AZOLES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs): MINI REVIEW

AZOLES AS NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs): MINI REVIEW

Rohit Singh ^*1, Shweta Gupta ², Jyoti Singh ² and Tarranum Arsi ²

Department of Pharmacy ¹, Birla Institute of Technology, Ranchi, Jharkhand, India.

Goel Institute of Pharmacy and Sciences ², Lucknow, Uttar Pradesh, India.

ABSTRACT: Non-nucleoside reverse transcriptase inhibitors (NNRTIs) in addition with Nucleoside reverse transcriptase inhibitors (NRTIs) and protease inhibitors (PIs) used in the treatment of HIV-1 infection. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) gained exact place in the treatment of HIV-1 infections. Starting from the HEPT and TIBO derivatives, different classes of compounds have been identified as NNRTIs, that is compounds that are specifically inhibitory to HIV-1 replication and targeted at the HIV-1 reverse transcriptase (RT). Two NNRTIs (nevirapine and delavirdine) have been formally licensed for clinical use and several others are (or have been) in preclinical and: or clinical development [tivirapine (TIBO R-86183), loviride (a-APA R89439), thiocarboxanilide UC-781, HEPT derivative MKC-442, quinoxaline HBY 097, DMP 266 (efavirenz), PETT derivatives (trovirdine, PETT-4, PETT-5) and the dichlorophenylthio (pyridyl) imidazole derivative [S-1153]. Several compounds acting as Reverse transcriptase inhibitors was proved to be highly valuable against HIV-1 replication with minimal toxicity. NNRTIs interact with a specific ‘pocket’ site of HIV-1 RT and thus inhibiting the translocation and further elongation of DNA strand. The major drawbacks of NNRTIs are their resistance and pharmacokinetic problems.HIV is no exception as it is a retrovirus, which means that it has capacity to insert its genetic material into the host cells and infect it.  In this review, we focus on the several moiety used against HIV-1 infection.

Reverse transcription, Human Immuno deficiency Virus (HIV), Azoles

INTRODUCTION: Human immunodeficiency virus was found to be a causative agent for development of AIDS ¹. Human immunodeficiency virus, also called retrovirus, has two subtypes i.e. HIV-1 (occurs worldwide) and HIV-2 (found mainly in Africa), consist of a single stranded RNA genome which is converted into double stranded DNA. This conversion occurs in the cytoplasm of newly HIV infected cell in the presence of a viral enzyme named as reverse transcriptase.

Anti HIV-1 drugs act on the reverse transcriptase enzyme and decrease the viral load and increase CD4 lymphocytes. There are three classes of Anti-Reverse Transcriptase Drugs- 1. Nucleoside Reverse Transcriptase Inhibitors (Zidovudine, Stavudine, Zalcitabine, Lamivudine, Didanosine and Abacavir etc). 2. Non- Nucleoside Reverse Transcriptase Inhibitors (Nevirapine, Efavirenz, Delavirdine etc). 3. HIV Protease Inhibitors (Saquinavir, Nelfinavir, Indinavir etc) ^2-4.

Through X-Ray crystallographic analysis inhibitor action of NNRTIs on HIV-1 mainly three mechanisms have given– 1. Esnouf et al proposed that NNRTIs change the conformation of DNA polymerase active site to an inactive site, thus inhibit DNA polymerase 2. Hsiou et al proposed that NNRTIs deform the structural element of polymerase active site that consist of the “Primer grip” which is a region of reverse transcriptase that is involved in the precise positioning of primer DNA strand. This deformation of primer grip may change the position of Template/Primer (T/P) substrate 3. Kohlstaedit et al observed that NNRTI-binding pocket act as a joint between palm and thumb, and movement of thumb help in translocation of Template/Primer. NNRTIs bind and inhibit the movement of thumb domain thus preventing the translocation and further elongation of DNA strand ^5-7.

