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
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A new series of 4-oxo-4H-pyrido[1,2-a]pyrimidine derivatives containing 1,3,4-oxadiazole and 1,3,4-thiadiazole rings as a part of the metal chelation motif were synthesized and evaluated for their in vitro anti-HIV-1 activity. Most of the tested compounds displayed moderate inhibitory properties against HIV-1 virus (NL4-3) in Hela cell cultures. Compounds 11e and 11b exhibited the highest activity among the synthesized compounds with inhibition rate of 51 and 48 % at concentration of 100 μM, respectively. Molecular docking study using the later crystallographic data available for PFV integrase (IN) showed that the designed compounds bind into the active site of IN such that the keto oxygen atom at position of C-4 and nitrogen atom of thiadiazole or oxadiazole ring moiety chelate the Mg2+ ion. Our results also showed that all tested compounds presented no significant cytotoxicity at concentration of 100 μM. Therefore, these compounds can provide a very good basis for the development of new hits.
Keywords4-Oxo-4H-pyrido[1,2-a]pyrimidines Oxadiazoles Thiadiazoles Anti-HIV-1 activity Molecular modeling
This study was financially supported by Research Deputy of Shahid Beheshti University of Medical sciences as part of Ph.D. thesis of Z. Hajimahdi.
- Kirschberg T, Parrish J (2007) Metal chelators as antiviral agents. Curr Opin Drug Discov Dev 10:460–472Google Scholar
- Scudiero DA, Shoemaker RH, Paull KD, Monks A, Tierney S, Nofziger TH, Currens MJ, Seniff D, Boyd MR (1998) Evaluation of a soluble tetrazolium/formazan assay for cell growth and drug sensitivity in culture using human and other tumor cell lines. Cancer Res 48:4827–4833Google Scholar
- Shimura K, Kodama E, Sakagami Y, Matsuzaki Y, Watanabe W, Yamataka K, Watanabe Y, Ohata Y, Doi S, Sato M, Kano M, Ikeda S, Matsuoka M (2008) Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol 82(2):764–774PubMedCrossRefGoogle Scholar
- Zhuang L, Wai JS, Embrey MW, Fisher TE, Egbertson MS, Payne LS, Guare JP, Vacca JP, Hazuda DJ, Felock PJ, Wolfe AL, Stillmock KA, Witmer MV, Moyer G, Schleif WA, Gabryelski LJ, Leonard YM, Lynch JJ, Michelson SR, Young SD (2003) Design and synthesis of 8-hydroxy-[1,6]naphthyridines as novel inhibitors of HIV-1 integrase in vitro and in infected cells. J Med Chem 46:453–456PubMedCrossRefGoogle Scholar