Review Article

Mini review on tricyclic compounds as an inhibitor of trypanothione reductase

Suresh Kumar, Md. Rahmat Ali, Sandhya Bawa

Department of ABSTRACT Pharmaceutical Chemistry, and are two most ruinous parasitic infectious diseases caused by Trypanosoma Faculty of Pharmacy, Jamia Hamdard, and Leishmania species. The disease affects millions of people all over the world and associated with high New Delhi, India morbidity and mortality rates. The review discuss briefly on current treatment of these parasitic diseases and trypanothione reductase (TryR) as potential targets for rational drug design. The enzyme trypanothione reductase Address for correspondence: (TryR) has been identified as unique among these parasites and has been proposed to be an effective target Dr. Sandhya Bawa, against for developing new drugs. The researchers have selected this enzyme as target is due to its substrate E‑mail: sandhyabawa761@ specificity in contrast to human analogous glutathione reductase and its absence from the host cell which yahoo.com makes this enzyme an ideal target for drug discovery. In this review we have tried to present an overview of the different tricyclic compounds which are potent inhibitors of TryR with their inhibitory activities against the parasites are briefly discussed. Received : 21‑10‑13 Review completed : 06‑11‑13 Accepted : 15‑11‑13 KEY WORDS: Tricyclic, trypanosomiasis and leishmaniasis, trypanothione reductase

he hemoflagellate protozoa of the family Trypanosomatidae resistance, low efficacy and poor safety. The development of new T are the causative agents of tropical diseases such chemotherapeutic agents for the treatment of these parasitic as human African sleeping sickness ( diseases has been hindered due to lack of interest shown by gambiense, T. brucei rhodesiense), Chagas’ disease (South top innovator pharmaceutical companies, which might be due American trypanosomiasis, ) and the to low profitability in this domain as poor are more sufferer of visceral, cutaneous and mucocutaneous manifestations of these disease.[1‑4] leishmaniasis (e.g., , , ). According to world health organization The present review focuses on the major human diseases caused was estimated to cause 48,000 deaths by trypanosomal and leishmanial infections and inhibitors and a disease burden of 1.5 million disability‑adjusted life of tryanothione reductase as potential targets for designing years (DALYs) annually; Chagas’ disease, 14,000 deaths and a chemotherapeutic agents against these diseases. Table 1 disease burden of 0.7 million DALYs annually; leishmaniasis, gives an outline of the major human trypanosomiasis and 51,000 deaths and a disease burden of 2.1 million DALYs leishmaniasis with their global annual disease burdens in terms annually. Recently drug discovery program directed toward of DALY The chemical structures of various antitrypnosomal leishmaniasis, malaria, and sleeping sickness and antileishmanial agents are presented as Figure 1. has increased sharply and not only because they are major killing diseases, but also because disease control becomes There are several targets in these parasites through which more difficult due to a number of factors that limit the utility drug or an investigational molecules act and some of these of current drugs such as high cost, poor compliance, drug targets includes deoxyribonucleic acid (DNA) topoisomerases, Access this article online Ergosterol biosynthesis, Purine salvage pathway, trypanothione [5] Quick Response Code: reductase (TryR), microtubule assembly inhibitor etc. Among Website: all the targets known for trypanosomes and Leishmania, TryR www.jpbsonline.org has gained a lot of attention as a potential target for discovering a new antiparasitic drug for the treatment of human African DOI: sleeping sickness caused by T. brucei gambiense, T. brucei 10.4103/0975-7406.142943 rhodesiense, Chagas’ disease (South American trypanosomiasis, T. cruzi) and the visceral, cutaneous and mucocutaneous

How to cite this article: Kumar S, Ali M, Bawa S. Mini review on tricyclic compounds as an inhibitor of trypanothione reductase. J Pharm Bioall Sci 2014;6:222-8.