FIG.1: THIS RIBBON REPRESENTATION OF RT ACTIVE DOMAIN (i.e P66 SUBUNIT) DESCRIBES ITS HAND- LIKE STRUCTURE, SHOWING FINGERS (BLUE), PALM (PINK), AND THUMB (GREEN). THE ACTIVE SITE (RED ATOMS), WHERE DNA IS ELONGATED, IS IN THE PALM REGION. ALSO SHOWS IN AN NNRTI DRUG (YELLOW) IN THE POCKET WHERE IT BINDS.

Chemistry of NNRTIs: For producing a large number of physiologically active compounds, the significance of heterocyclic and bicyclic compounds as intermediates have been reviewed by Avila and Jeyaraman ⁸. In therapy of HIV infections NNRTIs, the class of anti-reverse transcriptase inhibitors, are significantly used. The epoch of NNRTIs began about a decade with the identification of two classes of compounds i.e. 1-(2-hydroxyethoxymethyl)-6-(phenylthio)thymine [HEPT] (a) (Baba et al., 1989, Miyasaka et al., 1989) and tetrahydroimidazo[4,5,1-jkj] [1,4] benzodiazepin– 2(1H)-one and-thione[TIBO] (b) (Pauwels et al., 1990, Debyser et al., 1991) which have specific HIV-1 reverse transcriptase inhibitors activity (Pauwels et al., 1990, Baba et al., 1991a,b, Debyser et al., 1991).

Recently, it has been shown that 4-thiazolidinonederivatives have become a promising area of research because a large no. of activities such as- anticancer activity on leukemia (blood-cancer), ovarian, renal, breast cancer, CNS, colon, lung, melanoma are found in this nucleus. The growth on this scaffold from time-to-time have been reviewed by various researchers such as Newkome et al. in 1977 ⁹, Singh et al. in 1981 ¹⁰, Abdel-Rahman et al. in 2001 ¹¹, Verma et al. in 2008 ¹², Hamama et al. in 2008 ¹³ and Jain et al. in 2012 ¹⁴.

The continuous/discontinuous use of NNRTIs in AIDS patients finally cause resistance of virus strains against the drug. So, it is promising to discover new chemical molecule with a broad-spectrum activity against viral reverse transcriptase enzymes ¹⁵.

The term first generation NNRTIs related to nevirapine (c) and delavirdine (d) is strongly established in the literature, and the term second generation NNRTIs has an improved activity spectrm against the most common NNRTI – resistant HIV variants. Recently approved NNRTI is efavirenz which shows activity against various NNRTI mutants ^{16, 17}. Various new NNRTIs, which have various potencies, have been depicted ^18-20. Some of them such as emivirine (e) also called MKC-442 ²¹, HBYO97 ²² (f), Calanolide A ²³ (g), the phenylethylthiazolythiourea (PETT) derivatives also called MIV-150 ²⁴ and the quinazolinone derivatives also called DPC083 and DPC961 ²⁵ are undergoing to various clinical phases. But due to toxicity, unfavourable pharmacokinetic activities, poor in-vivo efficacy and potency against NNRTI-resistant viruses, most of these drugs has been removed. The thiocarboxanilide (h) also known as UC781 is still in progress due to potent microbicidal activity ²⁶.

(A) HEPT

(B) TIBO

(C) NEVIRAPINE

(D) DELAVIRDINE

(E) EMIVIRINE (MKC442)

(F) HBY097

(G) CALANOLIDE A

(H) THIOCARBOXANILIDE

Biological Activity:

Antiviral activity: Uncontrolled viral replication in CD4⁺⁺T cells cause HIV-1 disease ²⁷. In this situation, for synthesizing inhibitors, HIV-1 RT has been identified as a prime target for treatment of HIV/AIDS ^{28, 29}.

Thiazolidinone derivative: Several 2,3-diaryl-1,3-thiazolidin-4-ones have reported to beparticularly effective non-nucleoside HIV reverse transcriptase inhibitors (NNRTIs) ³⁰. A number of thiazolidin-4-one having adamantine moiety at position-2 and another substituent at N-atom of ring have been synthesized such as (±) -2- adamantan-1-yl-3-(4,6-dimethyl-pyridin-2-yl)-thiazolidin-4-one showed modest anti HIV activity. Adamantine moiety have capable to provide antiviral activity. A new series of thiazolidinone compound having an adamantly moiety at 3^rd position also exhibit anti HIV activity as well as cytostatic activity ³¹.

