Research Of Nonnucleoside HIV-1 Reverse Transcriptase Inhibitors â… : Structure Optimizations And SAR Research Of CH₂-DAPY Derivatives â…¡: Molecular Design, Synthesis And SAR Research Of BP Analogues

It is an efficient method to develop highly potent anti-HIV agents by disrupting the function of HIV-1 reverse transcriptase (RT), which plays a unique role in the HIV-1 life cycle. Up to now,18 reverse transcriptase inhibitors have been approved for the clinical treatment of HIV infection among the 34 currently FDA-approved anti-HIV drugs.Considerable efforts on the structure modifications of diarylpyrimidine analogues (DAPYs) as novel non-nucleoside reverse transcriptase inhibitors (NNRTIs) have been made by us. To explore more active DAPYs, a hydrazine group was designed to introduce to the CH2 linker of CH2-DAPY with the aim to improve the hydrogen-bonding interactions with RT using SurFlex-Dock protocol, and a series of aryl 2-[(4-cyanophenyl)amino]-4-pyrimidinyl ketone hydrazone derivatives MXDla-1t (Hyd-CH2-DAPYs) were synthesized and evaluated the anti-HIV activity. In terms of the biological activity, the newly synthesized Hyd-CH2-DAPYs exhibited 5-30 folder higher activity than the Oxi-CH2-DAPYs against the chosen HIV strains (HIV-1 IIIB, RES056 and HIV-2 ROD). Most of this class of compounds displayed excellent activity against HIV-1ⅢB, with EC50 in the range of 1.7-13.2 nM. Among them, analogue MXD1k was the best congener and displayed the most potent anti-HIV-1 activity (EC50=1.7 nM). Notably, compound MXDld (EC50=2.4 nM, SI =18461) showed the broad-spectrum inhibitory activity, with EC50 values of 2.4 nM against wild-type HIV-1ⅢB,5.3μM against HIV-1 double mutated strains RES056, and 5.5μM against HIV-2 ROD strain. Furthermore, the activity of compound MXDld and MXDlk against HIV-1 RT(WT), CCR5-tropic HIV virus and CXCR4-tropic HIV virus indicated that the target of Hyd-CH2-DAPYs was wild-type reverse transcriptase onlyBenzophenone derivatives (BPs), another type of typical NNRTIs, are very effective to inhibit both wild-type and clinically relevant NNRTI-resistant mutant HIV-1 strains. Led by GW678248, which has been progressed to phaseⅡclinical studies, a series of 1-naphthyl-substituted (B-ring) benzophenone derivatives MXD2a-2y were designed and synthesized in a bid to improve theπ-πinteractions with RT, and also, a series of N-phenylarylformamide derivatives MXD3a-3v and (±)-benzhydrol derivatives MXD4a-4t were designed to enhance the adaptation with RT by improving the flexibility of BPs. The anti-HIV activity of these target molecules were evaluated and indicated that most of N-phenylarylformamide derivatives were highly potent against HIV-1ⅢB with EC50 values ranging from 0.3 nM to 5.1 nM and selectivity index values ranging from 10616 to 271000. Nearly as potent as GW678248, compound MXD3g (EC50=0.30 nM, SI=184578), MXD31 (EC50=0.37 nM, SI=212819), MXD3m (EC50=0.32 nM, SI=260617) and MXD3r (EC50=0.27 nM, SI=271000) showed the highest activity against this type virus. Moreover, all of them were also active to inhibit the double mutant strain A17 with EC50 values of 0.29μM,0.14μM,0.10μM and 0.27μM, respectively. In particular, compound MXD3m, which displayed the broad-spectrum anti-HIV activity, was also effective to inhibit the HIV-2 ROD replication within 4.37 micromolar concentration. In the case of 1-naphthalene-substituted (B-ring) benzophenones, several analogues displayed strong capaticy to inhibit HIV-1ⅢB strain, and MXD2i (EC50=4.8 nM) were the highest inhibitor. For the series of (±)-benzhydrol derivatives, most of them demonstrated micromolar activity against both wild-type HIV-1ⅢB and the double mutant HIV-1 strain. Apparently, (±)-benzhydrol derivatives were less potent than lead compound GW678248 (nanomolar level activity), indicating that the keto group between the A and B rings of BPs was essential to maintain their strong capacity to inhibit all types of HIV-1 virus. Moreover, compound MXD2a, MXD2i, MXD3m and MXD3u displayed strong activity against HIV-RT(WT) enzyme with IC50 values of 202.3 nM,2.03 nM, 1.14 nM and 2.05 nM, respectively.Finally, the 3D-QSAR (CoMFA and CoMSIA) models of newly synthesized DAPYs and BPs were established, respectively. Based on these models, the further SARs of the title molecules were explored and will provide the basic theory for designing more potent NNRTIs.