DOCSLIB.ORG

Synthesis, Anticancer Activity, and Molecular Modeling of New Halogenated Spiro[Pyrrolidine-Thiazolo-Oxindoles] Derivatives

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Synthesis, Anticancer Activity, and Molecular Modeling of New Halogenated Spiro[Pyrrolidine-Thiazolo-Oxindoles] Derivatives applied sciences Article Synthesis, Anticancer Activity, and Molecular Modeling of New Halogenated Spiro[pyrrolidine-thiazolo-oxindoles] Derivatives Mohammad Shahidul Islam 1 , Abdullah Mohammed Al-Majid 1, Fardous F. El-Senduny 2 , Farid A. Badria 3 , A. F. M. Motiur Rahman 4 , Assem Barakat 1,5,* and Yaseen A. M. M. Elshaier 6,* 1 Department of Chemistry, College of Science, King Saud University, P. O. Box 2455, Riyadh 11451, Saudi Arabia; [email protected] (M.S.I.); [email protected] (A.M.A.-M.) 2 Department of Chemistry, Faculty of Science, Mansura University, Mansura 35516, Egypt; [email protected] 3 Department of Pharmacognosy, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt; [email protected] 4 Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia; [email protected] 5 Department of Chemistry, Faculty of Science, Alexandria University, P.O. Box 426, Ibrahimia, Alexandria 21321, Egypt 6 Department of Organic and Medicinal chemistry, Faculty of Pharmacy, University of Sadat City, Sadat City, Menoufiya 32958, Egypt * Correspondence: [email protected] (A.B.); [email protected] (Y.A.M.M.E.); Tel.: +966-11467-5901 (A.B.); Fax: +966-11467-5992 (A.B.) Received: 26 February 2020; Accepted: 12 March 2020; Published: 23 March 2020 Abstract: A one-pot, single-step, and an atom-economical process towards the synthesis of highly functionalized spirooxindoles analogues was efficiently conducted to produce a satisfactory chemical yields (70–93%) with excellent relative diastereo-, and regio-selectivity. An in vitro antiproliferative assay was carried out on different cancer cell lines to evaluate the biological activity of the synthesized tetrahydro-1’H-spiro[indoline-3,5’-pyrrolo[1,2-c]thiazol]-2-one 5a–n. The prepared hybrids were then tested in vitro for their antiproliferative effects against three cancer cell lines, namely, HepG2 (liver cancer), MCF-7 (breast cancer), and HCT-116 (colon cancer). The spirooxindole analogue 5g exhibited a broad activity against HepG2, MCF-7, and HCT-116 cell lines of liver, breast, and colorectal cancers when compared to cisplatin. Modeling studies including shape similarity, lipophilicity scores, and physicochemical parameters were calculated. The results of this study indicated that spirooxindole analogue 5g retained a good physiochemical parameters with acceptable lipophilicity scores. Keywords: spirooxindole; 1,3-dipolar cycloaddition; eco-friendly chemistry; ROCS; shape alignment; lipophilicity; anticancer activity 1. Introduction The design of highly complex spiro-heterocycles with multifunctional and potential pharmaceutical efficacy has attracted considerable attention from synthetic and medicinal chemists [1]. One of the most privileged aza-heterocyclic scaffolds is spiro[pyrrolidine-oxindole] [2], which is present in natural products and useful as a building block for the synthesis of significant biologically active compounds. This class of aza-heterocyclic compounds has gained great interest, owing to several reports of its pharmaceutical potency, including anticancer [3], antitumor [4], 5-HT3 receptor antagonist [5], Appl. Sci. 2020, 10, 2170; doi:10.3390/app10062170 www.mdpi.com/journal/applsci Appl. Sci. 2020, 10, x FOR PEER REVIEW 2 of 10 Appl. Sci. 2020, 10, 2170 2 of 11 antagonist [5], acetylcholinesterase-inhibitory [6], antibacterial [7], antibiotic [8], and MDM2–p53 inhibitoracetylcholinesterase-inhibitory [9] effects; selective cyclooxygenase [6], antibacterial COX-1 [7], antibiotic with TNF- [8], andα and MDM2–p53 