Design, Synthesis, Molecular Modeling and Anti-HIV Assay of Novel Quinazolinone Incorporated Coumarin Derivatives

Author(s): Mahdieh Safakish, Zahra Hajimahdi, Mohammad R. Aghasadeghi, Rouhollah Vahabpour, Afshin Zarghi*.

Journal Name: Current HIV Research

Volume 18 , Issue 1 , 2020

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Graphical Abstract:


Abstract:

Background: The emergence of drug-resistant viral strains has created the need for the development of novel anti-HIV agents with a diverse structure that targets key enzymes in the HIV lifecycle.

Objective: Considering the pharmacophore of integrase inhibitors, one of the validated targets for anti-HIV therapy, we designed a quinazolinone incorporated coumarin scaffold to affect HIV.

Methods: Coumarin is a beta enol ester and also a well-known drug scaffold. Designed structures were prepared using a one-pot three-component reaction from 3-amino-4-hydroxycoumarin, isatoic anhydride and benzaldehyde derivatives.

Results: In vitro anti-HIV and cytotoxicity assay indicated that more than half of the compounds had EC50 values lower than 50 µM. Unsubstituted phenyl derivative showed the highest activity and selectivity with an EC50 value of 5 µM and a therapeutic index of 7. Compounds were docked into the integrase active site to investigate the probable mechanism of action. Accordingly, the hydroxyl moiety of coumarin along with the carbonyl of the quinazolinone ring could function as the metal chelating group. Quinazolinone and phenyl groups interact with side chains of IN residues, as well.

Conclusion: Here, a novel anti-HIV scaffold is represented for further modification and in-vivo studies.

Keywords: Coumarin, quinazolinone, anti-HIV, molecular modeling, synthesis, integrase.

