the date is from reference 202 or 203; ‘‘b’’ represents that the date is from reference 204 or 205.

The potential clinical utility of the alkenyldiarylmethanes (ADAMs) NNRTIs could be affected by the metabolic instability of ester moieties that are prone to be hydrolyzed by human nonspecific esterases.202,203 The replacement of labile esters with some bioisosters, such as thioesters,204 various heterocycles,205–209 and nitriles,206 led to the successful development of several sub-micromolar NNRTIs that exhibited increased metabolic stability in rat plasma relative to their parent analogs (Table V). Especially, ADAM 58e demonstrated improved metabolic stability in rat plasma (t1/2 5 61 hr) along with the potency to inhibit HIV-1 RT and the replication of HIV-1IIIB and HIV-1RF strains in cell assay at submicromolar concentrations.207 Although the rat plasma half-lives of benzoxazolone derivative 58j was not optimized when compared to the prototype compounds, it was identified as one of the highly potent compounds, which inhibited the replication of both HIV-1IIIB and HIV-1RF with EC50 values of 90 and 30 nM, respectively, and inhibited HIV-1 RT with an 210 IC50 value of 20 nM (Fig. 35). In summary, a large number of exemplifications show that the bioisosterism principle is one of the most widely used medicinal chemistry strategies in NNRTI modifications. However, like any tool used in modern drug discovery, the bioisosterism principle has lim- itations that require researchers with experience, insight, and creativity to use it intelligently in the solution of the practical problems encountered in drug discovery.

2. Molecular Hybridization Concept: Me-Better Molecular hybridization is a novel concept in drug design and optimization based on the combination of basic structural elements (the pharmacophores) of different bioactive sub- stances to obtain a new hybrid entity with improved afﬁnity and potency, when compared to the prototypes.211,212 The conceptual approach illustrated by many examples of NNRTI hybrids, such as capravirine–efavirenz hybrid 61,79 HBY–efavirenz hybrid 113,213 pyridinone–efavirenz hybrid 114,214 pyridinone–HEPT hybrid 115,215a–d and pyridinone–DAPY hybrid 116,216a,b promises to be broadly useful in the search for new chemical entities and can contribute greatly to improve the speed and overall efﬁciency of drug optimization.211,212 Figure 36 shows the recent adcances in the discovery of novel NNRTI platforms based on the rational hybridization of two structurally distinct leads. The discovery of aryl phosphinate-indoles 117a (IDX-899) and 117b was the result of coordinated medicinal chemistry principles involving bioisosterism principle and molecular 217 hybridization (Fig. 37). In the structure of RTK103N/Y181C-117b complex, the newly

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HIV-1 NNRTIs K 33

OMe Me Me Me Me N F S O S O Me O OMe O OMe MeO OMe Me N OMe O N Me O Cl Cl O Me

N N O O 58c 58d O 58e N Me MeO O

MeO O MeO O MeO O S O Me Me Me OMe MeO OMe O O OMe N N Me Cl Cl Me MeO MeO

N N O N 58f 58b O 58g N MeO O Me Me

MeO O MeO O O OMe Me Me Me OMe OMe O O OMe O N N O N Me Me Me MeO MeO Me

OMe MeO O O 58i N 58j 58h O O

Figure 35. The strategy to improve the metabolic stability of ADAMs. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

introduced 3-substituent –CH==CH–CN of the phenyl points directly to the highly conserved W229. This must have contributed to its high potency. Because of its favorable safety proﬁle and predictable pharmacokinetics,217b a phase II clinical evaluation of IDX-899 has been initiated recently.217c As one of the most valuable structural modiﬁcation tools useful for the discovery of new ligands, the molecular hybridization approach has been successfully exploited across different NNRTIs families and may be an effective strategy in the discovery of the next generation NNRTI candidates.

3. Scaffold Hopping (Chemotype Switching): From One Hit to Another Attractive Series Scaffold hopping has been recently reviewed and defined.218a–e In chemoinformatics, searching for compounds with structural diversity and common biological activity is entitled scaffold hopping. On account of the structural similarity of NNRTIs families, scaffold hopping or chemotype switching via dismantlement and simplification of known NNRTIs is significant since it can be used to produce alternative scaffolds with improved efficiency and

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34 K ZHAN ET AL.

CN Capravirine-efavirenz hybrid HBY-efavirenz hybrid

Me Me NC O R F O O Me N F N Et O O N H 61a: R=Me, RT IC = 50nM N 61b: R=Et, RT IC = 25nM N O CF H 24b, HBY1293/GW867 N O H IC = 45 nM; IC = 4.8 nM Cl 113

F C Cl Cl S O Me

N N O Me H F C N 3, Efavirenz Me O N Me O Me N O H N R H O 114: IC = 32 nM 47, Capravirine N Pyridinone-efavirenz hybrid X Me O R Me