 222 Journal of Pharmacy and Bioallied Sciences October-December 2014 Vol 6 Issue 4 Kumar, et al.: Tricyclic compounds inhibitor of TryR manifestations of leishmaniasis (e.g., L. donovani, L. tropica, dinucleotide phosphate‑oxidase‑dependent flavoprotein L. braziliensis). oxidoreductase which maintains an intracellular reducing environment by the recycling of trypanothione disulfide

As potential drug target in trypanosomes and Leishmania, T[S] 2 to its dithiol T[SH] 2 form. Trypanothione is oxidized

TryR has been identified through the discovery of a back to T[S] 2 following reaction with potentially damaging fundamental difference between the redox defense system radicals and oxidants generated by aerobic metabolism and of the trypanosomal/leishmanial parasite and the infected by host macrophages. By maintaining a high intracellular ratio host. The mammalian redox defense system is based on of T[SH] 2 the TryR redox cycle is a primary line of defense glutathione (l‑g‑glutamyl‑l‑cysteinylglycine) and glutathione for these parasites against respiratory burst responses from disulfide reductase (glutathione reductase (GR); EC 1.6.4.2), the mammalian host. The trypanothione system is necessary this system is replaced in trypanosomatids by an analogous for protozoan survival because the dithiol trypanothione is system based on trypanothione (N, N‑bis [glutathionyl] required for the synthesis of DNA precursors, the homeostasis spermidine) and trypanothione disulfide reductase (TryR; EC of ascorbate, the detoxification of hydroperoxides and the 1.6.4.8). The structures of the disulfide substrates for TryR and sequestration/export of thiol conjugates. Moreover, the GR are illustrated in Figure 2. TryR is a nicotinamide adenine majority of peroxidases that eliminate the reactive oxygen

Table 1: The major trypanosomiasis and leishmaniasis and their causative agents current treatments Disease Causative agents Some widely used or recently introduced Disadvantages drugs or drug combinations (year first used) African T. brucei gambiense Suramine (1920), pentamidine (1939), Risk of severe adverse effects with all drugs. suramin and trypanosomiasis or and T. brucei melarsoprol (1949), eflornithine (1991) pentamidine not effective in late stage disease, eflornithine sleeping sickness rhodesiense expensive and only effective against T. brucei gambiense American T. cruzi Benznidazole (1974) nifurtimox (1970) Long treatment courses and adverse effects limit compliance; trypanosomiasis or not effective in late‑stage disease Chagas disease Visceral L. donovani Pentamidine (1939); pentavalent Efficacy loss/drug resistance to pentamidine and antimonials. leishmaniasis or antimonials (1950) liposomal amphotericin Cost high for liposomal amphotericin B. Adverse effects well kalazar B (1999) miltefosine (2002) described for other drugs. miltefosine is contraindicated in women of child‑bearing age T. brucei: Trypanosoma brucei, T. cruzi: Trypanosoma cruzi, L. donovani: Leishmania donovani

+ 62  2 +  1 + 1 1  1 +  1 2 26 1 1 6 $V &+ 2+ 2  1 6 1+  + 62 6XUDPLQH 0HODUVRSURO 2 1 &22+ &22+ 21 1 1 1+ +2 2+ 2 2 2 6  2 1 6E 6E +2 2 2 2 2+ 2 2 21 2+ 2+

1LWULIXULPD[ %HQ]QLGD]ROH 3HQWRVWDP Figure 1: Structures of various drugs used for the treatment of trypanosomiasis and leishmaniasis

a b Figure 2: (a) Structure of Trypanothione and glutathione and their reduced form. (b) Mechanism of redox recycling of T[S]2 to T[SH]2 and GSSG to GSH in parasite and host cell respectively

Journal of Pharmacy and Bioallied Sciences October-December 2014 Vol 6 Issue 4 223  Kumar, et al.: Tricyclic compounds inhibitor of TryR species generated in the aerobic metabolism are trypanothione several tricyclic derivatives were identified as a potent inhibitor dependent. Disabling the function of TryR in Leishmania and TryR [Figure 3]. T. brucei has been shown to markedly increase the parasites’ sensitivity to oxidative stress. Recently, lunarine a spermidine‑based macrocyclic alkaloid [Figure 4] has been identified as a competitive,

T[S] 2 differs from glutathione disulfide (GSSG) by the time‑dependent inhibitor of TryR. Lunarine is composed of a presence of a spermidine cross‑link between the two glycyl spermidine chain with the terminal nitrogen atoms forming amide carboxyl groups [compare GSSG and T[S] 2 in Figure 2]. linkages with two α, β‑unsaturated carboxylic acid functions