IL-6 inhibitors inhibitor [10]; [9] effandects; potentialselective hypoglycemic cyclooxygenase dual COX-1 inhibitory with TNF- activityα and against IL-6 inhibitors α-amylase [10 and]; and α-glucosidase potential hypoglycemic [11] (Figure dual1). Toinhibitory date, prolonged activity efforts against haveα-amylase been exerted and αto-glucosidase expand divergent [11] (Figure complexity1). To and date, to prolongeddevelop efficient e fforts synthetichave been routes exerted for tothese expand valuable divergent privileged complexity aza-heterocyclic and to develop scaffolds, efficient which synthetic would routes remarkably for these enhancevaluable their privileged bioactivityaza-heterocyclic [1,12]. In particular, scaffolds, [3+2] which cycloaddition would remarkably is one of enhance the most their efficient bioactivity synthetic [1,12 ]. approachesIn particular, to produce [3+2] cycloaddition these valuable is one scaffolds of the with most stereoselective efficient synthetic method approaches and high to yield produce [13]. these To extendvaluable our scapreviousffolds with research, stereoselective we explored method the effe andct of high halogen yield [substitution13]. To extend on ourthe isatin previous ring. research, we explored the effect of halogen substitution on the isatin ring. FigureFigure 1. 1.NaturalNatural (Spirotryprostatin (Spirotryprostatin A Aand and B) B) and and othe otherr synthetic synthetic spirooxindole spirooxindole scaffolds scaffolds with with high high biologicalbiological importance importance and and structure-activity structure-activity relationship. relationship. OurOur previous previous studies studies [9] [9 ]revealed revealed that that the the pres presenceence of of dihalide dihalide substitution substitution on on acyl acyl moiety moiety substantiallysubstantially increased increased the theanticancer anticancer activity activity of the of resulting the resulting product(s). product(s). Moreover, Moreover, it was reported it was [9]reported that chlorinated [9] that indole chlorinated moiety indole retained moiety better retainedactivity, as better illustrated activity, in Figure as illustrated 1. (a). Subsequently, in Figure1a. this study was designed to introduce two bromo atoms on the indole ring, presumably to enhance Appl. Sci. 2020, 10, 2170 3 of 11 Subsequently,Appl. Sci. 2020,this 10, x FOR study PEER was REVIEW designed to introduce two bromo atoms on the indole ring, presumably3 of 10 to enhance the activity of the examined spirooxindole compounds shown in Figure1. The aza-heterocyclic compoundsthe activity were of the prepared examined via spirooxindole a multicomponent compounds eco-friendly shown in strategy Figure using1. The oxindoleaza-heterocyclic as a core structure.compounds The resultingwere prepared hybrids via were a multicomponent biologically evaluated eco-friendly using strategy an in vitrousingantiproliferative oxindole as a core assay againststructure. three diThefferent resulting cell lineshybrids for were liver, biologically breast, and evaluated colorectal using cancer. an In inaddition, vitro antiproliferative molecular properties assay andagainst lipophilicity three studiesdifferent were cell conductedlines for liver, to get breast insight, and about colorectal “drug cancer. properties In addition, consideration” molecular and to discoverproperties the compounds’ and lipophilicity structure-property studies were relationship conducted (SPR).to get insight about “drug properties consideration” and to discover the compounds’ structure-property relationship (SPR). 