Structural-Functional Analysis of 2,1,3-Benzoxadiazoles and Their N-oxides As HIV-1 Integrase Inhibitors

Overview

Journal Acta Naturae

Specialty Biology

Date 2013 Apr 5

PMID 23556131

Citations 3

Authors

S P Korolev

O V Kondrashina

D S Druzhilovsky

A M Starosotnikov

M D Dutov

M A Bastrakov

I L Dalinger

D A Filimonov

S A Shevelev

V V Poroikov

Y Y Agapkina

M B Gottikh

Affiliations

Soon will be listed here.

Abstract

Human immunodeficiency virus type 1 integrase is one of the most attractive targets for the development of anti-HIV-1 inhibitors. The capacity of a series of 2,1,3-benzoxadiazoles (benzofurazans) and their N-oxides (benzofuroxans) selected using the PASS software to inhibit the catalytic activity of HIV-1 integrase was studied in the present work. Only the nitro-derivatives of these compounds were found to display inhibitory activity. The study of the mechanism of inhibition by nitro-benzofurazans/benzofuroxans showed that they impede the substrate DNA binding at the integrase active site. These inhibitors were also active against integrase mutants resistant to raltegravir, which is the first HIV-1 integrase inhibitor approved for clinical use. The comparison of computer-aided estimations of the pharmacodynamic and pharmacokinetic properties of the compounds studied and raltegravir led us to conclude that these compounds show promise and need to be further studied as potential HIV-1 integrase inhibitors.

Citing Articles

Synthesis and Facile Dearomatization of Highly Electrophilic Nitroisoxazolo[4,3-]pyridines.

Bastrakov M, Fedorenko A, Starosotnikov A, Fedyanin I, Kokorekin V Molecules. 2020; 25(9).

PMID: 32397095 PMC: 7248838. DOI: 10.3390/molecules25092194.

Rapid activity prediction of HIV-1 integrase inhibitors: harnessing docking energetic components for empirical scoring by chemometric and artificial neural network approaches.

Thangsunan P, Kittiwachana S, Meepowpan P, Kungwan N, Prangkio P, Hannongbua S J Comput Aided Mol Des. 2016; 30(6):471-88.

PMID: 27314501 DOI: 10.1007/s10822-016-9917-0.

Activation of EGFR by small compounds through coupling the generation of hydrogen peroxide to stable dimerization of Cu/Zn SOD1.

Sakanyan V, Hulin P, Alves de Sousa R, Silva V, Hambardzumyan A, Nedellec S Sci Rep. 2016; 6:21088.

PMID: 26883293 PMC: 4756678. DOI: 10.1038/srep21088.

References

Hare S, Vos A, Clayton R, Thuring J, Cummings M, Cherepanov P . Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc Natl Acad Sci U S A. 2010; 107(46):20057-62. PMC: 2993412. DOI: 10.1073/pnas.1010246107. View

Johnson A, Marchand C, Patil S, Costi R, Di Santo R, Burke Jr T . Probing HIV-1 integrase inhibitor binding sites with position-specific integrase-DNA cross-linking assays. Mol Pharmacol. 2006; 71(3):893-901. DOI: 10.1124/mol.106.030817. View

Smolov M, Gottikh M, Tashlitskii V, Korolev S, Demidyuk I, Brochon J . Kinetic study of the HIV-1 DNA 3'-end processing. FEBS J. 2006; 273(6):1137-51. DOI: 10.1111/j.1742-4658.2006.05139.x. View

Korolev S, Agapkina Y, Gottikh M . Clinical Use of Inhibitors of HIV-1 Integration: Problems and Prospects. Acta Naturae. 2012; 3(3):12-28. PMC: 3347602. View

Delelis O, Malet I, Na L, Tchertanov L, Calvez V, Marcelin A . The G140S mutation in HIV integrases from raltegravir-resistant patients rescues catalytic defect due to the resistance Q148H mutation. Nucleic Acids Res. 2009; 37(4):1193-201. PMC: 2651800. DOI: 10.1093/nar/gkn1050. View

Akimov D, Filimonov D, Prikazchikova T, Gottikh M, Poroikov V . [Computer search for novel HIV-1 integrase inhibitors]. Biomed Khim. 2005; 51(3):335-40. View