Due to structural and charge differences between T[S] 2 and disposed upon an unusual 3‑oxohexahydrodibenzofuranyl GSSG, TryR and GR are mutually exclusive with respect tricyclic scaffold.[11] to substrate specificity. Thus the essential requirement of TryR in trypanosomal/leishmanial parasite and its absence in A study done by Hamilton et al.[12] presented a possible host metabolism make it an attractive therapeutic target for mechanism for this time dependent inhibition, which involves designing specific inhibitor. In the preceding section we have the covalent modification of a redox‑active cysteine residue tried to compile various tricyclic compounds, which have shown in the active site of TryR (C53) by conjugate addition to potent inhibiting activity against TryR.[6‑8] one of these unsaturated amide moieties in the lunarine macrocycle [Figure 5]. This was supported by both the Tricyclic trypanothione reductase (TryR) inhibitors requirement for the enzyme in its reduced form and the presence of a potential Michael acceptor unit in the inhibitor. Knowing the fact that both TryR and GR has exclusive substrate specificity, various molecules have been explored as inhibitors of The Hamilton et al.[13] further explored this approach by TryR which includes hydrophobic linear polyamine derivatives preparing some benzofuranyl‑based acyclic bis‑polyamine and the naturally occurring bis (tetrahydrocinnamoyl) spermine, analogues (1‑5) of lunarine. In their approach they Ponasik et al.[9] removed skew boat cyclohexanone moiety of lunarine leaving a planar bicyclic benzofuranyl scaffold. The acyclic To further address the need for new compounds and new bis‑polyamine derivatives were chosen since bis‑polyamine compound classes, Richardson et al.[10] initiated screening functionalized disulfides such as the naturally occurring of 1266 pharmacologically active compounds from the N1‑glutathionylspermidine disulfide and the synthetic Sigma‑Aldrich LOPAC1280 library. These compounds were bis‑dimethylaminopropyl‑ and bis‑N‑methylpiperazinyl screened against TryR and the top hits counter‑screened amides of Ellman’s reagent (DTNB) are known TryR against GR and live T. brucei parasites, yielding the IC values, substrates. These three polyamine chains were chosen selectivity for TryR over GR and antiparasitic activity. Among all for functionalisation of a 3, 5‑disubstituted benzofuranyl the 1266 compounds from Sigma‑Aldrich LOPAC1280 library, template to give potential inhibitors (1‑5).

Figure 3: Structures of various tricyclic drug having potent trypanothione reductase inhibiting activity and selectivity of human glutathione reductase

 224 Journal of Pharmacy and Bioallied Sciences October-December 2014 Vol 6 Issue 4 Kumar, et al.: Tricyclic compounds inhibitor of TryR

2+

2+

2 + 1 +1 +1 +1 2 2+ 2 1+

2+

+1 +1 2

2 + 2 .XNRDPLQH$ /XQDULQH Figure 4: Structure of Kukoamine A and Lunarine

Figure 5: Proposed mechanism for time-dependent inactivation of trypanothione reductase by the reversible formation of a covalent adduct between an active site thiol (C53) and one of the α, β-unsaturated amide groups of lunarine