Me N O H 41a, L697,661: X = NH, R = Cl 41b, L-696,229: X = CH , R = H X Me R Me

Me N O 115 H S Pyridinone-HEPT hybrid Me O N a: R = COOEt, X = S. EC = 3 nM, SI > 3333 b: R = NO , X = S. EC = 6 nM, SI > 1666 O N O c: R = NH , X = CO. EC = 6 nM, SI > 1666 H d: R = NHCHO, X = CH . EC = 3 nM, SI > 3333 OH e: R = N(Me) , X = CH . EC = 0.2 nM, SI > 5000 39a, HEPT f: R = I, X = O. EC = 1.3 nM, SI = 9000 (LAI); EC = 3 nM (K103N); EC = 20 nM (Y181C)

a: R = -CN, X = C(=O), R = R = Me R EC (nM) = 2 (LAI), 6 (K103N), 40 (Y181C), 398 (Y188L) 116 R SI = 6310 (LAI) b: R = -C=C-CN, X = C(=O), R = R = Me X EC (nM) = 1 (LAI), 2 (K103N), N 16 (Y181C), 158 (Y188L) Me R Me Me SI = 10,000 (LAI) R c: R = -C=C-CN, X = CH , R = Me, R = Et NH Me N O N EC (nM) = 1 (LAI), 2 (K103N), H X 32 (Y181C), 251 (Y188L) N SI = 10,000 (LAI) d: R = -C=C-CN, X = CH , R = Me, R = -(CH ) OMe N N Y H EC (nM) = 1 (LAI), 20 (K103N), 40 (Y181C), 316 (Y188L) 4a, TMC125: R = -CN, X = Br, Y = NH Pyridinone-DAPY hybrid SI = 10,000 (LAI) 4b, TMC278: R = -C=C-CN, X = Y = H

Figure 36. Representative cases of hybrid NNRTIs. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

unexpected side effects. In this section, the current use of scaffold hopping in the NNRTI optimization is reviewed based on the representative examples of scaffold hopping in the literature.

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HIV-1 NNRTIs K 35

Me N N

O O S X O MeO P Cl NH Cl NH2 2 Me Me HN N NH N O N O H H N 117a, X= H 25, L-737,126 4b, TMC 278 117b, X = F

W229 Y188 Me F227 N

V106 O L234 F MeO P Cl NH2 H235 O L100 N O P236 H Y318 H O N N103 K101

217a,b Figure 37. Strategy for phosphoindole NNRTI discovery and schematic structure of RTK103N/Y181C with117b. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

DAMNI derivative RS1478 (64), an open-analog derived from thiazoloisoindolone 8b by disruption of two nitrogen linkages of the thiazolidine ring, was identified as a potential NNRTI candidate for anti-HIV-1 assays. Imidazole was chosen as a terminal ring because of its presence in the structures of many tricyclic NNRTIs.82 LY300046-HCl (56a), a phenethylthiazolylthiourea (PETT) analog, obtained from the dismantling of the rigid tricyclic nucleus of the tetrahydroimidazobenzodiazepinthione (TIBO) derivative (Fig. 38), was more inhibitory to the Y188, Y181, and L100 mutations of HIV-1 RT than was the parent compound 9-Cl-TIBO. Besides the minimal pharmacophoric moieties of the TIBO structure necessary for antiviral activity, the presence of an additional torsional freedom degree in LY300046 relative to earlier rigid TIBO analogs also probably contributes to the excellent resistance profiles of LY300046.72c By dismantling the rigid tricyclic nucleus of the thiazolobenzimidazole (TBZ) prototype lead, 2,3-diaryl-1,3-thiazolidin-4-one (49a),65 1,3-dihydro-2H-benzimidazol-2-one (33b),98 and 1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (34a)47a–c were developed as new NNRTIs, which proved to be more active than TBZs in inhibiting HIV-1 proliferation. These compounds can be envisaged as ‘‘open models’’ of TBZs since they keep the basic pharmacophoric elements of the TBZs necessary for the HIV-1 RT inhibitory activity. The above mentioned and some other typical examples167–169 indicated that the conformational flexibility and positional adaptability of an NNRTI can contribute to the inhibitor retaining efficacy against a variety of drug-resistant HIV-1 strains. It is worth

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36 K ZHAN ET AL.

A Me B S S O HN HN Disconnect N N S N Disconnect HN Me CH N O N Cl N Cl HN Me Me O 64, RS1478 5b, 9-Cl-TIBO (R82913) 8b Me Me EC = 200 nM, SI >500 Isolation of potential pharmacophore

S S C F F HN HN 2 HN HN F Disconnect: 2 S F F N N N N EC = 1100 nM, N Br HCl 1 SI = 45 N 7, NSC 625487 F 56a, LY300046 hydrochloride Disconnect: 2 Me 34a Disconnect: 1

F Cl Cl F Cl S N Me N N O N H O 33b 49a EC = 240 nM, SI > 1766

Figure 38. The discovery of DAMNIs (A),82 PETTs (B),72c 2,3-diaryl-1,3-thiazolidin-4-one (49a),65 1,3-dihydro-2H-benzimidazol-2-one (33b)98 and1-(2,6-difluorobenzyl)-2-(2,6-difluorophenyl)benzimidazole (34a)47a--c (C) by dismantling of the rigid tricyclic nucleus of the prototype leads. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

highlighting that, in certain NNRTIs, reduced conformational ﬂexibility could also improve inhibitory potency against HIV and RT enzyme together with selectivity, provided that the conformationally restricted analogs with at least one conformation, among a few en- ergetically allowed conformations, could be recognized by the binding site.219 Analysis of the bound conformation of tetra(tri)azole-based NNRTIs via molecular modeling and NMR permitted the scaffold hopping from azoles to novel tertiary thiocarbamate-based NNRTIs. Although these compounds did not provide the ideal improvement in metabolic stability, they represent a novel, potent family of NNRTIs with a broad spectrum of antiviral activity.67e,195f Analysis of the SARs of the thiocarbamate-based NNRTIs contributed to the design of novel tetrahydroquinoline derivatives as potent NNRTIs with nanomolar intrinsic activity against the WT and key mutant RTs and potent anti-HIV activity in infected cells. In addition, the sulfur methylene linker was replaced with a cis-cyclopropyl ring. A modeling study demonstrated that the conformation of a cis- cyclopropyl amide could mimic the thiocarbamate.220 Also, the SAR conclusion, crystallography, and molecular modeling of tetra(tri)azole and benzophenone-based NNRTIs permitted the scaffold hopping to a novel series of diaryl ether NNRTIs which have excellent potency against WT and key mutant viruses (Fig. 39).221 Further systematic optimizations of the lead structure 121 resulted in the discovery of compound 63a, which is the prototype of a potent and novel NNRTI family. In Figure 40, as hypothesized, the two pyrrolo nitrogen atoms of the indazole moiety could be used as a surrogate for the amide group, which appear to form two direct hydrogen bond interactions with the carbonyl and imino of the backbone of K103.81 Following up on the aurintricarboxylic acid (ATA) lead, Mark Cushman and his cow- orkers then described an ATA derivative cosalane (Fig. 41), in which one salicylic acid