Benzimidazole derivative: Benzimidazole and their derivatives shows antiviral activity through interaction with different enzymes such as human cytomegalovirus (HCMV), human herpes simplex virus (HSV-1), human immunodeficiency virus (HIV), and hepatitis B and C virus (HBV and HCV). Luo et al. explored the hepatitis B virus (HBV) activity and cytotoxicity of novel benzimidazole derivatives in the HepG2.2.15 cell line. Its cytotoxicity (CC_{50 ¼} 33.3 mM) was over six times less than lamivudine (CC50 ¼ 5 mM), it had nearly three times higher selectivity than lamivudine ³².

Monforte et al. synthesized N-1-aryl-benzimidazoles 2-substituted analogs and screened them as novel HIV-1 nonnucleosidereverse transcriptase inhibitors (NNRTIs). Some of thecompounds were effective in inhibiting the replication of humanimmunodeficiency virus (HIV) at nanomolarconcentration and alsopossessed low cytotoxicity. Among the series, compounds 13 and14 surfaced out as the most promising candidates having potentactivity and as well as no toxicity ³³.

                        Benzimidazole moiety               Aryl thioacetamide moiety

FIG.2: STRUCTURAL ACTIVITY RELATIONSHIP OF ARYL THIOACETAMIDE MOIETY

Thiocarboxanilide derivatives: The selective anti-HIV-1 activity of oxathin (thio) carboxanilides was given in 1991 ³⁴. These drugs are represented as second generation NNRTIs. The lead compound of this class is designated UC-84 (39), contains an oxathiin moiety connect by a carboxamide group to the isopropyl ester of 2-chlorobenzoic acid. These compounds have EC50 values from 0.015 to 0.07 lM against the mutant virus strains ³⁵. The first NNRTIs having strong binding in the NNIBP, which is an important feature for NNRTIs use as microbicides. NNRTIs are in general having hydrophobic nature and should readily cross membranes such as the HIV envelope. The hydrophobic nature of this compound would allow inflow and outflow of the NNRTIs from the virion. The hydrophobic UC781 penetrate by the virion membrane envelope and capsid core would allow binding to RT. The tight-binding property of the compound lowest the dissociation of the NNRTI from RT, and grabbing the NNRTI within the virion particle shows a prolonged inhibition of RT activity.

FIG.3: THIOCARBOXANILIDE UC-781 POSITIONED IN THE NNRTI-BINDING POCKET OF HIV-1 RT ³⁶.

2-Aminopyrimidines derivative: The development of pyrimidines as NNRTIs was the effect of 18years of research of its protype4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk] [1,4] benzo diazepin-2(1H)-ones (TIBO) (b), derivative ³⁷. The structure-based lead discovery started with this find. This group of non nucleoside RT inhibitors (NNRTI’s) interferes with the function of viral polymerase through interaction at a common “allosteric” binding site which is in close proximity to the catalytic site of DNA synthesis.

Imidazole derivative: A series of imidazole were synthesized with the aim to develop novel imidazole analogue with broad spectrum anti HIV activity ³⁸. Imidazole have been known as antiviral drug, one of the example being capravirine. Capravirine was one of the most promising NNRTI because it has a favorable profile to many drug resistance mutations ³⁹. The use of Capravirine has newlybeen prohibited due to vasculitis (an inflammation of the blood vessels) in animals that taken high doses of Capravirine ⁴⁰. In, the synthesis of novel Capravirineanalogues was achieved by synthesis of 2-(aminocarbonylmethylthio)-1H-imidazoles and they were tested for their biological activity against HIV-1.

Arylazolylthioacetanilide derivative: Currently, arylazolylthioacetanilides, a particular series of five membered heterocyclic derivatives, given more attention to the discovery of new NNRTIs because it having more potency against wild-type and resistant HIV-1 strains, maximum bioavailability and low toxicity ^41-48. The newly synthesized imidazopyridinylthioacetanilide derivatives were tested for anti-HIV activity by determining their ability to inhibit the replication of the HIV-1 IIIB strain, HIV-1 mutant strain RES056 (K103 N/Y181C double RT mutant), and HIV-2 ROD strain in MT-4 cells in comparison with other NNRTs such as nevirapine, delaverdine etc.