In their series of compounds the bis‑polyaminoacrylamide T. brucei trypomastigote stage. They also studied cytotoxicity derivatives (1‑3) were shown to be competitive inhibitors, toward human MRC‑5 cells (diploid embryonic lung cell line). but only the bis‑4‑methyl‑piperazin‑1‑yl‑propylacrylamide Their study revealed that in the aromatic series the most potent derivative 3 displayed time‑dependent activity. Analysis of TR inhibition was observed for polyphenyl derivatives 7 and in vitro activity showed that these compounds were simple 8 (IC50 of 32 and 28 μM) respectively. These two compounds competitive inhibitors of TryR, with respect to T[S] 2. The showed 100% Inhibition on T. brucei at a concentration of 6.3 starting material 4, 5 and 6 which do not have polyamine and 3.1 μM. side chain were also evaluated for enzyme inhibitory activity against TryR. It was observed that due to the absence of any A study done by Chibale et al.[15] reported design and synthesis polyamine side chains, neither the diester 6 nor the diacid of 9, 9‑dimethylxanthene derivatives (9‑14) as potential 4 showed any inhibitory activity towards TryR at 100 μM inhibitor of TR. They designed target compounds in which concentrations. 9, 9‑dimethylxanthene ring was exploited as an aromatic hydrophobic tricyclic moiety that bears resemblance to the Bonnet et al.[14] designed and synthesized a series of symmetrical aromatic hydrophobic tricyclic moieties found in other tricyclic substituted 1,4‑bis (3‑aminopropyl) piperazines derivatives. The compounds already reported as competitive inhibitors of TR, compounds were prepared by reacting 1,4‑bis (3‑aminopropyl) where the tricyclic moiety binds in the hydrophobic pocket piperazine with various aldehydes via reductive amination. All involved in recognition of the spermidine moiety of trypanothione compounds were tested for their inhibitory potency towards disulfide, the substrate for TR. Moreover, in 9, 9‑dimethylxanthene TryR from T. cruzi and their trypanocidal effects upon T. cruzi system potential multiple sites are provided by chemically reactive trypomastigote as well as for their trypanocidal effect upon 2, 7 and 4, 5 positions for introducing chemical diversity. Apart

Journal of Pharmacy and Bioallied Sciences October-December 2014 Vol 6 Issue 4 225  Kumar, et al.: Tricyclic compounds inhibitor of TryR from these functions, they also introduced terminal tertiary TR compared to derivatives with two or three carbon methylene amino group (exemplified by the dimethylamino group) into spacer (12, 13 and 14) [Figure 6]. compounds (9‑14) to provide a positive charge which has been shown to favor TryR over GR, the closest related host enzyme. They concluded that within the series of compounds (9‑15), Thorough analysis of results of TryR inhibitions study [Table 2], there is no clear correlation between potency as inhibitors it was found that compounds (9‑11) bearing either one (10) or of TR and the in vitro antiparasitic activities and that there no methylene spacer (9 and 11) between the tricyclic moiety and is no apparent single structural feature controlling in vitro the secondary nitrogen atom generally show weaker inhibition of antiparasitic activities.

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5 10H 10H 5 5&+2 5 + 1 1+  11  +1 +1 1 1 1 1 10H ; ; 10H 2 +1 2 +1

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1 1

1 1

&O 1 1 &O

6

3URFKORUSHUD]LQH  Figure 6: Potential compounds from different literature

 226 Journal of Pharmacy and Bioallied Sciences October-December 2014 Vol 6 Issue 4 Kumar, et al.: Tricyclic compounds inhibitor of TryR

In another study by Chibale et al.[16] had shown that chemical derivatives were superior inhibitors of TryR relative to quinacrine structures of agents which increase accumulation and/or with the best compound being 40 times more potent. Results of reverse chloroquine (CQ) resistance reveals the importance of a their studies revealed that sulfonamide derivatives were more hydrophobic group and a protonatable nitrogen and incidentally active than urea in inhibiting TryR and this trend of activity these are the same chemical features known to be important for did not correlate with the in vitro activities against L. donovani, potent and selective against TR inhibitor. This was exemplified in T. cruzi, and T. brucei. the antimalarial acridine quinacrine and tricyclic antidepressants promazine and clomipramine. A wide variety of structurally diverse Girault et al.[18] designed and optimized various bis drugs (including Mepacrine, Promazine and clomipramine) have (2‑aminodiphenylsulfides) derivatives and tested for also been described as CQ resistance reversal agents. inhibitory activity against TryR from T. cruzi. In the series bis (2‑aminodiphenylsulfides) compounds possessing three side Based on this observation it was envisaged by Chibale et al. chains were synthesized and various moieties were introduced that these tricyclic could be utilized as dual purpose scaffolds at the end of the third side chain, including acridinyl or biotinyl for the discovery and development of CQ resistance reversal moieties for fluorescent labeling studies. The results of the TR agents and inhibitors of TryR. They designed and developed a inhibition screening showed that most potent inhibitor (24) series of xanthenes derivatives as potential TR inhibitor. All the with IC50 = 200 nM, whereas the tricyclic derivatives (25) tested compounds showed weak TR inhibitory activity against exhibited IC50 of 250 nM. All the compounds were also tested T. cruzi TryR. Among the all derivatives of xanthenes, compound in vitro upon T. cruzi and amastigotes,