2. Results and Discussion 2. Results and Discussion 2.1. Synthesis of 5a–n 2.1. Synthesis of 5a–n The requisite spirooxindoles analogous were prepared by a multicomponent reaction (Scheme1). The advantagesThe requisite of this spirooxindoles efficient method analogous were low-cost were prepared and readily by a multicomponent available synthons reaction for the (Scheme synthesis 1). The advantages of this efficient method were low-cost and readily available synthons for the of highly divergent compounds with high-importance applications. Fourteen analogues were synthesis of highly divergent compounds with high-importance applications. Fourteen analogues prepared through the reactions of bis-benzylidine 1a–n, which had been prepared according to were prepared through the reactions of bis-benzylidine 1a–n, which had been prepared according to ourour previous previous publication publication [9 [9]] with with thioproline thioproline andand 5,7-dibromoisatin, to to afford afford the the requisite requisite target target compounds.compounds. The The chemical chemical featuresfeatures ofof thethe requisiterequisite compounds compounds were were assigned assigned based based on onHNMR, HNMR, CNMR,CNMR, IR, IR, and and CHN CHN analysis. analysis. SchemeScheme 1. Synthesis1. Synthesis of of tetrahydro-1 tetrahydro-10H′H-spiro[indoline-3,5’-pyrrolo-spiro[indoline-3,5’-pyrrolo [1,2- [1,2-c]thiazol]-2-onec]thiazol]-2-one 5a–n5a–n. Appl. Sci. 2020, 10, 2170 4 of 11 Appl. Sci. 2020, 10, x FOR PEER REVIEW 4 of 10 AccordingAccording to Scheme to Scheme2 and 2 and based based on on our our previous previous studystudy [9], [ 9 ],the the reaction reaction proceeds proceeds via onevia potone pot reaction,reaction, in which in which initially initially 5,7-dibromoisatin 5,7-dibromoisatin2 reacted 2 reacted with with thioproline thioproline3 a3ff affordingording the the azomethine azomethine ylide afterylide the removal after the ofremoval carbon of dioxide carbon dioxide from the from intermediate. the intermediate. Subsequently, Subsequent thely, azomethine the azomethine ylide ylide reacted with thereactedbis-benzylidine with the bis1a–n-benzylidineto provide 1a–n the to target provide compounds the target in compou a regioselectivends in a regioselective and diastereoselective and manner.diastereoselective The reaction proceededmanner. Thevia reactionpath A regio-selectivelyproceeded
Load more

Recommended publications
  • FDA-Approved Drugs with Potent in Vitro Antiviral Activity Against Severe Acute Respiratory Syndrome Coronavirus 2
    pharmaceuticals Article FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2 1, , 1, 2 1 Ahmed Mostafa * y , Ahmed Kandeil y , Yaseen A. M. M. Elshaier , Omnia Kutkat , Yassmin Moatasim 1, Adel A. Rashad 3 , Mahmoud Shehata 1 , Mokhtar R. Gomaa 1, Noura Mahrous 1, Sara H. Mahmoud 1, Mohamed GabAllah 1, Hisham Abbas 4 , Ahmed El Taweel 1, Ahmed E. Kayed 1, Mina Nabil Kamel 1, Mohamed El Sayes 1, Dina B. Mahmoud 5 , Rabeh El-Shesheny 1 , Ghazi Kayali 6,7,* and Mohamed A. Ali 1,* 1 Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt; [email protected] (A.K.); [email protected] (O.K.); [email protected] (Y.M.); [email protected] (M.S.); [email protected] (M.R.G.); [email protected] (N.M.); [email protected] (S.H.M.); [email protected] (M.G.); [email protected] (A.E.T.); [email protected] (A.E.K.); [email protected] (M.N.K.); [email protected] (M.E.S.); [email protected] (R.E.-S.) 2 Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt; [email protected] 3 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; [email protected] 4 Department of Microbiology and Immunology, Zagazig University, Zagazig 44519, Egypt; [email protected] 5 Pharmaceutics Department, National Organization for Drug Control and Research, Giza 12654, Egypt; [email protected] 6 Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas, Houston, TX 77030, USA 7 Human Link, Baabda 1109, Lebanon * Correspondence: [email protected] (A.M.); [email protected] (G.K.); [email protected] (M.A.A.) Contributed equally to this work.