CONCLUSION: Concerted efforts are being made worldwide by medicinal chemists, biologists and clinicians to wipe out most advanced HIV strains. The combination therapy to date involving synthetic drugs has been successful for partial cure of patients ailing from AIDS.  Although extensive efforts have been made in developing efficient molecules for the management of AIDS, search is still on as the virus undergoes rapid mutation making the existing drugs active only for a short span. A variety of anti-HIV agents with diverse chemical structures are presented in this review and these have shown heartening activities but with some drawbacks or the other.

The present review summarises recent advances made in anti-HIV/AIDS research.

ACKNOWLEDGMENT: The authors acknowledge Birla Institute of Technology, Mesra, Ranchi and Goel Institute of Pharmacy and Sciences for providing Technical and financial support. One of the authors Rohit Singh gratefully acknowledges the University Grants Commission for providing all kind of support during the work.

CONFLICT OF INTREST: Authors declare no conflict of interest.

REFERENCES:

1. Turner BG, Summers MF: J. Mol. Biol., 1999, 285, 1.
2. Drake SM, NNRTIs a new class of drugs for HIV: J. Antimicrob. Chemother., 2000, 45, 417–420.
3. Katlama C: Review of NNRTIs “today and tomorrow”: Int. J. Clin. Pract. Suppl., 1999, 103, 16–20.
4. Pedersen OS and EB Pedersen: Non-nucleoside reverse transcriptase inhibitors: the NNRTI boom Antivir. Chem. Chemother, 1999, 10:285–314.
5. Kohlstaedt LA, Wang J, Friedman JM, Rice PA ands Steitz TA: Crystal structure at 3.5 A resolution of HIV-1 reverse transcriptase complexed with an inhibitor:  Science 1992, 26, 1783-1790. [PubMed: 1377403]
6. Esnouf R, Ren J, Ross C, Jones Y, Stammers D and Stuart D: Mechanism of inhibition of HIV reverse transcriptase by non-nucleoside inhibitors: Nat StructBiol, 1995, 2, 303–308. [PubMed: 7540935]
7. Hsiou Y, Ding J, Das K, Clark AD Jr, Hughes SH and Arnold E: Structure of unliganded HIV-1 reverse transcriptase at 2.7 A resolution: implications of conformational changes for polymerization and inhibition mechanisms, 1996, 15, 853–860.
8. Jeyaraman R and Avila S: Chem. Rev, 81, 1981, 149.
9. Newkome GR and Nayak A: Heterocycl. Chem., 25, 1979, 83.
10. Singh SP, Parmar SS, Raman K and Stenberg VI: Chem. Rev., 81, 1981, 175-203.
11. Abdel-Rahman RM: Chim. Farm., 140, 2001, 401-410.
12. Verma A and Saraf SK: Eur. J. Med. Chem., 43, 2008, 897-905.
13. Hamama WS, Ismail MA, Shaaban S and Zoorob HH:  Heterocycl. Chem., 45, 2008, 939-956.
14. Jain AK, Vaidya A, Ravichandran V, Kashaw SK and  Agrawal RK: Bioorg. Med.Chem., 20, 2012, 3378-3395.
15. Ren J, Esnouf R, Garman E, Somers D, Ross C, Kirby I, Keeling J, Darby G,  Jones Y, Stuart  D and Stammers  D: Nat. Struct. Biol., 1995, 2, 293.
16. De Clercq E: Non-nucleoside reverse transcriptase inhibitors (NNRTIs): past, present and future. Chemistry & Biodiversity, 2004, 1, 44-64.
17. Balzarini J: Current status of the non-nucleoside reverse transcriptase inhibitors of human immunodeficiency virus type 1, Curr Top Med Chem., 2004, 4, 921-944.
18. Campiani G, Ramunno A, Maga G, Nacci V, Fattorusso C, Catalanotti B, Morelli E and Novellino E: Non-nucleoside HIV-1 RT inhibitors: past, present and future perspectives. Curr Pharm Des, 2002, 8, 615-657.
19. Ren J, Milton J, Weaver KL, Short SA, Stuart DI and Stammers DK: Structural basis for the resilience of efavirenz (DMP-266) to drug resistance mutations in HIV-1 reverse transcriptase. Structure, 2000, 8, 1089-1094.