[1]
Gottlieb MS, Schanker HM, Fan PT, Saxon A, Weisman JD. Pneumocystis pneumonia—Los Angeles. Morb Mortal Wkly Rep 1981; 30: 1-3.
[2]
Barré-Sinoussi F, Chermann JC, Rey F, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983; 220(4599): 868-71.
[http://dx.doi.org/10.1126/science.6189183] [PMID: 6189183]
[3]
Gallo RC, Sarin PS, Gelmann EP, et al. Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS). Science 1983; 220(4599): 865-7.
[http://dx.doi.org/10.1126/science.6601823] [PMID: 6601823]
[4]
Merson MH, O’Malley J, Serwadda D, Apisuk C. The history and challenge of HIV prevention. Lancet 2008; 372(9637): 475-88.
[http://dx.doi.org/10.1016/S0140-6736(08)60884-3] [PMID: 18687461]
[5]
Levy JA. Pathogenesis of human immunodeficiency virus infection. Microbiol Rev 1993; 57(1): 183-289.
[PMID: 8464405]
[6]
Greene WC, Peterlin BM. Charting HIV’s remarkable voyage through the cell: Basic science as a passport to future therapy. Nat Med 2002; 8(7): 673-80.
[http://dx.doi.org/10.1038/nm0702-673] [PMID: 12091904]
[7]
Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis 2006; 194(1): 11-9.
[http://dx.doi.org/10.1086/505147] [PMID: 16741877]
[8]
Porter K, Babiker A, Bhaskaran K, et al. Determinants of survival following HIV-1 seroconversion after the introduction of HAART. Lancet 2003; 362(9392): 1267-74.
[http://dx.doi.org/10.1016/S0140-6736(03)14570-9] [PMID: 14575971]
[9]
Messiaen P, Wensing AM, Fun A, Nijhuis M, Brusselaers N, Vandekerckhove L. Clinical use of HIV integrase inhibitors: A systematic review and meta-analysis. PLoS One 2013; 8(1)e52562
[http://dx.doi.org/10.1371/journal.pone.0052562] [PMID: 23341902]
[10]
Ray M, Logan R, Sterne JA, et al. The effect of combined antiretroviral therapy on the overall mortality of HIV-infected individuals. AIDS 2010; 24(1): 123-37.
[http://dx.doi.org/10.1097/QAD.0b013e3283324283] [PMID: 19770621]
[11]
Cohen MS, Chen YQ, McCauley M, et al. Prevention of HIV-1 infection with early antiretroviral therapy. N Engl J Med 2011; 365(6): 493-505.
[http://dx.doi.org/10.1056/NEJMoa1105243] [PMID: 21767103]
[12]
Bon I, Calza L, Musumeci G, et al. Impact of Different Antiretroviral Strategies on Total HIV-DNA Level in Virologically Suppressed HIV-1 Infected Patients. Curr HIV Res 2017; 15(6): 448-55.
[PMID: 29210661]
[13]
Carcelli M, Rogolino D, Sechi M, et al. Antiretroviral activity of metal-chelating HIV-1 integrase inhibitors. Eur J Med Chem 2014; 83: 594-600.
[http://dx.doi.org/10.1016/j.ejmech.2014.06.055] [PMID: 24996145]
[14]
Billamboz M, Bailly F, Lion C, et al. 2-hydroxyisoquinoline-1,3(2H,4H)-diones as inhibitors of HIV-1 integrase and reverse transcriptase RNase H domain: influence of the alkylation of position 4. Eur J Med Chem 2011; 46(2): 535-46.
[http://dx.doi.org/10.1016/j.ejmech.2010.11.033] [PMID: 21185110]
[15]
Craigie R. The molecular biology of HIV integrase. Future Virol 2012; 7(7): 679-86.
[http://dx.doi.org/10.2217/fvl.12.56] [PMID: 23024700]
[16]
Delelis O, Carayon K, Saïb A, Deprez E, Mouscadet J-F. Integrase and integration: biochemical activities of HIV-1 integrase. Retrovirology 2008; 5(1): 114.
[http://dx.doi.org/10.1186/1742-4690-5-114] [PMID: 19091057]
[17]
Hazuda DJ. HIV integrase as a target for antiretroviral therapy. Curr Opin HIV AIDS 2012; 7(5): 383-9.
[http://dx.doi.org/10.1097/COH.0b013e3283567309] [PMID: 22871634]
[18]
Lesbats P, Engelman AN, Cherepanov P. Retroviral DNA Integration. Chem Rev 2016; 116(20): 12730-57.
[http://dx.doi.org/10.1021/acs.chemrev.6b00125] [PMID: 27198982]
[19]
Li B-W, Zhang F-H, Serrao E, et al. Design and discovery of flavonoid-based HIV-1 integrase inhibitors targeting both the active site and the interaction with LEDGF/p75. Bioorg Med Chem 2014; 22(12): 3146-58.
[http://dx.doi.org/10.1016/j.bmc.2014.04.016] [PMID: 24794743]
[20]
Voet ARD, Maeyer MD, Christ F, Debyser Z. De Clercq E (ed). Antiviral Drug Strategies, vol 50. Methods and Principles in Medicinal Chemistry.WILEY-VCH, Weinheim, Germany 2010; pp. 51-64.