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HIV-1 NNRTIs K 37

O Cl O Cl H H Me N N N S N S Me Me O Cl O SO NH SO NH 118a 2 2 2 2 119 IC50(wt): 8 nM IC50(wt): 1 nM IC (K103N): 9 nM 50 IC50(K103N): 1 nM Me IC (Y181C): 80 nM Cl 50 IC50(Y181C): 4 nM

O Cl H N O Cl Me N S H N Cl O N cis Cl O 118b 120 SO2CH3 CH2COOH IC (wt): 18 nM IC50(wt): 34 nM 50 IC (K103N): 18 nM Me Me IC50(K103N/Y181C): 35 nM 50 Me Cl IC50(Y181C): 99 nM Tertiary thiocarbamate-based NNRTIs Tetrahydroquinoline-based NNRTIs

Scaffold hopping

Me NN Cl H H N X N O O N S R O O R6 R2 SO2NH2 SO2NH2

X = N, CH

R1 Cl R Tetr(tri)azole-based NNRTIs 4 Benzophenone-based NNRTIs

Scaffold hopping

Cl Y181/Y188/W229 H Y181/Y188/W229 C N CN O Scaffold hopping CN O O NNH SO2NH2 A B O Cl O H Cl O H N N Cl Solvent Cl Solvent K103 K103 121 63a V179 V179

IC50(wt): 0.14 nM IC50(wt): 1.35 nM EC (wt): 4.7 nM IC50(K103N): 0.21 nM IC50(K103N): 1.12 nM 50 IC50(Y181C): 0.28 nM IC50(Y181C): 2.62 nM EC50(K103N/Y181C): 141 nM Diaryl ether-based NNRTIs Diaryl ether/pyrazole-based NNRTIs

Figure 39. Scaffold hopping paradigm for tetr(tri)azole-based NNRTIs and proposed binding mode for compounds 121 and 63a.67e,195f, 220 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

moiety is replaced by one cholestane group. Alkenyldiarylmethanes (ADAMs), structurally related to cosalane, represent an addition to the group of NNRTIs.222 The crystallographic studies revealed that ADAMs are highly hydrophobic and the shape of the NNIBP is unique among other disclosed NNRTI-RT crystal structures.223

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38 K ZHAN ET AL.

Figure 40. The X-ray crystal structure of compound 63a (blue) in the WT-NNIBP (2.7 — resolution, PDB code is 3C6U). (Hydrogen bonds are shown as broken lines).81 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

OH OH OH OH Cl Me O O Me Me OH OH OH Scaffold hopping Me Me O O O

HO O HO Cl 122, Aurintricarboxylic acid 123, Cosalane

MeO O MeO O MeS O Me

MeO OMe O OMe N Cl Cl Me MeO

OMe OMe Br O N O 58b 58g Scaffold hopping N MeO O OMe Me

O MeO O O OMe Me Me Me MeO O OMe O OMe Br 124 N O N EC = 7.1 5.0 M Me Me (HIV-1 /CEM-SS cells) MeO Me

58h O OMe 58j MeO O

Figure 41. Historical synopsis of the discovery and development of the ADAM-type NNRTIs. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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HIV-1 NNRTIs K 39

4. The Usage of the Tolerant Region in the Modification of NNRTIs (a) To improve pharmacokinetic properties Interestingly, certain moiety in many NNRTI families sits between V106 and P236, and points toward the solvent-exposed region. Consequently, this feature should be beneficial for the modulation of the physicochemical properties of the NNRTIs. GW678248 (62b), a novel benzophenone NNRTI, potently inhibits WT and mutant RTs in enzyme inhibition assays, with an IC50 between 0.8 and 6.8 nM. An N-propionyl sulfo- namide derivative GW695634 (62c), designed as amide prodrug of GW678248, displayed improved solubility and bioavailability in clinical trials (Fig. 43).224 The N-2 position of pyridazinone 95c, a potent NNRTI that has limited aqueous solubility, was derivatized into a set of hydroxymethyl esters and carbonates as well as one phosphate. These derivatives served as prodrugs to effectively deliver 95c to rat plasma upon oral treatment at 50 mg/kg. Increases of 4.3- to 8.6-fold in 24-hr exposure of 95c (over that of prototype) were observed, while the prodrugs and the hydroxymethyl derivative 95c-1 were undetectable.225 An N-pyridinyl pyrimidinedione (KRV-2110, 39f) was previously identified as a potent NNRTI (Fig. 42).226a However, pharmacokinetics in three animal models (rat, dog, and monkey) demonstrated that once-daily dosage in humans was unlikely. Endeavor to improve the suboptimal pharmacokinetic profile of 39f led to the discovery of compounds 39g and 39h, which represent the promising compounds in this series with similar antiviral potency as inhibitor 39f and improved pharmacokinetics that may support once-daily dosage.226b,c In the tetrazolyl series, it has been demonstrated that the introduction of substituents (i.e. alkynyl fragment) at the para position of the anilide in 51f led to substantial improvement in the overall physicochemical profiles of the molecule while keeping excellent potency against the K103N/Y181C double mutant RT. As shown in Figure 42D, extensive SAR and pharmacokinetic evaluation resulted in the discovery of candidate 51i with favorable oral bioavailability and PK properties in rats.67f

