Design, synthesis and HIV-1 Integrase Inhibitory Activity of Novel Quinoxaline Derivatives

Abstract

HIV-1integrase enzyme with no cellular equivalent in human body is a potential target for development of antiretroviral drug. In course of my research work to design novel HIV-1 integrase computational approach was used. Pharmacophore model was generated using 17 structurally diverse molecules using DISCOtech refined with GASP module of Sybyl. Out of obtained four refined models, model_2 containing four features; two donor sites, one acceptor atom and one hydrophobic region had highest fitness score and best validation results. Hence best model, model_2 was used as a query for virtual screening in NCI database and 6 compounds with Qfit value ≥98 were retrieved. 3D-QSAR was carried on 35, 5-hydroxy-6-oxo-1,6- dihydropyrimidine-4-carboxamide derivatives. Contour map analysis of best CoMFA and CoMSIA model suggested that by substituting hydrophobic, bulky and electronegative group potency of the compound can be increased. The quinoxaline ring which is bio-isostere of pteridine ring retrieved as hit in virtual screening was selected as core moiety. 50 quinoxaline derivatives with different substitution designed on basis of both ligand based drug design approach were mapped on pharmacophore model. 32 quinoxaline derivatives which mapped pharmacophore model with Qfit > 80 were docked into active site of integrase enzyme and in-silico ADMET properties were also predicted. Synthesis of top 7 quinoxaline derivatives was carried out and spectral characterization was carried out using Mass, 1H-NMR and 13C-NMR spectroscopy. Purity of compound was checked using HPLC. Synthesized derivatives were subjected to in-vitro HIV-1 integrase inhibitory activity and cytotoxicity study. None of the compound showed cytotoxicity.