[21]
Zhang D, Debnath B, Yu S, et al. Design and discovery of 5-hydroxy-6-oxo-1,6-dihydropyrimidine-4-carboxamide inhibitors of HIV-1 integrase. Bioorg Med Chem 2014; 22(19): 5446-53.
[http://dx.doi.org/10.1016/j.bmc.2014.07.036] [PMID: 25150089]
[22]
Maertens GN, Hare S, Cherepanov P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 2010; 468(7321): 326-9.
[http://dx.doi.org/10.1038/nature09517] [PMID: 21068843]
[23]
Summa V, Petrocchi A, Bonelli F, et al. Discovery of raltegravir, a potent, selective orally bioavailable HIV-integrase inhibitor for the treatment of HIV-AIDS infection. J Med Chem 2008; 51(18): 5843-55.
[http://dx.doi.org/10.1021/jm800245z] [PMID: 18763751]
[24]
Cocohoba J, Dong BJ. Raltegravir: the first HIV integrase inhibitor. Clin Ther 2008; 30(10): 1747-65.
[http://dx.doi.org/10.1016/j.clinthera.2008.10.012] [PMID: 19014832]
[25]
Sato M, Motomura T, Aramaki H, et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J Med Chem 2006; 49(5): 1506-8.
[http://dx.doi.org/10.1021/jm0600139] [PMID: 16509568]
[26]
Shimura K, Kodama EN. Elvitegravir: a new HIV integrase inhibitor. Antivir Chem Chemother 2009; 20(2): 79-85.
[http://dx.doi.org/10.3851/IMP1397] [PMID: 19843978]
[27]
Johns BA, Kawasuji T, Weatherhead JG, et al. Carbamoyl pyridone HIV-1 integrase inhibitors 3. A diastereomeric approach to chiral nonracemic tricyclic ring systems and the discovery of dolutegravir (S/GSK1349572) and (S/GSK1265744). J Med Chem 2013; 56(14): 5901-16.
[http://dx.doi.org/10.1021/jm400645w] [PMID: 23845180]
[28]
Kawasuji T, Johns BA, Yoshida H, et al. Carbamoyl pyridone HIV-1 integrase inhibitors. 2. Bi- and tricyclic derivatives result in superior antiviral and pharmacokinetic profiles. J Med Chem 2013; 56(3): 1124-35.
[http://dx.doi.org/10.1021/jm301550c] [PMID: 23316884]
[29]
Hajimahdi Z, Zarghi A. Progress in HIV-1 integrase inhibitors: A review of their chemical structure diversity. Iran J Pharm Res 2016; 15(4): 595-628.
[PMID: 28243261]
[30]
Zeinalipour-Loizidou E, Nicolaou C, Nicolaides A, Kostrikis LG. HIV-1 integrase: from biology to chemotherapeutics. Curr HIV Res 2007; 5(4): 365-88.
[http://dx.doi.org/10.2174/157016207781023965] [PMID: 17627500]
[31]
Neamati N. Patented small molecule inhibitors of HIV-1 integrase: A ten-year saga. Expert Opin Ther Pat 2002; 12: 709-24.
[http://dx.doi.org/10.1517/13543776.12.5.709]
[32]
Maurin C, Bailly F, Cotelle P. Structure-activity relationships of HIV-1 integrase inhibitors--enzyme-ligand interactions. Curr Med Chem 2003; 10(18): 1795-810.
[http://dx.doi.org/10.2174/0929867033456981] [PMID: 12871105]
[33]
Gordon CP, Griffith R, Keller PA. Control of HIV through the inhibition of HIV-1 integrase: a medicinal chemistry perspective. Med Chem 2007; 3(2): 199-220.
[http://dx.doi.org/10.2174/157340607780059558] [PMID: 17348857]
[34]
Kirschberg T, Parrish J. Metal chelators as antiviral agents. Curr Opin Drug Discov Devel 2007; 10(4): 460-72.
[PMID: 17659488]
[35]
Plewe MB, Butler SL, Dress KR, et al. Azaindole hydroxamic acids are potent HIV-1 integrase inhibitors. J Med Chem 2009; 52(22): 7211-9.
[http://dx.doi.org/10.1021/jm900862n] [PMID: 19873974]
[36]
Hu L, Zhang S, He X, et al. Design and synthesis of novel β-diketo derivatives as HIV-1 integrase inhibitors. Bioorg Med Chem 2012; 20(1): 177-82.
[http://dx.doi.org/10.1016/j.bmc.2011.11.014] [PMID: 22154762]
[37]
Vandurm P, Guiguen A, Cauvin C, et al. Synthesis, biological evaluation and molecular modeling studies of quinolonyl diketo acid derivatives: new structural insight into the HIV-1 integrase inhibition. Eur J Med Chem 2011; 46(5): 1749-56.
[http://dx.doi.org/10.1016/j.ejmech.2011.02.028] [PMID: 21385662]
[38]
Dayam R, Gundla R, Al-Mawsawi LQ, Neamati N. HIV-1 integrase inhibitors: 2005-2006 update. Med Res Rev 2008; 28(1): 118-54.
[http://dx.doi.org/10.1002/med.20116] [PMID: 17979144]
[39]