    [Show full text]
  • Molecular Obesity, Potency and Other Addictions in Drug Discovery
    Molecular Obesity, Potency and other Addictions in Drug Discovery Mike Hann Bio-Molecular Structure MDR Chemical Sciences GSK Medicines Research Centre Stevenage, UK [email protected] The challenge of drug discovery – Patients are still in need of more effective drugs for many diseases. – Payers are increasingly only prepared to pay for innovative rather than derivative drugs. – Investors believe they can get a better return on investment elsewhere – Legislators are demanding that only the very safest possible drugs are licensed. – Researchers are equally frustrated – despite all the accumulated knowledge from the new technologies, the challenge of successfully navigating through everything to find novel drugs seems to get harder rather than easier. – the fruit is possibly not as low hanging as before – The consequence of all this is that the average cost is now $1.8bn*! – We owe it to patients and society to do better than this. – *How to improve R&D productivity: the pharmaceutical industry's grand challenge. S. M. Paul, D. S. Mytelka, C. T. Dunwiddie, C. C. Persinger, B. H. Munos, S. R. Lindborg and A. L. Schacht, Nat. Rev. Drug Discovery, 2010, 9, 203. Learning from our mistakes – the resurgence of reason based on metadata from big Pharma Emergence of rules of thumb as guidance – Permeability/solubility: Pfizer analysis of existing drugs and oral absorption profile – (Lipinski, Adv. Drug. Del. Revs. 1997, 23, 3) – Mol Wt <500, LogP <5, OH + NH count <5, O + N count <10: 90% of oral drugs do not fail more than one of these rules. – Lipinski Rule of 5 – Receptor Promiscuity: AZ analysis of 2133 compounds in >200 Cerep Bioprint® assays – (Leeson & Springthorpe, Nat.
    [Show full text]
  • Improving Drug Discovery Efficiency Via in Silico Calculation of Properties
    Improving Drug Discovery Efficiency via In Silico Calculation of Properties D. Ortwine 1 16th North American Regional ISSX meeting , 10/18/09 Outline • Background: Why Calculate Properties? • Calculable properties • Modeling Methods and Molecule Descriptors • Reporting Results From Calculations • Available Commercial Software • Strategies for Implementation • A Real Project Example • The Future • Conclusions • References 2 16th North American Regional ISSX meeting , 10/18/09 Lead Optimization in Drug Discovery The Needle in the Haystack 3 16th North American Regional ISSX meeting , 10/18/09 Why Calculate Properties? They can be related to the developability of drugs! Most marketed oral drugs have defined “property profiles” Paul D. Leeson and Brian Springthorpe, “The Influence of Drug-Like Concepts on Decision-Making in Medicinal Chemistry”, Nature Reviews Drug Discovery, vol. 6, pp. 881-890, 2007. Mark C. Wenlock, et.al, “A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs”, J. Med. Chem, 2003, 46, 1250-1256. 4 16th North American Regional ISSX meeting , 10/18/09 Why Calculate Properties? They can also be related to the ADMET Profile M. Paul Gleeson. Generation of a Set of Simple, Interpretable ADMET Rules of Thumb. J. Med. Chem. (2008), 51(4), 817-834. 5 16th North American Regional ISSX meeting , 10/18/09 Why Calculate Properties? • Prioritize synthesis -> Generate virtual individual molecules or combinatorial libraries, calculate properties, map back to R groups • Build an understanding of SAR •
    [Show full text]
  • Part I Introduction to Lead Generation
    1 Part I Introduction to Lead Generation 3 1 Introduction: Learnings from the Past – Characteristics of Successful Leads Mike Hann Contemporary nodding sages in drug discovery will often be heard to say “Tut, tut, if I wanted to get there, I wouldn’tstartfromhere.” Such comments are based on their experience (aka insights from hindsight!) where failure of com- pounds in late lead optimization, preclinical, or clinical work can all too often be associated with poor chemical and physicochemical properties of the chemical series being pursued. It is, of course, one of the basic truisms of science that where we start an optimization process will likely have profound influences on where it ends up! If this is true then why does so much of medicinal chemistry, and hence drug discovery, still suffer from a lack of awareness of these facts? After all they can save enormous amounts of time and money that are spent on taking forward compounds that fall outside of “drug-like space” until they predictably failed. Is it (1) because people still do not believe in a drug-like space and thus ignore the fact that compounds invariably get bigger and more lipophilic as lead optimi- zation progresses in the search for potency? Or is it (2) because they believe they will be exceptional in their skills and that this will allow their project to be equally exceptional and succeed outside of received or accepted wisdom? Or is it (3) that they just cannot find a good starting point that will deliver or, possibly, they have not tried hard enough to find such a starting point? Or is it (4) that such a poor choice of target that finding a small molecule to effectively interact with it is nigh impossible? All or any of these can be crucial in determining what course a project takes, but one of the biggest confounding issues is that although it can be argued (see below) that a drug-like space exists, there are many good drugs that fall outside of this drug-like space.
