2,4,5-Trisubstituted thiazole derivatives: A novel and potent class of non-nucleoside inhibitors of wild type and mutant HIV-1 reverse transcriptase

•2,4,5-Trisubstituted thiazole, a novel scaffold as NNRTIs.•30 compounds inhibited HIV-1 replication with IC50 0.046–9.59 μM.•Compounds 8, 9, 21, 23, 24 showed inhibition against WT and seven common mutants.•We studied the SAR and the possible binding mode of this type NNRTIs.•The 3D-QSAR results gave the further direction to the research.

Novel 2,4,5-trisubstituted thiazole derivatives (TSTs) were designed and synthesized as HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). Among the thirty-eight synthesized target compounds, thirty TSTs showed potent inhibition against HIV-1 replication in wild type HIV-1 at submicromolar concentrations (from 0.046 to 9.59 μM). Compounds 21, 23 and 24 were also tested on seven NNRTI-resistant HIV-1 strains, and all exhibited inhibitory effects with fold changes in IC50 ranging from 2.6 to 111, which were better than those of nevirapine (15.6-fold–371-fold). Docking simulations of compound 24 revealed a reasonable mechanism for the binding mode, and three-dimensional quantitative structure activity relationship (3-DQSAR) studies on this novel series of TST further elucidated the structure–activity relationship (SAR). The results suggested the great potential of TSTs as a novel class of NNRTIs with antiviral efficacy and a good resistance profile.

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