(b) Multiple ligands design strategy Designed multiple ligands (DML), an emerging and appealing drug discovery strategy, using a single chemical entity to inhibit multitargets, should be effective in improving patient compliance, reducing problems of dosing complexity, drug–drug interactions and toxicities, as well as diminishing the likelihood of virus–drug resistance.166 The exploration of DML strategy should be valuable in anti-HIV drug discovery.166 Apparently, the key to rational DML strategy would be to identify a tolerant region in the drug target. Crystallographic studies have shown that the phenyl group in the N-1 substituent of the HEPT type of NNRTIs and the methylsulfonamide group at the C-5 position of delavirdine are situated in an open area (the solvent-exposed region) controlled by the P236 loop where structural alternations could be tolerated. Based on these general knowledge and the DML strategy,165,166 several series of RT/IN (integrase) dual inhibitors were designed and synthesized via incorporation of an IN pharmacophore element to this tolerant region of a known potent NNRTI (Fig. 43), and many inhibitors demonstrate activity against RT at low to submicromolar range, and against HIV at nanomolar range (compounds 126a and 126b), which also conﬁrms that the introduction of a second pharmacophore to these NNRTIs does not seriously impair their binding with RT. In addition, moderate anti-IN activity was also observed.227a–d Undoubtedly, the growing efforts in recent years to discover multitarget agents resulting from the rational combination of pharmacophoric moieties of different known lead compounds will bring a new perspective for the treatment of AIDS.

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40 K ZHAN ET AL.

A Me Me H H N N O O O O H NC O NH2 NC O N S S Me O O O O O

Cl Cl Cl Cl

62b, GW678248 62c, GW695634 B F F NC O N NC O N NH N O

Cl O Cl O

CN 95c Me CN 95c-1 ~ 95c-9 Me

O O O O

OH P NH2 H ONa N ONa HCl O HCl

95c-1 95c-2 95c-3 95c-4 95c-5

O O O O O H NH2 N NMe2 N O O HCl HCl HCl HCl 95c-6 95c-7 95c-8 95c-9

C O Me O Me O Me

HN Me HN Me HN Me O O O O N O N O N

H2N

N N Me CN Me CN Me CN F F 39f, KRV-2110 39g 39h D NN Cl NN Cl H H N N N N H N S N S N 51g:R= NH O O Cl Cl Me Me O

H R OH 51h:R= N 51f H Me Me O EC (WT) = 82 nM O EC (K103N/Y181C) = 505 nM t =4min(RLM) 51g:EC = 1.1 nM(WT); 8.1 nM(K103N/Y181C) 51i:R= OH t =109min(RLM) 51h:EC = 1.6 nM(WT); 13 nM(K103N/Y181C) Me Me t = 79 min (RLM) O O O 51i:EC = 7.1 nM(WT); 58 nM(K103N/Y181C) t = 90 min (RLM) S 51j:R= N Me 51j:EC = 4.2 nM(WT); 27 nM(K103N/Y181C) H t = 82 min (RLM) Me Me

Figure 42. Successful cases of NNRTIs modifications inthe tolerant regionto improve pharmacokinetic profiles. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

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HIV-1 NNRTIs K 41

O Me Me HN

O N RT IC = 0.016 μM O RT IC >100 μM O μ IN IC =0.093 μM IN IC > 100 M OH HIV-1 EC = 0.016 μM HIV-1 EC =0.16 μM O OH IN inhibitor SI> 61 RT inhibitor 39e,TNK651 SI> 610 125

O O Me Me Me Me

HN HN

O N O N Me Me

O O O O

126a OH 126b OH O OH O OH

RT IC = 0.024 μM RT IC = 0.028 μM IN IC = 4.4 μM IN IC = 14 μM HIV-1 EC = 0.0097 μM HIV-1 EC = 0.014 μM RT/IN dual inhibitor SI> 1000 SI> 710

Figure 43. Discovery of RT/IN dual inhibitors 126a and 126b against RTand IN, combining RT inhibitor 39e with IN inhibitor 125. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

(c) Multivalency drug design strategy (to form additional protein–ligand interactions) By the classical concept for drug design, a favorable inhibitor should efficiently enter and maximally occupy the binding site, thus interacting effectively with the residues around the binding pocket.228 Therefore, the larger the NNRTI, the stronger is the interaction with residues around the NNIBP, provided that the NNRTI can enter efficiently inside the NNIBP. This is partly supported by docking studies that the overall shape and chemical structure of larger second generation NNRTIs enables them to occupy more space in the NNIBP than the smaller and less active NNRTIs such as nevirapine,229 and thereby form additional protein–ligand interactions, especially the strong interactions of the drug with the conserved regions or polypeptide backbone in the NNIBP, which is regarded as a primary strategy to improve the potency of NNRTIs against resistant mutations. This is consistent with the concept of ‘‘multivalency’’, that using one entity to bind multiple targets or binding additional sites in one target, simultaneously, could result in a significantly improved efficiency.230,231 For example, several novel 8-substituted nevirapine-based analogs (127a–h) display excellent broad antiviral activity against a panel of prevalent RT mutants and excellent pharmacokinetic profiles (Fig. 44).232–235 Especially, BILR 355 BS (127h) was once advanced into Phase II clinical trials in 2005.236 X-ray crystallographic study reveals that while the dipyridodiazepinone core of BILR 355 BS and its analogs bind in an overall similar conformation to that of nevirapine, it has a greater ability to accommodate its orientation in the NNIBP of the mutants. Additionally, the extended C-8 substituent off the dipyridodiazepinone core likely make additional favorable binding contacts with RT (including

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42 K ZHAN ET AL.