20. Bacheler L, Jeffrey S, Hanna G, D’Aquila R, Wallace L, Logue K, Cordova B, Hertogs K, Larder B and Buckery R et al.: Genotypic correlates of phenotypic resistance to efavirenz in virus isolates from patients failing nonnucleoside reverse transcriptase inhibitor therapy. J Virol, 2001, 75, S4999-5008.
21. Baba M, Shigeta S, Yuasa S, Takashima H, Sekiya K, Ubasawa M, Tanaka H, Miyasaka T, Walker RT and De Clercq E: Preclinical evaluation of MKC-442, a highly potent and specific inhibitor of human immunodeficiency virus type 1 in vitro. Antimicrob Agents Chemother., 1994, 38:688-692.
22. Kleim JP, Bender R, Kirsch R, Weichsner C, Paessens A: Ro¨ sner M, Ru¨ bsamen-Waigmann H, Kaiser R, Wichers M and Schneweis KE et al.: Preclinical evaluation of HBY 097, a new non-nucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 replication. Antimicrob Agents Chemother., 1995, 39:2253-2257.
23. Kashman Y, Gustafson KR, Fuller RW, Cardellina JH II, McMahon JB, Currens MJ, Buckheit RW Jr, Hughes SH, Cragg GM and Boyd MR: The calanolides, a novel HIV-inhibitory class of coumarin derivatives from the tropical rainforest tree, Calophyllumlanigerum. J Med Chem., 1992, 35:2735-2743.
24. Sahlberg C, Nore´ en R, Engelhardt P, RO gberg M, Nangasmetsa J, Vrang L and Zhang H: Synthesis and anti-HIV activities of urea- PETT analogs belonging to a new class of potent nonnucleoside HIV-1 reverse transcriptase inhibitors. Bioorg Med ChemLett., 1998, 8:1511-1516.
25. Corbett JW, Ko SS, Rodgers JD, Gearhart LA, Magnus NA, Bacheler LT, Diamond S, Jeffrey S, Klabe RM and Cordova BC et al.: Inhibition of clinically relevant mutant variants of HIV-1 by quinazoline non-nucleoside reverse transcriptase inhibitors. J Med Chem., 2000, 43:2019-2030.
26. Balzarini J, Pelemans H, Aquaro S, Perno CF, Witvrouw M, Schols D, De Clercq E and Karlsson A: Highly favourable antiviral activity and resistance profile of the novel thiocarboxanilidepentenyloxy ether derivatives UC-781 and UC-82 as inhibitors of human immunodeficiency virus type 1 (HIV-1) replication. Mol Pharmacol., 1996, 50:394-401.
27. Turner BG and Summers MF: J. Mol. Biol., 285, 1999, 1-32.
28. Arnold E, Das K, Ding J, Yadav PN, Hsiou Y, Boyer PL and Hughes SH: Des. Discov., 13,1996, 29-47.
29. Gazzard B and Moyle G: Lancet, 352, 1998, 314-316.
30. Barreca ML, Chimirri A, L. De Luca, Monforte AM,  Monforte P,  Rao A, Zappala M,  Balzarini J, E. De Clercq,  Pannecouque C and  Witvrouw M:  Med. Chem. Lett., 11, 2001, 1793-1796.
31. Balzarini J, Orzeszko B, Maurin JK and Orzeszko A: J. Med. Chem., 42, 2007, 993-1003.
32. Luo JP, Yao L Yang, Feng CL, Tang W, Wang GF and W. Lu: Design andsynthesis of novel benzimidazole derivatives as inhibitors of hepatitis B virus, Bioorg. Med. Chem., 18, 2010, 5048-5055.
