Research Of Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors

Diarylpyrimidine analogues (DAPYs), one of the representative classes of non-nucleoside reverse transcriptase inhibitors (NNRTIs) against HIV-1, have been the focus of developing new anti-retroviral drugs for their high efficacy, low cytotoxicity, especially, for their effective against clinical mutant strains.The advances on DAPY analogues and their SAR were reviewed in chapter 1.In chapter 2, based on the analysis of DAPYs/HIV-1 RT complex, along with the summarization of the SAR of DAPY analogues, a series of Naph-DAPY analogues (DSM01-DSM34) were designed, synthesized and evaluated for their cytotoxicity and anti-HIV activity in MT-4 cells. Among the newly synthesized congeners, compound DSM23 was proved to be the most active inhibitors against HIV (EC50 (HIV-1ⅢB) =2.35nM, EC50 (RES056)=6.57μM, EC50 (HIV-2)=15.94μM).In chapter 3, according to the molecular docking analysis of DAPYs/RT complexes, a new series of C (=NOH)-DAPYs (DSM35-DSM53) were synthesized and evaluated for their cytotoxicity and anti-HIV activity in MT-4 cells. Among the newly synthesized congeners, compound DSM48 was proved to be the most active inhibitors against HIV (EC50 (HIV-1ⅢB)=0.025μM, EC50 (RES056)=8.72μM, EC50 (HIV-2)=8.31μM).The 3D-QSAR (CoMFA and CoMSIA) models of newly synthesized DAPY analogues were established in chapter 4. Preliminary SAR of these compounds was explored considering steric, electrostatic, hydrophobic and H-bond donor fields.