Me Me Me Me O O O N N N

8 N Cl N Cl Cl N N S N N N N N N Me Me Me 127a 127b 127c

Me Me Me O H O O N N N

Me N Cl N Cl Cl N N N N N S N O N O N Me Me Me

Me 127d 127e 127f N N O O

Me Me O O N N

N N N N Me O N O N Me Me

127g 127h N HO O O

Figure 44. 8-Substituted nevirapine-based NNRTIs. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Me Me

O Me O Me I I Me S O Me N O Me N O H H

1152f 115g, R221239

Figure 45. Pyridinone NNRTI115g (R221239) and its contacts with RT (PDB code: 2BE2). [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

P236 and K103 backbone) that may stabilize binding of these 8-substituted analogs even in the presence of NNRTI-resistance mutations.236 Compared with pyridinone derivative 115f,208d R221239 (115g) contains a flexible linker and a connected furan ring which permits close contacts with V106, F227, and P236. These additional interactions appear to enhance the inhibitory activity of R221239 against the HIV-1 strains carrying the V106A, Y188L, and F227C mutations (Fig. 45).171 Compared with benzimidazole 34a, its analog 34b is apparently able to make significant interactions with the RT backbone via additional hydrogen bonds (Fig. 46), which are unlikely to be disrupted by side chain mutations and contribute significantly to the compacted binding for the inhibitor, and eventually, significantly improve the resistance profile of this inhibitor.47a–c

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HIV-1 NNRTIs K 43

F F

F F F F N N

N N F F Me O O 34a 34b IC = 0.2 μM,EC = 0.44 μM(WT) μ 50 50 EC50 ( M) = 0.062 (WT); 0.068 (L100I); SI > 100 0.025 (K101E); 0.027 (K103N); 0.013 (V108I); 2.32 (Y181C); 0.033 (Y188C); 4.5 (V106A)

Figure 46. Benzimidazole-based NNRTIs.47a--c [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

O Me

HN Me O O N

H2N

N Me CN F 39f, KRV-2110

Figure 47. Compound 39f bound in the NNRTI binding pocket of HIV-1RT (PDB code 3LAK, 2.3 — resolution).218b [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

As mentioned above, one difference in the binding manner of different NNRTIs are the hydrogen bond interactions with the protein backbone. For instance, diarylpyrimidine (DAPY) NNRTIs could make a hydrogen bond from the imino (connected to pyrimidine) to the backbone carbonyl of K101, while the benzophenone family has a hydrogen bond interaction between its amide carbonyl and the imino of the K103 amide. Interestingly, some promising NNRTIs are capable to make double hydrogen bond interactions with K101 and K103. Antiviral proﬁles revealed that HEPT derivative 39f exhibited potent activity against Y181C and K103N mutant strains. Detailed crystallographic analysis of 39f/HIV RT complex structure indicated that an additional hydrogen bond was formed between the amino of the aminoﬂuoropyridyl moiety and the backbone carbonyl of the K103 besides the hydrogen bond between the imino of the pyrimidinedione and the backbone carbonyl of K101 (Fig. 47).226b Compared with etravirine, piperidine-linked aminopyrimidine derivatives 128a and 128b possess favorable potency against WT RT as well as several important mutant strains (including the K103N/Y181C and Y188L mutants) (Table VI). Crystal structure analysis of this series compounds showed that, besides a hydrogen bond from the aminopyrimidine imino to the backbone carbonyl of K101, the piperidine nitrogen could probably make an additional hydrogen bond with the K103 backbone (via a bridging water molecule).237a,b

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44 K ZHAN ET AL.

Table VI. Activity of 128a, 128b, and Etravirine Against WT RT as well as Several Important Mutant Strains

SO2CH3 CONH2 N N

Ν Cl Ν

Me Me F Me ONNH ONNH

N N Br Br 128a 128b WT K103N/Y181C K103N/L100I Y188L G190A V106A Compds (nM) (nM) (nM) (nM) (nM) (nM)

128a237a 6.1 7.3 5.9 2.8 1.8 2.0 128b237b 6 5 ND 29 ND ND Etravirine237a 2.1 9.2 9.5 3.1 1.1 2.0

O Me N O HN Me

N O

Cl N 129

238

Figure 48. Cocrystal structure of 129 in the NNIBP (3FFI).238 [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Similarly, pyridone inhibitor 129, which was found to strongly inhibit the WT and NNRTI-resistant K103N and Y181C mutant HIV RT, could not only interact with the carbonyl group of K101 through a strong traditional hydrogen bond but also engage in additional hydrogen bond interaction with the backbone amide of K103 (Fig. 48).238 In comparison with that of compound 33b, the improved potency of compounds 33a and 101 might be owing to the electronic characteristics of the sulfonyl moiety and the phenyl group carrying a cyano group, respectively (Fig. 49). Molecular modeling indicated that the sulfonyl linker in compound 33a was able to form tight interactions with residues Y181, Y188, V179, and V106, while the methylene linker of compound 33b forms contacts only with residues Y188 and V179.46

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HIV-1 NNRTIs K 45

Me NC Br

F Me O

O F S F O Cl N Cl N N O O O N N N H H H

33b 33a 101 IC = 5 nM, EC = 2 nM EC50 = 240 nM, SI > 1766 50 50 IC50 (WT) = 13 nM, IC50 (K103N/Y181C) = 8 nM SI = 17,846 EC50 (WT) = 5 nM, EC50 (K103N/Y181C) = 46 nM