Ramkumar K, Serrao E, Odde S, Neamati N. HIV-1 integrase inhibitors: 2007-2008 update. Med Res Rev 2010; 30(6): 890-954.
[http://dx.doi.org/10.1002/med.20194] [PMID: 20135632]
[40]
Seo BI, Uchil VR, Okello M, et al. Discovery of a Potent HIV Integrase Inhibitor that Leads to a Prodrug with Significant anti-HIV Activity. ACS Med Chem Lett 2011; 2(12): 877-81.
[http://dx.doi.org/10.1021/ml2001246] [PMID: 22328963]
[41]
Flefel EM, Tantawy WA, El-Sofany WI, El-Shahat M, El-Sayed AA, Abd-Elshafy DN. Synthesis of Some New Pyridazine Derivatives for Anti-HAV Evaluation. Molecules 2017; 22(1): 148.
[http://dx.doi.org/10.3390/molecules22010148] [PMID: 28106751]
[42]
El-Sayed AA, El-Shahat M, Rabie ST, Flefel EM, Abd-Elshafyc DN. New pyrimidine and fused pyrimidine derivatives: Synthesis and anti Hepatitis A virus (HAV) evaluation. Int J Pharm 2015; 5: 69-79.
[43]
Abdelhameed RM, El-Sayed HA, El-Shahat M, El-Sayed AA, Darwesh OM. Novel Triazolothiadiazole and Triazolothiadiazine Derivatives Containing Pyridine Moiety: Design, Synthesis, Bactericidal and Fungicidal Activities. Curr Bioact Compd 2018; 4: 169-79.
[44]
Hajimahdi Z, Ranjbar A, Abolfazl Suratgar A, Zarghi A. QSAR Study on anti-HIV-1 activity of 4-oxo-1,4-dihydroquinoline and 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives using SW-MLR, artificial neural network and filtering methods. Iran J Pharm Res 2015; 14(Suppl.): 69-75.
[PMID: 26185507]
[45]
Hajimahdi Z, Zabihollahi R, Aghasadeghi MR, Ashtiani SH, Zarghi A. Novel quinolone-3-carboxylic acid derivatives as anti-HIV-1 agents: design, synthesis, and biological activities. Med Chem Res 2016; 25: 1861-76.
[http://dx.doi.org/10.1007/s00044-016-1631-x]
[46]
Hajimahdi Z, Zabihollahi R, Aghasadeghi MR, Zarghi A. Design, synthesis and docking studies of new 4-hydroxyquinoline-3-carbohydrazide derivatives as anti-HIV-1 agents. Drug Res (Stuttg) 2013; 63(4): 192-7.
[http://dx.doi.org/10.1055/s-0033-1334964] [PMID: 23487403]
[47]
Hajimahdi Z, Zarghi A, Zabihollahi R, Aghasadeghi MR. Synthesis, biological evaluation, and molecular modeling studies of new 1,3,4-oxadiazole- and 1,3,4-thiadiazole-substituted 4-oxo-4H-pyrido[1,2-a]pyrimidines as anti-HIV-1 agents. Med Chem Res 2013; 22: 2467-75.
[http://dx.doi.org/10.1007/s00044-012-0241-5]
[48]
Hajimahdi Z, Zabihollahi R, Aghasadeghi MR, Zarghi A. Design, Synthesis, Docking Studies and Biological Activities Novel 2,3- Diaryl-4-Quinazolinone Derivatives as Anti-HIV-1 Agents. Curr HIV Res 2019; 17(3): 214-22.
[http://dx.doi.org/10.2174/1570162X17666190911125359] [PMID: 31518225]
[49]
Theivendren PS, Palanirajan VK. Quinazoline marketed drugs – A review. Res Pharm 2011; 1: 1-21.
[50]
Zarghi A, Hajimahdi Z. Substituted oxadiazoles: a patent review (2010 - 2012). Expert Opin Ther Pat 2013; 23(9): 1209-32.
[http://dx.doi.org/10.1517/13543776.2013.797409] [PMID: 23663160]
[51]
Abida PN, Rana A, Imran M. An updated review: Newer quinazoline derivatives under clinical trial. Int J Pharm Biol Arch 2011; 2: 1651-7.
[52]
Borges F, Roleira F, Milhazes N, Santana L, Uriarte E. Simple coumarins and analogues in medicinal chemistry: occurrence, synthesis and biological activity. Curr Med Chem 2005; 12(8): 887-916.
[http://dx.doi.org/10.2174/0929867053507315] [PMID: 15853704]
[53]
Olmedo D, Sancho R, Bedoya LM, et al. 3-Phenylcoumarins as inhibitors of HIV-1 replication. Molecules 2012; 17(8): 9245-57.
[http://dx.doi.org/10.3390/molecules17089245] [PMID: 22858844]
[54]
Mao PC-M, Mouscadet J-F, Leh H, Auclair C, Hsu L-Y. Chemical modification of coumarin dimer and HIV-1 integrase inhibitory activity. Chem Pharm Bull (Tokyo) 2002; 50(12): 1634-7.
[http://dx.doi.org/10.1248/cpb.50.1634] [PMID: 12499608]
[55]
Wang Z, Wang M, Yao X, et al. Design, synthesis and antiviral activity of novel quinazolinones. Eur J Med Chem 2012; 53: 275-82.
[http://dx.doi.org/10.1016/j.ejmech.2012.04.010] [PMID: 22546200]
[56]
Hypercube, Inc, 1115 NW 4th Street, Gainesville, Florida 32601, USA..
[57]
Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, et al. Automated Docking Using a Lamarckian Genetic Algorithm and and Empirical Binding Free Energy Function. J Comput Chem 1998; 19: 1639-62.
[http://dx.doi.org/10.1002/(SICI)1096-987X(19981115)19: 14<1639:AID-JCC10>3.0.CO;2-B]
[58]
Dowlati Beirami A, Hajimahdi Z, Zarghi A. Docking-based 3D-QSAR (CoMFA, CoMFA-RG, CoMSIA) study on hydroquinoline and thiazinan-4-one derivatives as selective COX-2 inhibitors. J Biomol Struct Dyn 2019; 37(11): 2999-3006.
[http://dx.doi.org/10.1080/07391102.2018.1502687] [PMID: 30035675]
[59]
Faraji N, Zebardast T, Zarghi A, Hajimahdi Z. QSAR Modeling of Aminopeptidase N/CD13 (APN) Inhibitory Activity of some Leucine Ureido Derivatives by GA-MLR and SW-MLR Methods. Lett Drug Des Discov 2017; 14: 1348-57.
[http://dx.doi.org/10.2174/1570180814666170529084557]
[60]
Sabakhi I, Topuzyan V, Hajimahdi Z, Daraei B, Arefi H, Zarghi A. Design, Synthesis and Biological Evaluation of New 1, 4-Dihydropyridine (DHP) Derivatives as Selective Cyclooxygenase-2 Inhibitors. Iran J Pharm Res 2015; 14(4): 1087-93.
[PMID: 26664375]
[61]
Zarghi A, Sabakhi I, Topuzyan V, Hajimahdi Z, Daraie B. Design, synthesis and biological evaluation of 5-oxo-1,4,5,6,7,8 hexahydroquinoline derivatives as selective cyclooxygenase-2 inhibitors. Iran J Pharm Res 2014; 13(Suppl.): 61-9.
[PMID: 24711830]
[62]
Zabihollahi R, Sadat SM, Vahabpour R, et al. Development of single-cycle replicable human immunodeficiency virus 1 mutants. Acta Virol 2011; 55(1): 15-22.
[http://dx.doi.org/10.4149/av_2011_01_15] [PMID: 21434701]
[63]
Zabihollahi R, Vahabpour R, Hartoonian C, et al. Evaluation of the in vitro antiretroviral potential of some Biginelli-type pyrimidines. Acta Virol 2012; 56(1): 11-8.
[http://dx.doi.org/10.4149/av_2012_01_11] [PMID: 22404604]
[64]
Alimi Livani Z, Safakish M, Hajimahdi Z, et al. Design, synthesis, molecular modeling, in silico ADME studies and anti-HIV-1 assay of new diazocoumarin derivatives. Iran J Pharm Res 2018; 17(Suppl. 2): 65-77.
[PMID: 31011343]
[65]
Parizadeh N, Alipour E, Soleymani S, et al. Synthesis of novel 3-(5-(alkyl/arylthio)-1,3,4-oxadiazol-2-yl)-8-phenylquinolin-4(1H)-one derivatives as anti-HIV agents. Phosphorus Sulfur Silicon Relat Elem 2018; 193: 225-31.
[http://dx.doi.org/10.1080/10426507.2017.1394302]
[66]
Safakish M, Hajimahdi Z, Zabihollahi R, Aghasadeghi MR, Vahabpour R, Zarghi A. Design, synthesis, and docking studies of new 2-benzoxazolinone derivatives as anti-HIV-1 agent. Med Chem Res 2017; 26: 2718-26.
[http://dx.doi.org/10.1007/s00044-017-1969-8]
[67]
Safakish M, Hajimahdi Z, Vahabpour R, Zabihollahi R, Zarghi A. Novel benzoxazin-3-one derivatives: Design, synthesis, molecular modeling, anti-HIV-1 and integrase inhibitory assay. Med Chem In Press
[http://dx.doi.org/10.2174/1573406415666190826161123] [PMID: 31448713]
[68]
Faghihi K, Safakish M, Zebardast T, Hajimahdi Z, Zarghi A. Molecular Docking and QSAR Study of 2-Benzoxazolinone, Quinazoline and Diazocoumarin Derivatives as Anti-HIV-1 Agents. Iran J Pharm Res 2019; 18(3): 1253-63.
[69]
Lin CC, Cheng HY, Yang CM, Lin TC. Antioxidant and antiviral activities of Euphorbia thymifolia L. J Biomed Sci 2002; 9(6 Pt 2): 656-64.
[http://dx.doi.org/10.1159/000067281] [PMID: 12432232]
[70]
Scudiero DA, Shoemaker RH, Paull KD, et al. Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 1988; 48(17): 4827-33.
[PMID: 3409223]
[71]
Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 2010; 464(7286): 232-6.
[http://dx.doi.org/10.1038/nature08784] [PMID: 20118915]
[72]
Hare S, Maertens GN, Cherepanov P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J 2012; 31(13): 3020-8.
[http://dx.doi.org/10.1038/emboj.2012.118] [PMID: 22580823]


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Year: 2020
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DOI: 10.2174/1570162X17666191210105809
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