Zatsepin T, Kachalova A, Romanova E, Stestenko D, Gait M, Oretskaia T . [Synthesis and characteristics of modified oligodeoxyribonucleotides containing 2'-O-(2,3-dihydroxypropyl)uridine and 2'-O-(2-exoethyl)uridine]. Bioorg Khim. 2001; 27(1):45-51. DOI: 10.1023/a:1009579002330. View

Quashie P, Sloan R, Wainberg M . Novel therapeutic strategies targeting HIV integrase. BMC Med. 2012; 10:34. PMC: 3348091. DOI: 10.1186/1741-7015-10-34. View

Ko G, Reddy A, Garg R, Kumar S, Hadaegh A . Computational modeling methods for QSAR studies on HIV-1 integrase inhibitors (2005-2010). Curr Comput Aided Drug Des. 2012; 8(4):255-70. DOI: 10.2174/157340912803519624. View

10.

Ghose A, Herbertz T, Hudkins R, Dorsey B, Mallamo J . Knowledge-Based, Central Nervous System (CNS) Lead Selection and Lead Optimization for CNS Drug Discovery. ACS Chem Neurosci. 2012; 3(1):50-68. PMC: 3260741. DOI: 10.1021/cn200100h. View

11.

Cara A, Guarnaccia F, Reitz M, Gallo R, Lori F . Self-limiting, cell type-dependent replication of an integrase-defective human immunodeficiency virus type 1 in human primary macrophages but not T lymphocytes. Virology. 1995; 208(1):242-8. DOI: 10.1006/viro.1995.1148. View

12.

Ma K, Wang P, Fu W, Wan X, Zhou L, Chu Y . Rational design of 2-pyrrolinones as inhibitors of HIV-1 integrase. Bioorg Med Chem Lett. 2011; 21(22):6724-7. DOI: 10.1016/j.bmcl.2011.09.054. View

13.

Shukla S, Kumar P, Das N, Moorthy N, Shrivastava S, Trivedi P . Synthesis, characterization, biological evaluation and docking of coumarin coupled thiazolidinedione derivatives and its bioisosteres as PPARγ agonists. Med Chem. 2012; 8(5):834-45. DOI: 10.2174/157340612802084388. View

14.

Michel F, Crucifix C, Granger F, Eiler S, Mouscadet J, Korolev S . Structural basis for HIV-1 DNA integration in the human genome, role of the LEDGF/P75 cofactor. EMBO J. 2009; 28(7):980-91. PMC: 2670869. DOI: 10.1038/emboj.2009.41. View

15.

Keseru G, Makara G . The influence of lead discovery strategies on the properties of drug candidates. Nat Rev Drug Discov. 2009; 8(3):203-12. DOI: 10.1038/nrd2796. View

16.

Johnson B, Metifiot M, Pommier Y, Hughes S . Molecular dynamics approaches estimate the binding energy of HIV-1 integrase inhibitors and correlate with in vitro activity. Antimicrob Agents Chemother. 2011; 56(1):411-9. PMC: 3256025. DOI: 10.1128/AAC.05292-11. View

17.

Marcelin A, Ceccherini-Silberstein F, Perno C, Calvez V . Resistance to novel drug classes. Curr Opin HIV AIDS. 2010; 4(6):531-7. DOI: 10.1097/COH.0b013e328331d4b1. View

18.

Krishnan L, Li X, Naraharisetty H, Hare S, Cherepanov P, Engelman A . Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc Natl Acad Sci U S A. 2010; 107(36):15910-5. PMC: 2936642. DOI: 10.1073/pnas.1002346107. View

19.

Lutzke R, Vink C, Plasterk R . Characterization of the minimal DNA-binding domain of the HIV integrase protein. Nucleic Acids Res. 1994; 22(20):4125-31. PMC: 331899. DOI: 10.1093/nar/22.20.4125. View

20.

Cooper D, Steigbigel R, Gatell J, Rockstroh J, Katlama C, Yeni P . Subgroup and resistance analyses of raltegravir for resistant HIV-1 infection. N Engl J Med. 2008; 359(4):355-65. DOI: 10.1056/NEJMoa0708978. View