Figure 49. Benzimidazolone-based NNRTIs.46,197d [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

K101 V179 C O O B K103 V106 Me HN Y318 P95 D R Me S 2 N F227 R R Y181 F F P225 MeO Y188 A P236 40d W229 F227 L100 L234

EC50: 0.07 nM (WT); 36 nM (K103N); 13 nM (Y181C); 1.5 nM (Y188L); CC50: 14640 nM

Figure 50. Interactions of a C2-arylalkyl S-DABO (40d) within the NNIBP.239b [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

It seems likely that extended phenyl ring in compound 101 (Fig. 49) could (i) occupy an hydrophobic space near the top of the NNIBP, thus creating additional intermolecular contacts with the adjoining residues and (ii) increase the hydrophobic interaction with the highly conserved W229 at the ‘‘roof’’ of NNIBP, thereby decreasing the dependence on binding with Y181.197d The structural modifications of S-DABO NNRTIs were aimed at exploring the SAR of the C2-functionalization in pyrimidine core,239a,b leading to the discovery of a potent inhibitor 40d having picomolar activity against WT RT and nanomolar activity against many key mutant strains. The introduction of an arylalkyl group in C2 significantly increased the antiviral activity due to profitable hydrophobic interaction with a large pocket (zone D) of the allosteric pocket. Especially, the cyclopropyl group, as a bulky lipophilic substituent, probably formed additional interactions with the hydrophobic residues of zone D, giving an additional contribution to the affinity with the allosteric site (Fig. 50).239b When introducing modifications in the indolylarylsulfone (IAS) type of NNRTIs,240,241 new potent candidates 25c–g were obtained by coupling several kinds of amino acids to the 2-carboxamide of the indole core (Fig. 51). In human T-lymphocyte (CEM) cell assay, the

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46 K ZHAN ET AL.

Me Me NH O Me Me 25c: R = 25f: R = S Me O NH O O O S S NH O O 25d: R = Cl NH Cl HN R O O 25g: R = S NH N O N O NH Me O H H 25e: R = 25b 25c-g O

Figure 51. The structures of novel indolylarylsulfones bearing natural and unnatural amino acids.241

IASs could inhibit the HIV-1 replication at low/subnanomolar concentrations and with weak cytotoxicity. The antiviral potency against the K103N, Y181C, and L100I mutant strains in CEM cells was comparable to that of EFV. With the aim to investigate the conceivable binding mode of the new IASs, the highly potent compound 25e (IC50 5 26 nM; EC50 5 0.70 nM) was selected for docking studies into the NNIBP of WT RT (PDB code 2RF2) and L100I RT (PDB codes 1S1T, 2OPQ). From docking 25e into the NNIBP were the newly formed interactions of the N-(3-amino-3-oxopropyl)carboxamide moiety with the residues K101 and E138 at the bottom of the NNIBP, which seemed to be particularly important for the anti-HIV activity. Mutation of leucine to isoleucine did not affect the binding mode.241 In addition, the highly potent pyrazolo[3,4-c]pyridazine derivatives discovered by structure-based optimization of diaryl ether NNRTIs could bind RT in an expanded volume relative to most other analogs in the diaryl ether family, and probably engage in additional interactions with RT.197a Besides the above described NNRTIs, several series of divalent RT inhibitors by tethering one molecule of NRTI to an NNRTI structure via a ﬂexible linker were designed and synthesized to occupy the distinct but proximal catalytic site and NNIBP simultaneously. However, the results of their anti-HIV assay were not satisfactory.242

5. The Usefulness of Stereochemistry in Overcoming Drug Resistance Molecular modeling studies pointed to the asymmetric geometry of the NNIBP, and experimental data proved that the regiochemistry and stereochemistry of NNRTIs can in- ﬂuence their anti-HIV activity substantially.243a–d The introduction of different stereocenters in important pharmacophoric sites of promising NNRTIs scaffold could allow the emerge of a collection of enantiopure drugs with improved efﬁcacy and potential usefulness in managing drug-induced mutations. Typically, the chiral cyclopropane ring-containing oxindole 29,44 quinolones 30,45a S-DABO 40d,239 urea-PETT analogs 56c, 56d,74a,b 56e,74c,d and tetrahydroquinoline 120220 exhibited nanomolar activity against several clinically relevant mutants (Fig. 52).

C. Computational Chemistry Approaches for NNRTIs Optimization In the past 15 years, with the significantly increased computer speed and program efficiency, the role of computational chemistry in drug design has expanded exponentially. Recently, the applicability of computational chemistry and the computer-aided drug design (CADD) techniques on NNRTIs has been intensively reviewed by Hannongbua244,245 and Jorgensen et al.246 Pharmacophore modeling, database searching, and de novo methodologies have been described in the above sections. Thus, the aim of this section is to summarize the applications of computational chemistry to the structural modification of HIV-1 NNRTIs. The following applications are emphasized, including quantitative structure-activity relationship (QSAR),

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HIV-1 NNRTIs K 47

OEt O O R Me Br Cl CO R HN O Me S N N N O H H F F MeO 29a R = (CH ) CHCH , nPent 40d R = Et, Me, Allyl 30

Me Me O O F OH O O Cl H F N N cis F F Cl O SO Me Br HN NC HN O HN N N N O O O O N N N 120 H H H Cl NH H N 56c, MSC-204 56d, MSC-372 56e