    [Show full text]
  • Multi-Parameter Optimisation in Drug Discovery
    Discovery Technology Multi-Parameter Optimisation in Drug Discovery Drug discovery activities are producing ever-larger volumes of By Matthew Segall at Optibrium Ltd complex data that carry significant levels of uncertainty; multi- parameter optimisation methods enable this data to be better utilised to quickly target compounds with a good balance of properties – but they all have their strengths and weaknesses. One of the major challenges of drug discovery is to a compromise on less important properties in order to identify a compound with a good balance of the achieve critical requirements. many physicochemical and biological properties necessary to become a successful, efficacious and safe The challenge of simultaneously optimising multiple drug. Having identified poor pharmacokinetics (PK) factors has been previously addressed in many fields, as a major cause of clinical failure in the later 1990s, from engineering disciplines such as automotive projects now routinely attempt to mitigate this risk and aeronautical design, to economics. The methods by assessing the absorption, distribution, metabolism used to achieve this are described as multi-parameter and elimination (ADME) properties of compounds in optimisation (MPO), multi-dimensional optimisation early drug discovery. However, more recently, safety has (MDO) or multi-objective optimisation (MOOP). For become a greater cause of failure in the clinic leading to simplicity, we will use the term MPO to refer to all of the assessment of toxicity earlier in the drug discovery these methods. We can learn from these approaches process. The result has been an increase in cost and to better use the data generated in drug discovery a reduction in the productivity of drug discovery, but in order to quickly design and select compounds unfortunately a corresponding increase in the success with a good balance of properties.
    [Show full text]
  • ADME Studies and Preliminary Safety Pharmacology of LDT5, a Lead Compound for the Treatment of Benign Prostatic Hyperplasia
    Brazilian Journal of Medical and Biological Research (2016) 49(12): e5542, http://dx.doi.org/10.1590/1414-431X20165542 ISSN 1414-431X 1/9 ADME studies and preliminary safety pharmacology of LDT5, a lead compound for the treatment of benign prostatic hyperplasia F. Noël1*, J.B. Nascimento-Viana1, L.A.S. Romeiro2, R.O. Silva2,3, L.F.N. Lemes3, A.S. Oliveira2,3, T.B.S. Giorno4, P.D. Fernandes4 and C.L.M. Silva1* 1Laboratório de Farmacologia Bioquímica e Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil 2Departamento de Farmácia, Faculdade de Ciências da Saúde, Universidade de Brasília, Brasília, DF, Brasil 3Laboratório de Desenvolvimento de Estratégias Terapêuticas, Universidade Católica de Brasília, Brasília, DF, Brasil 4Laboratório de Farmacologia da Dor e Inflamac¸ão, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brasil Abstract This study aimed to estimate the absorption, distribution, metabolism and excretion (ADME) properties and safety of LDT5, a lead compound for oral treatment of benign prostatic hyperplasia that has previously been characterized as a multi-target antagonist of a1A-, a1D-adrenoceptors and 5-HT1A receptors. The preclinical characterization of this compound comprised the evaluation of its in vitro properties, including plasma, microsomal and hepatocytes stability, cytochrome P450 metabolism and inhibition, plasma protein binding, and permeability using MDCK-MDR1 cells. De-risking and preliminary safety pharmacology assays were performed through screening of 44 off-target receptors and in vivo tests in mice (rota-rod and single dose toxicity). LDT5 is stable in rat and human plasma, human liver microsomes and hepatocytes, but unstable in rat liver microsomes and -6 hepatocytes (half-life of 11 min).
