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In our continued efforts to discover more active and less toxic HIV-1 non-nucleoside reverse transcriptase inhibitors, we recently designed a novel series of piperidine-linked pyridine analogues on the basis of diarylpyrimidine derivatives, among which two drugs-etravirine and rilpivirine-are approved for use by the US FDA. The title compounds were evaluated for activity against wild-type and resistant mutant strains of HIV-1 as well as HIV-2 in MT-4 cells. The highly potent compound BD-c1 (EC50 =10 nM, CC50 ≥146 μM, SI≥14 126) displays lower cytotoxicity and higher selectivity than etravirine (EC50 =2.2 nM, CC50 =28 μM, SI=12 884) against wild-type HIV-1. Compound BD-e2 (EC50 =5.1 nM) shows greater antiviral efficacy against wild-type HIV-1 than do the four reference drugs nevirapine, delavirdine, efavirenz, and zidovudine. Many compounds were also found to be active against the frequently observed drug-resistant double mutant (K103N+Y181C) HIV-1 strain. Herein we report the design, synthesis, anti-HIV evaluation, preliminary structure-activity relationships, and molecular simulations of novel piperidine-linked pyridine analogues.
A series of 3,4,5-trisubstituted isothiazoles has been screened against HIV-1 (III B ) and HIV-2 (ROD) at sub-toxic concentrations in acutely infected MT-4 cells. Among the tested compounds, only 3-mercapto-5-phenyl-4-isothiazolecarbonitrile was found to inhibit the replication of HIV-1 (III B ) and HIV-2 (ROD) at 50% effective concentrations (EC 50 ) of 7.8 and 9.7 μg/ml, respectively. The presence of a thioalkyl chain or dialkylamino function in the 3-position caused a loss of anti-HIV activity. New 4-cyano-5-phenylisothiazoles with other substituents in the 3-position have also been synthesized and studied as potential anti-HIV agents. Our results have demonstrated that 5-phenyl-3-(4-cyano-5-phenylisothiazol-3-yl) disulphanyl-4-isothiazolecarbonitrile and S-(4-cyano-5-phenylisothiazol-3-yl)- O-ethyl thiocarbonate are effective against both HIV-1 (III B ) (EC 50 =13.6 and 15.2 μg/ml, respectively) and HIV-2 (ROD) (EC 50 =17.4 and 13.4 μg/ml, respectively).
