Design, synthesis, and antiviral evaluation of novel hydrazone-substituted thiophene[3,2-d]pyrimidine derivatives as potent human immunodeficiency virus-1 inhibitors.

In the previous studies of our laboratory, the thiophene[3,2-d]pyrimidine was identified as a promising scaffold for seeking highly potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). In this study, we designed, synthesized, and biologically evaluated a series of thiophene[3,2-d]pyrimidine derivatives with changed linker between the thiophenepyrimidine core and the right wing. Some of the synthesized compounds exhibited excellent HIV-1 inhibitory potency with low (double-digit) nanomolar 50% effective concentration (EC50 ) values. Among them, compound 13a exhibited the most potent anti-HIV-1 activity (EC50  = 21.2 nM), which was 10-fold greater than that of NVP (EC50  = 281 nM). Moreover, 13a showed much lower cytotoxicity (CC50  = 183 μM) and higher selection index (SI = 8,632) than NVP, ETV, and AZT. Besides, some physicochemical properties and water solubility were calculated or measured. The preliminary structure-activity relationships and molecular simulation studies of these compounds were also discussed comprehensively to provide valuable direction for further design and optimization.