    [Show full text]
  • Perspectives
    PERSPECTIVES attrition outside the ‘drug-like space’; and A GUIDE TO DRUG DISCOVERY — OPINION maintaining sufficient potency to provide an efficacious dose (BOX 1). Considering only Finding the sweet spot: two of the most important (although not completely independent) physicochemical properties — molecular mass and cLogP — the role of nature and nurture it seems that sufficient potency usually requires a certain molecular mass (or com- in medicinal chemistry plexity) and lipophilicity that could be in conflict with the constraints of drug-like Michael M. Hann and György M. Keserü space, as initially formulated in Lipinski’s seminal paper2. The consequences of higher Abstract | Given its position at the heart of small-molecule drug discovery, lipophilicity, its linkage to the quest for medicinal chemistry has an important role in tackling the well-known productivity potency and the overall impact of these challenges in pharmaceutical research and development. In recent years, extensive factors on the attrition of compounds analyses of successful and failed discovery compounds and drug candidates have during drug development have been termed ‘molecular obesity’14,15. improved our understanding of the role of physicochemical properties in drug We would like to emphasize that attrition attrition. Based on the clarified challenges in finding the ‘sweet spot’ in medicinal may be due to multiple reasons, including chemistry programmes, we suggest that this goal can be achieved through a flaws in the therapeutic hypothesis being combination of first identifying chemical starting points with appropriate ‘nature’ pursued (for example, owing to insufficiently and then rigorously ‘nurturing’ them during lead optimization. Here, we discuss rigorous target validation), insufficient efficacy and ADMET problems, as well as scientific, strategic, organizational and cultural considerations for medicinal commercial and strategic issues.
    [Show full text]
  • Glossary of Terms Used in Medicinal Chemistry. Part II (IUPAC Recommendations 2013)*
    Pure Appl. Chem., Vol. 85, No. 8, pp. 1725–1758, 2013. http://dx.doi.org/10.1351/PAC-REC-12-11-23 © 2013 IUPAC, Publication date (Web): 29 July 2013 Glossary of terms used in medicinal chemistry. Part II (IUPAC Recommendations 2013)* Derek R. Buckle1,‡, Paul W. Erhardt2, C. Robin Ganellin3, Toshi Kobayashi4, Thomas J. Perun5, John Proudfoot6, and Joerg Senn-Bilfinger7 1DRB Associates, 18 Hillfield Road, Redhill, Surrey, RH1 4AP, UK; 2University of Toledo, College of Pharmacy, Center for Drug Design and Development, 2801 West Bancroft Street, Toledo, OH 43606-3390, USA; 3Department of Chemistry, Christopher Ingold Laboratory, University College London, 20 Gordon Street, London, WC1H 0AJ, UK; 4PhRMA, 4th Floor, Landic II Toranomon Building, 3-7-8 Minato-ku, 105-000 Japan; 547731 Old Houston Highway, Hempstead, TX 77445, USA; 6Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, CT 06877, USA; 7Altana Pharma AG, Byk-Gulden Str. 2, D-78467 Konstanz, Germany Abstract: The evolution that has taken place in medicinal chemistry practice as a result of major advances in genomics and molecular biology arising from the Human Genome Project has carried with it an extensive additional working vocabulary that has become both inte- grated and essential terminology for the medicinal chemist. Some of this augmented termi- nology has been adopted from the many related and interlocked scientific disciplines with which the modern medicinal chemist must be conversant, but many other terms have been introduced to define new concepts and ideas as they have arisen. In this supplementary Glossary, we have attempted to collate and define many of the additional terms that are now considered to be essential components of the medicinal chemist’s expanded repertoire.
