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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