The Study Of HIV-1 Inhibitors

Diarylpyrimidine derivatives (DAPYs), a novel class of non-nucleoside reverse transcriptase inhibitors (NNRTIs), have been attracted considerable attention due to their excellent potency against wild-type and mutant strains of HIV-1 reverse transcriptase (HIV-1 RT) relative to other NNRTIs. Etravirine (TMC125) has been approved by the FDA for treatment of patients infected with HIV-1 variants resistant to other antiretroviral drugs, and the second generation DAPY compound TMC278 (Rilpivirine) is currently in phase III clinical tials.According to 2D-QSAR studied results and docking model of DAPY,75 newly naphthoxy (or 8-quinolinoxy) substituted DAPY, characterized by different substitution patterns on the pyrimidine and naphthalene ring, were designed and synthesized in a straightforward fashion by means of parallel synthesis in the first part. The antiviral and cytotoxicity evaluation indicated that most of the compounds displayed strong activity against wild-type HIV-1. Eighteen compounds displayed activity against HIV-1 wild-type lower than 10 nm, and the activity of nine compounds is higher than the second generation NNRTI efavirenz:8bf(0.003μM), 8bg(0.002μM),8bj(0.003μM),8bh(0.004μM),8bk(0.002μM),8bl(0.001μM), 8bn(0.002μM),8bo(0.002μM) and 8bv(0.003μM). The most active compound 8bk and 8bl with a cyano group at the position 6 on the naphthalene ring exhibited activity against HIV-1 wild-type at an EC50 of 1.6 nM and 1 nM, a selectivity index for the compound 8bk against wild-type is greater than 180 000 (the highest SI value among DAPY analogues). In order to investigate the anti drug resistant potency of these compounds, the activities against the double mutant strains 103N+181C were tested.5 compounds (8bk,8bn,8bp,8bq and 8bw) displayed activity against HIV-1 wild-type higher than efavirenz (EC50=0.41μM), the most active compounds 8bp and 8bq are selected and named as "FDU-lr" and "FDU-1t" for development as the candidate anti-HIV drugs.On the basis of the test activities of 75 newly DAPY derivatives, the 3D-QSAR (CoMFA and CoMSIA) models were established. Based on the 3D QSAR models, the further SAR of these newly synthesized compounds were explored in the aspects of steric, electrostatic, hydrophobic, H-bond donor and acceptor fields. The conclusions summarized from these results will provide useful information for design new DAPYs as potent HIV-1 inhibitors.In the second part, we designed and synthesized the dual inhibitors based on the integrase (IN) inhibitor raltegravir and the non-nucleoside RT inhibitors DABO (dihydroalkoxybenzyloxo-pyrimidines) according to the concept of designed multifunctional ligands (DML). Introduction of the hydroxy group at position C-5 on the pyrimidine ring of DABO compounds allows the incorporation of a second pharmacophore to generate acivity against IN. However, these dual inhibitors exhibited low activity against HIV-1 RT, and displayed no activity against HIV-1 wild type virus in MT-4 cells.