    [Show full text]
  • The Role of Ligand Efficiency Measures in Drug Discovery
    NATURE REVIEWS DRUG DISCOVERY 13(2): 105-121 (2014) doi:10.1038/nrd4163 The Role of Ligand Efficiency Measures in Drug Discovery Andrew L. Hopkins, 1 György M. Keserű, 2 Paul D. Leeson, 3* David C. Rees, 4 Charles H. Reynolds 5 1. Division of Biological Chemistry and Drug Discovery, College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom. [email protected] 2. Hungarian Academy of Sciences, 1025 Budapest, Pusztaszeri út 59-67, 1525 Budapest, P.O. Box 17, Hungary. [email protected] 3. GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire, SG1 2NY, United Kingdom. [email protected] 4. Astex Pharmaceuticals , 436 Cambridge Science Park, Milton Road, Cambridge, CB4 0QA, United Kingdom. [email protected] 5. Gfree Bio, LLC, 3805 Old Easton Road, Doylestown, Pennsylvania 18902, United States. [email protected] Summary Ligand efficiency measures quantify the molecular properties, particularly size and lipophilicity, of small molecules that are required to gain binding affinity to a drug target. For example, ligand efficiency, is the binding free energy per heavy atom count (LE = G/HA) and lipophilic ligand efficiency (LLE = pIC50 or Ki – cLogP/D). There are additional efficiency measures for groups in a molecule, and for combinations of size and lipophilicity. The application of ligand efficiency metrics has been widely reported in the selection and optimisation of fragments, hits, and leads. In particular, optimisation of lipophilic ligand efficiency shows that it is possible to increase affinity and reduce lipophilicity at the same time, even with challenging ‘lipophile-preferring’ targets.
    [Show full text]
  • Hit to Lead Michael Rafferty 1
    Hit to Lead Michael Rafferty Hit to Lead Michael Rafferty Ph.D. Department of Medicinal Chemistry University of Kansas [email protected] 1 Background • Ph.D. Medicinal Chemistry, University of Kansas • Postdoctoral Fellowship, NIH • 25+ years experience in drug discovery with Parke-Davis, Bristol-Myers, Searle, and Pfizer • Current affiliations: Adjunct Prof., Department of Medicinal Chemistry, University of Kansas 2 Recommended readings • Alanine et al. (2003) Lead Generation- Enhancing the Success of Drug Discovery by Investing in the Hit to Lead Process, Combinatorial Chemistry and High Throughput Screening 6: 51-66 • Barelier and Krimm (2011) Ligand Specificity, Privileged Substructures and Protein Druggability from Fragment-Based Screening, Curr. Opin. Chem. Biol. 15: 469-474 • Bleicher et al. (2003) Hit and Lead Generation: Beyond High Throughput Screening, Nat. Rev. Drug Disc. 2: 369-378 • Ferenczy and Keseru (2010) Enthalpic Efficiency of Ligand Binding, J. Chem. Inf. Model. 50: 1536-1541 • Ferenczy and Keseru (2012) Thermodynamics of Fragment Binding, J. Chem. Inf. Model. 52: 1039-1045 • Gleeson et al. (2011) Probing the Links Between in vitro Potency, ADMET, and Physicochemical Parameters, Nat. Rev. Drug. Disc. 10: 197-208 • Hann (2011) Molecular Obesity, Potency, and Other Addictions in Drug Discovery, Med. Chem. Commun. 2: 349-355 • Hann and Keseru (2012) Finding the Sweet Spot: The Role of Nature and Nurture in Medicinal Chemistry, Nat. Rev. Drug Disc. 11: 355-365 •Hannet al. (2001) Molecular Complexity and its Impact on the Probability of Finding Leads for Drug Discovery, J. Chem. Inf. Comput. Sci. 41: 856-864 • Keseru and Makara (2009) The Influence of Lead Discovery Strategies on the Properties 3 of Drug Candidates, Nat.
