Structural Optimization And SAR Study Of Diarylpyrimidines As HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors

The human immunodeficiency virus type 1 (HIV-1) is the main cause of the acquired immune deficiency syndrome (AIDS). Nonnucleoside reverse transcriptase inhibitors (NNRTIs), which target HIV-1 reverse transcriptase (HIV-1 RT), have become a research hotspot in the field of anti-HIV drugs due to their high potency and low cytotoxicity. Among structurally diverse NNRTIs, diarylpyrimidines (DAPYs) have attracted more attention. Nowadays, five NNRTIs have been approved by the United States Food and Drug Administration (USFDA) for clinical use as anti-HIV drugs, among which Etravirine and Rilpivirine belong to DAPYs.In our previous study, we have made considerable modifications on the linker between the left wing and the pyrimidine ring of DAPYs and obtained lots of new NNRTIs with strong potency against both HIV-1 wild-type and mutant strains. On thebasis of SAR information of these DAPYs, three new types of DAPY analogues were designed with the aid of computer-aided drug design (CADD). (1) DAPY analogues FDUla-r featuring a hydrophobic group at CH(OH) linker between the left wing and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. Most of the target compounds displayed moderate antiviral activity with EC50 values ranging from 7.21 to 0.067 μM. Among them, compound FDUld showed the most potent anti-HIV-1 activity (EC50=0.067 μM, SI=592), which was 12-fold and 1.5-fold more active than delavirdine and nevirapine, respevtively. However, all the synthesized compounds showed no inhibitory activities against the double mutant strain K103N/Y181C. (2) DAPY analogues FDU2a-s characterized by a halogen atom at CH2 linker between the left wing and the central pyrimidine were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. All the target compounds exhibited good antiviral activity with EC50 values ranging from 7.88 to 0.005 μM. The most active compounds FDU2f and FDU2g displayed anti-HIV activity with EC50 values of 0.005 μM and 0.009 μM, along with SI of 5162 and 3106, respectively, which were more active than delavirdine, nevirapine and lamivudine, and as potent as AZT and efavirenz. Specially, compound FDU2g also showed high activity against the double mutant strain K103N/Y181C with EC50 value of 8.2 μM, which deserves the further investigation. (3) DAPY analogues FDU3a-w featuring a semicarbazone group at CH2 linker were synthesized and evaluated for their anti-HIV activity in MT-4 cell cultures. Most of them lacked inhibitory activities against both HIV-1 wild type and double mutant strain K103N/Y181C. Interestingly, compound FDU3k had low nanomolar EC50 value of 0.002 μM and SI of 800, which was as potent as etravirine. FDU3k dispayed strong activiry against HIV-RT(WT) enzyme with IC50 values of 0.030 μM.Finally, the 3D-QSAR (CoMFA and CoMSIA) models of newly synthesized FDU2a-s were established. Based on these models, the further SAR of the title molecules was explored. The conclusions summarized from these results will provide useful information for design of more potent DAPYs as NNRTIs.