Figure 52. NNRTIs containing a chiral cyclopropane ring. [Color figures can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

molecular docking, free energy perturbation (FEP)-guided lead optimization, and sub- structural molecular fragments (SMF) method. Many applications have been reported on the use of two- and three-dimensional QSAR (2D/3D-QSAR) studies to understand the NNRTI-RT interactions and help in the design of more effective analogs.247–256 The 3D-QSAR model based on the docked conformation reveals an excellent capability to predict the activity and provides valuable information on possible improvement in the ligand structure for increasing potency of the inhibitors. Combination of structure-based docking simulation with ligand-based QSAR will enhance the likelihood for finding novel lead compounds. Moreover, the particular interaction energy trend calculated from quantum chemical calculations (QCC) of the NNRTIs and individual residues in the NNIBP and QM/MM methodology (such as ONIOM method ‘‘our own N-layered integrated molecular orbital and molecular mechanics’’) should increase the understanding of NNRTI-RT interaction mechanism as well as providing some insights into drug resistance, which can be used as a promising descriptor identifying a key structural element for QSAR study.244,245 To rationalize the most relevant SARs of potent NNRTIs and to investigate the orientation and estimated binding energy of NNRTIs in the NNIBP, molecular docking simulations were usually performed. The docking results gave an insight into the pharmacophoric structural requirements for efficient RT inhibition of related NNRTIs, providing an informative guideline in designing new derivatives. To manage the conformational flexibility of RT, the inclusion of structural variability in a docking study and the concept of ligand- induced fit by cross-docking approach (the process of docking each ligand into the binding site of a number of different ligand–receptor complexes) have been taken into account.96,257 Dock molecular mechanics-generalized born/surface area (MM-GB/SA-ADME) is a useful tool to predict the affinity of NNRTIs with the RT and further screen for promising candidate drugs though CADD.258,259 FEP-guidedleadoptimizationisregardedas a valuable approach for molecular design including drug discovery.260 Efficient optimization of an inactive 2-anilinyl-5-benzyloxadiazole

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48 K ZHAN ET AL.

A Me Me CN Me FEP-Guided Optimization X X X O NH Y O NH

NN N Cl 46a, inactive Cl 46e, X= Cl, Y = H, EC50= 22 nM O NH 46f, X= F, Y = H, EC50= 13 nM 46g, X= F,Y = Cl, EC 50= 6 nM NN

46b, X= Cl, Y= H. EC50= 820 nM 46c, X= Y= Cl. EC50= 310 nM 46d, X= CN, Y= H. EC50= 130 nM B Me Me Me

Me Me Me

O FEP-Guided O FEP-Guided O Optimization Cl Optimization R2 S N N

N N N N R1 N N H H H

77: EC50 = 10,000 nM 43a: EC50 = 200 nM 43b: R1 = MeO, R2 = Cl. EC50 = 10 nM FEP-Guided 43c: R1 = MeO, R2 = CN. EC50 = 2 nM Optimization 43d: R1 = MeNH, R2 = CN. EC50 = 5 nM

Me Me Me

O O O Y O Cl N Cl CN X N N

N N N N X N N H H H 130a: X = CH, EC = 6 nM, SI = 4167 50 131: EC50 = 19 nM, SI = 1053 43e: X = MeS, Y = H. EC 50 = 5 nM 130b: X = N, EC = 5 nM, SI = 3400 50 43f: X = MeO, Y = NH 2. EC50 = 9 nM

Figure 53. The application of free energy perturbation (FEP)-guided lead optimization.

46 (false-positive molecule in virtual screening) and the less potent thiazole 77 (generated by de novo design) has been guided by FEP calculations to provide potent anilinylbenzyloxa- (dia)zole-based NNRTIs62a–d and diarylamine-based NNRTIs,59a–c,261,262 respectively (Fig. 53). More importantly, achieving simultaneous efﬁcacy for the WT RT and a panel of commonly observed mutants can be highly automated by running FEP calculations in parallel for a given designed NNRTI with all known, common mutant forms of the RT. The SMF method was also applied for computer-aided design of new NNRTIs potentially possessing high anti-HIV activities, such as TIBO and HEPT derivatives.263 The innovative computational approach ‘‘GRID-Based Pharmacophore Model’’ (GBPM) was believed to have great value in the identiﬁcation of conserved regions of the HIV-1 RT, to be targeted for the development of novel therapeutic agents.264

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HIV-1 NNRTIs K 49

Totally, as more structural information has become available and a wide range of computational approaches have proven to have reasonable predictive value, CADD should play increasingly important roles in designing novel NNRTIs to defeat the nagging resistance issue and handling the ﬂexibility of the target site (NNIBP).

6. SUMMARY AND PERSPECTIVES

In recent years, in spite of the rapid growth of HIV-1 RT 3D-structural information, the difficulty in structure-based de novo design of NNRTI scaffolds and docking-based virtual screening lies in the following two aspects: (i) The flexibility of NNIBP, formed by conformational changes in the RT on binding of the NNRTI ligand; (ii) The NNRTI-resistant mutations situated in and around the NNIBP. Therefore, as reviewed above, structure-based and ligand-based combined drug design methodology was carried out to facilitate both drug lead generation and lead optimization. Quite a few cases illustrated the benefits for NNRTIs design of closely coupled traditional medicinal chemistry, structural biology, computational chemistry methodology, and several other disciplines.265,266 In the NNRTI lead discovery process, compared to the structure-based de novo design and computer-aided in silico screening, large chemical libraries, combinatorial chemistry, HTS, and naturally occurring products still serve as approaches or sources of new active NNRTI leads to be further developed as anti-AIDS drug candidates. Yet, such screenings and the subsequent optimization of the inhibitors by systematic chemical modifications are highly time- and resource consuming. In the NNRTIs modification process, the crystallographic studies, providing a basis for understanding the interactions or tolerant region between the bound NNRTIs and the sur- rounding amino acid residues, contributed to the improved resilience or affinity of the optimized compounds. Great progress has been made in the development and application of medicinal chemistry strategies, such as bioisosterism, molecular hybridization, scaffold hopping, and multiple/multivalent ligand design strategy. The coordination of computational chemistry and crystallography is playing an increasingly important role in attempting to understand and defeat virus–drug resistance and the target site flexibility problem.246 For instance, cross-docking experiments on the WT and mutated RTs were conducted to consider the enzyme flexibility as an inevitable problem for structure-based drug design studies and to gain insight into the mode of action of new NNRTIs active against both WT and resistant strains. The fundamental goal of medicinal chemists is to make drug discovery more efficient by reducing the number of compounds that need to be synthesized and assayed; the ultimate goal is to obtain novel anti-HIV drugs with high levels of potency against WT and key mutant HIV strains without allowing breakthrough, excellent oral bioavailability, and overall pharmacokinetics. It is clear that only multidisciplinary coordination could help to achieve these goals.