    [Show full text]
  • Structure−Activity Relationships, Ligand Efficiency, and Lipophilic
    Article pubs.acs.org/jmc Structure−Activity Relationships, Ligand Efficiency, and Lipophilic Efficiency Profiles of Benzophenone-Type Inhibitors of the Multidrug Transporter P-Glycoprotein Ishrat Jabeen,† Karin Pleban,† Uwe Rinner,‡ Peter Chiba,§ and Gerhard F. Ecker*,† † University of Vienna, Department of Medicinal Chemistry, Althanstrasse 14, 1090, Vienna, Austria ‡ University of Vienna, Department of Organic Chemistry, Wahringerstrassë 38, 1090, Vienna, Austria § Medical University of Vienna, Institute of Medical Chemistry, Wahringerstrassë 10, 1090, Vienna, Austria *S Supporting Information ABSTRACT: The drug efflux pump P-glycoprotein (P-gp) has been shown to promote multidrug resistance (MDR) in tumors as well as to influence ADME properties of drug candidates. Here we synthesized and tested a series of benzophenone derivatives structurally analogous to propafenone-type inhibitors of P-gp. Some of the compounds showed ligand efficiency and lipophilic efficiency (LipE) values in the range of compounds which entered clinical trials as MDR modulators. Interestingly, although lipophilicity plays a dominant role for P-gp inhibitors, all compounds investigated showed LipE values below the threshold for promising drug candidates. Docking studies of selected analogues into a homology model of P-glycoprotein suggest that benzophenones show an interaction pattern similar to that previously identified for propafenone-type inhibitors. ■ INTRODUCTION and stresses the need for a more detailed knowledge on the Membrane transporters are increasingly
    [Show full text]
  • In Silico Strategies to Support Fragment-To-Lead Optimization in Drug Discovery
    REVIEW published: 18 February 2020 doi: 10.3389/fchem.2020.00093 In silico Strategies to Support Fragment-to-Lead Optimization in Drug Discovery Lauro Ribeiro de Souza Neto 1†, José Teófilo Moreira-Filho 2†, Bruno Junior Neves 2,3†, Rocío Lucía Beatriz Riveros Maidana 1,4, Ana Carolina Ramos Guimarães 4, Nicholas Furnham 5*, Carolina Horta Andrade 2* and Floriano Paes Silva Jr. 1* 1 LaBECFar – Laboratório de Bioquímica Experimental e Computacional de Fármacos, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil, 2 LabMol – Laboratory for Molecular Modeling and Drug Design, Faculdade de Edited by: Farmácia, Universidade Federal de Goiás, Goiânia, Brazil, 3 Laboratory of Cheminformatics, Centro Universitário de Anápolis Teodorico Castro Ramalho, – UniEVANGÉLICA, Anápolis, Brazil, 4 Laboratório de Genômica Funcional e Bioinformática, Instituto Oswaldo Cruz, Universidade Federal de Lavras, Brazil Fundação Oswaldo Cruz, Rio de Janeiro, Brazil, 5 Department of Infection Biology, London School of Hygiene and Tropical Medicine, London, United Kingdom Reviewed by: Hyun Lee, University of Illinois at Chicago, Fragment-based drug (or lead) discovery (FBDD or FBLD) has developed in the last United States Salvatore Guccione, two decades to become a successful key technology in the pharmaceutical industry for University of Catania, Italy early stage drug discovery and development. The FBDD strategy consists of screening Daiana Mancini, low molecular weight compounds against macromolecular targets (usually proteins) Universidade Federal de Lavras, Brazil of clinical relevance. These small molecular fragments can bind at one or more sites *Correspondence: Nicholas Furnham on the target and act as starting points for the development of lead compounds. In [email protected] developing the fragments attractive features that can translate into compounds with Carolina Horta Andrade [email protected] favorable physical, pharmacokinetics and toxicity (ADMET—absorption, distribution, Floriano Paes Silva Jr.
    [Show full text]