16 showed highest TryR inhibitory activity of IC50 of 35.7 μM upon T. brucei trypomastigotes. and intrinsic antimalarial activity of IC50 = 1.748 μM. In order to provide improved tricyclic derivatives as an A series of sulfonamide and urea derivatives of quinacrine with inhibitor of TryR, Richardson et al.[10] have reported structural varying methylene spacer lengths have been tested for inhibition modification of Prochlorperazine which shown IC50 of 7.46 μM of TryR and for activity in vitro against strains of the parasitic against TryR. They prepared a derivative having additional protozoa Trypanosoma, Leishmania and Plasmodium by Kelly propylbenzene ring on piperazine moiety of Prochlorperazine [17] et al. The results of the studies revealed [Table 3] that these and found 10 fold increase in IC50 against TryR (IC50 = 0.75 μM).

Table 2: Percentage inhibition of TryR and ED50 of Conclusion compounds (9‑14) The enzyme TryR from trypanosomal and leishmanial parasites Compound % inhibition ED50 (μg/ml) (μM) of TryR meets most of the ideal features as a drug target needed for L. donovani T. cruzi T. brucei developing a potent and specific inhibitor for treating infections Pentostam ‑ 12.5 (10.7) ‑ ‑ caused by trypanosomal and leishmanial parasites. Of various Benznidazole ‑ ‑ 8.5 (32.7) ‑ Pentamidine ‑ ‑ ‑ 0.01 (0.03) class of compounds developed as an inhibitor of TryR, tricyclic 9 40 >30 >30 4.5 (9.66) derivatives have come up with potential to be further exploited 10 13.8 >30 >30 3.32 (7.58) as the drug candidate for the treatment of trypanosomiasis and 11 28.4 0.32 (0.55) 0.28 (0.48) 0.01 (0.02) Leishmaniasis. Although a lot research work has been done to 12 58 17.03 (32.6) >30 4.3 (8.24) provide tricyclic based derivatives as future therapeutic agents 13 63 >30 >30 0.07 (0.14) 14 52 >30 >30 0.06 (0.098) against these parasitic diseases, but yet none of tricyclic agent is able to reach at the level of approval as an effective therapy Not tested, TryR: Trypanothione reductase, T. brucei: Trypanosoma for trypanosomiasis and Leishmaniasis. brucei, T. cruzi: Trypanosoma cruzi, L. donovani: Leishmania donovani Acknowledgments Table 3: In vitro sensitivity of the parasite to quinacrine analogue (17‑19) and (20‑23) The author wish to gratefully acknowledge Professors A. H. Fairlamb of

Compound No. of CH2 TR IC50 ED50 (μg/ml) University of Dundee, UK and others who are pioneer in the research groups (n) (μM) L. donovani T. cruzi T. brucei work on biochemistry of trypanothione reductase and many of their research have been cited in this review. Pentostam NA NT 8.9 NT NT Benznidazole NA NT NT 12.4 NT Pentamidine NA NT NT NT 0.0002 References Quinacrine NA 133±11 NT NT NT 17 2 5.9±0.6 5.8 >30 0.47 1. Stuart K, Brun R, Croft S, Fairlamb A, Gürtler RE, McKerrow J, et al. 18 3 3.3±0.3 1.9 23.9 0.078 Kinetoplastids: Related protozoan pathogens, different diseases. 19 4 5.0±0.2 3.3 >30 0.12 J Clin Invest 2008;118:1301‑10. 20 2 19.3±1.0 10.7 >30 0.42 2. Barrett MP, Burchmore RJ, Stich A, Lazzari JO, Frasch AC, Cazzulo JJ, 21 3 13.1±0.7 1.9 22.0 0.083 et al. The trypanosomiases. Lancet 2003;362:1469‑80. 22 4 15.5±0.8 1.9 <1 0.043 3. Chatelain E, Ioset JR. Drug discovery and development for neglected 23 6 11.4±0.7 5.8 6.8 0.46 diseases: The DNDi model. Drug Des Devel Ther 2011;5:175‑81. 4. Pink R, Hudson A, Mouriès MA, Bendig M. Opportunities and TR: Tricyclic trypanothione reductase, T. brucei: Trypanosoma brucei, challenges in antiparasitic drug discovery. Nat Rev Drug Discov T. cruzi: Trypanosoma cruzi, L. donovani: Leishmania donovani 2005;4:727‑40.