33. Monforte AM, Ferro S, Luca LD, Surdo GL,  Morreale F,  Pannecouque C, Balzarini A and  Chimirri A: Design and synthesis of N1-aryl-benzimidazoles 2-substituted as novel HIV-1 nonnucleoside reverse transcriptase inhibitors.
34. Bader JP, Mcmahon JB, Schultz RJ, Narayanan VL, Pierce JB, Harrison WA, Weislow OS, Midelfort CF, Stinson SF and Boyd MR: Natl. Acad. Sci. U.S.A., 1991, 88, 6740.
35. Balzarini J, Brouwer WG, Dao DC, Osika EM and De Clercq E: Agents Chemother. 1996, 40, 1454.
36. Ren J, Esnouf RM, Hopkins AM, Warren J, Balzarini J, Stuart DI and Stammers DK: Biochemistry, 1998, 37, 14394.
37. Pauwels R, Andries K, Desmyter J, Schols D, Kukla M, Breslin H, Raeymaekers A, Van Gelder J, Woestenborghs R, Heykants J, Schellekens K, Janssen MAC, De Clercq E and Janssen P: Nature 1990, 343, 470.
38. Ren JJ, Nicolas C, Bird LE, Fujiwara T, Sugimoto T, and Stuart D: Binding of the secondgeneration non–nucleoside inhibitor S-1153 to HIV-1 reverse transcriptase involves extensive main chain hydrogen bonding, Biol. Chem., 275, 2000, 14316–14320, DOI: 10.1074/jbc.275.19.14316.
39. (a) Ren J, Nichols C, Bird LE, Fujiwara T, Sugimoto H, Stuart DI and Stammers DKJ: Biol.Chem. 2000, 275, 14316; (b) Fujiwara , Sato A, El-Farrash M, Miki S, Abe K, Isaka Y, Kodama M, Wu Y, Chen BL, Harada H, Sugimoto H, Hatanaka M and Hinuma Y: Antimicrob. Agents Chemother., 1998, 42, 1340.
40. From AIDs meds .com_s home page: http://www.aidsmeds.com/drugs/capravirine.htm.
41. Zhan P, Li Z, Liu X and De Clercq E: Rev. Med. Chem., 2009, 9, 1014.
42. Wang Z, Wu B, Kuhen KL, Bursulaya B, Nguyen TN, Nguyen DG and He Y: Med. Chem. Lett., 2006, 16, 4174.
43. De La Rosa M, Kim HW, Gunic E, Jenket G, Boyle U, Koh YH, Korboukh I, Allan M, Zhang W, Chen H, Xu W, Nilar S, Yao N, Hamatake R, Lang SA, Hong Z, Zhang Z and Girardet JL:  Med. Chem. Lett., 2006, 16, 4444.
44. Muragli E, Kinze OD, Laufer R, Miller MD, Moyer G, Munshi V,Orvieto F, Palumbi GM, Pescatore G, Rowley M, Williams PD and Summa V: Med. Chem. Lett., 2006, 16, 2748.
45. Meara JA, Jakalian A, LaPlante S, Bonneau PR, Coulombe R, Faucher AM, Guse I, Landry S, Racine J, Simoneau B, Thavonekham B and Yoakim C: Med. Chem. Lett., 2007, 17, 3362.
46. Gagnon A, Amad MH, Bonneau JM, Coulombe J, DeRoy PL, Doyon J, Duan J, Garneau M, Guse I, Jakalian A, Jolicoeur E, Landry S, Malenfant E, Simoneau B and Yoakim C: Med. Chem. Lett., 2007, 17, 4437.
47. Gagnon A, Landry S, Coulombe R, Jakalian A, Guse I, Thavonekham B, Bonneau PR, Yoakim C and  Simoneau B:  Med. Chem. Lett., 2009, 19, 1199.
    

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    How to cite this article:

    Singh R, Gupta S, Singh J and Arsi T: Azoles as non-nucleoside reverse transcriptase inhibitors (NNRTIs): mini review. Int J Pharm Sci Res 2017; 8(1): 29-34.doi: 10.13040/IJPSR.0975-8232.8(1).29-34.

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