REFERENCES

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Dr. Peng Zhan was born in 1983 in Ji’nan, Shandong province, China. He obtained his B.S. degree from Shandong University, China, in 2005. Then, he earned his M.S. degree and Ph.D. in medicinal chemistry from Shandong University under the supervision of Prof. Xinyong Liu in 2008 and 2010, respectively. He is now working as a young researcher in the lab of Prof. Xinyong Liu. His research area involves design and synthesis of novel HIV-1 non-nucleoside reverse transcriptase inhibitors.

Xuwang Chen was born in 1987 in Zoucheng, Shandong province, China. He graduated from Shandong University and obtained his B.S. degree in 2009. At the same year he was recommended without examination to study for his Ph.D. in the Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University.

Dongyue Li was born in 1984 in Guyuan, Ningxia province, China. In 2007, he graduated from the School of Pharmaceutical Sciences in Shandong University. He is currently studying for master degree in the Department of Medicinal Chemistry of the School of Pharmaceutical Sciences in Shandong University.

Medicinal Research Reviews DOI 10.1002/med 中国科技论文在线 http://www.paper.edu.cn

72 K ZHAN ET AL.

Zengjun Fang received his M.S. degree from Shandong University in 2007. His Ph.D. project, which was under the supervision of Prof. Xinyong Liu, was on the design and synthesis of novel HIV-1 non-nucleoside reverse transcriptase inhibitors as potential antiviral therapeutics.

Erik De Clercq, M.D., Ph.D. has been the Chairman of the Department of Microbiology and Immunology of the Medical School at the Katholieke Universiteit Leuven (K.U.Leuven) as well as Chairman of the Board of the Rega Institute for Medical Research (until September 2006). He is currently the President of the Rega Foundation, a member of the Belgian (Flemish) Royal Academy of Medicine, a member of the Academia Europaea, and Fellow of the American Association for the Advancement of Science. He has also been the titular of the Prof. P. De Somer Chair for Microbiology at the K.U.Leuven. Professor De Clercq received in 1996 the Hoechst Marion Roussel (now called ‘‘Aventis’’) award (American Society for Microbiology), and in 2000 the Maisin Prize for Biomedical Sciences (National Science Foundation, Belgium) for his pioneering efforts in the field of antiviral research. He is an honorary doctor of several Universities [i.e. Ghent (Belgium), Athens (Greece), Ferrara (Italy), Shandong (Jinan, China), Charles University (Prague, Czech Republic), and Jihocˇeska´ University (Ceske´ Budejovice, Czech Republic)]. In 2008 he was elected European Inventor of the Year (Life time achievement award). His scientific interests are in the antiviral chemotherapy field, and, in particular, the development of new antiviral agents for various viral infections, including herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV), human immunodeficiency virus (HIV), hepatitis B virus (HBV), human papilloma virus (HPV), and hepatitis C virus (HCV). He has (co)-discovered a number of antiviral drugs, currently used in the treatment of HSV infections (valaciclovir, Valtrexs, Zelitrexs), VZV infections (brivudin, Zostexs, Briviracs, Zerpexs), CMV infections (cidofovir, Vistides), HBV infections (adefovir dipivoxil, Hepseras), and HIV infections (AIDS) (tenofovir disoproxil fumarate, marketed as Vireads, and, in combination with emtricitabine, as Truvadas, and, in combination with both emtricitabine and efavirenz, as Atriplas). Vireads has also recently been approved for the treatment of HBV infections (chronic hepatitis B).

Prof. Dr. Xinyong Liu was born in 1963 in Qingdao, Shandong province, China. He received his B.S. and M.S. degrees from School of Pharmaceutical Sciences, Shandong University, in 1984 and in 1991, respectively. From 1997 to 1999 he worked at Instituto de Quimica Medica (CSIC) in Spain as a senior visiting scholar. He obtained his Ph.D. from Shandong University in 2004. He is currently a distinguished professor, a designated Ph.D. advisor, Director of the Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University. His research work is partly engaged in rational drug design, synthesis, and bio-evaluation of a variety of molecules targeted at the specific enzymes and receptors. At present time, his research interests are mainly focused on the design and synthesis of novel anti-HIV agents based on the mechanism of drug’s action and computer-assisted drug design, such as HIV-1 (non)nucleoside reverse transcriptase inhibitors, HIV-1 transactivation inhibitors based on HIV-1 Tat-TAR interaction, and Rev-RRE interaction in the viral transcription step. His second ongoing program is total synthesis and structural modifications of some natural products from Chinese Traditional Medicine active in cerebro- and cardio-vascular biology. He has contributed to about 150 scientific publications and patents as well as many monographs.

Medicinal Research Reviews DOI 10.1002/med