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5. Chawla B, Madhubala R. Drug targets in Leishmania. J Parasit Dis 13. Hamilton CJ, Saravanamuthu A, Fairlamb AH, Eggleston IM. 2010;34:1‑13. Benzofuranyl 3,5‑bis‑polyamine derivatives as time‑dependent inhibitors 6. Fairlamb AH, Blackburn P, Ulrich P, Chait BT, Cerami A. Trypanothione: of trypanothione reductase. Bioorg Med Chem 2003;11:3683‑93. A novel bis (glutathionyl) spermidine cofactor for glutathione 14. Bonnet B, Soullez D, Girault S, Maes L, Landry V, Davioud‑Charvet E, reductase in trypanosomatids. Science 1985;227:1485‑7. et al. Trypanothione reductase inhibition/trypanocidal activity 7. Augustyns K, Amssoms K, Yamani A, Rajan PK, Haemers A. relationships in a 1,4‑bis (3‑aminopropyl) piperazine series. Bioorg Trypanothione as a target in the design of antitrypanosomal and Med Chem 2000;8:95‑103. antileishmanial agents. Curr Pharm Des 2001;7:1117‑41. 15. Chibale K, Visser M, Yardley V, Croft SL, Fairlamb AH. Synthesis and 8. Khan MO. Trypanothione reductase: A viable chemotherapeutic target evaluation of 9,9‑dimethylxanthene tricyclics against trypanothione for antitrypanosomal and antileishmanial drug design. Drug Target reductase, Trypanosoma brucei, Trypanosoma cruzi and Leishmania Insights 2007;2:129‑46. donovani. Bioorg Med Chem Lett 2000;10:1147‑50. 9. Ponasik JA, Strickland C, Faerman C, Savvides S, Karplus PA, 16. Chibale K, Visser M, Schalkwyk D, Fairlamb AH. Smith PJ, Ganem B. Kukoamine A and other hydrophobic acylpolyamines: Saravanamuthu A. Exploring the potential of xanthene derivatives Potent and selective inhibitors of Crithidia fasciculata trypanothione as trypanothione reductase inhibitors and chloroquine potentiating reductase. Biochem J 1995;311 (Pt 2):371‑5. agents. Tetrahedron 2003;59:2289‑96. 10. Richardson JL, Nett IR, Jones DC, Abdille MH, Gilbert IH, Fairlamb AH. 17. Chibale K, Haupt H, Kendrick H, Yardley V, Saravanamuthu A, Improved tricyclic inhibitors of trypanothione reductase by screening Fairlamb AH, et al. Antiprotozoal and cytotoxicity evaluation of and chemical synthesis. Chem Med Chem 2009;4:1333‑40. sulfonamide and urea analogues of quinacrine. Bioorg Med Chem 11. Bond CS, Zhang Y, Berriman M, Cunningham ML, Fairlamb AH, Lett 2001;11:2655‑7. Hunter WN. Crystal structure of Trypanosoma cruzi 18. Girault S, Davioud‑Charvet TE, Maes L, Dubremetz JF, Debreu MA, trypanothione reductase in complex with trypanothione, and the Landry V, et al. Potent and specific inhibitors of trypanothione structure‑based discovery of new natural product inhibitors. Structure reductase from Trypanosoma cruzi: Bis (2‑aminodiphenylsulfides) 1999;7:81‑9. for fluorescent labeling studies. Bioorg Med Chem 2001;9:837‑46. 12. Hamilton CJ, Fairlamb AH, Eggleston IM. Regiocontrolled synthesis of the macrocyclic polyamine alkaloid (±)-lunarine, a time- dependent inhibitor of trypanothione reductase. J Chem Soc Perkin Source of Support: Nill, Conflict of Interest: None declared. 1 2002;1:1115‑23.

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