Structure-guided design of novel HEPT analogs with enhanced potency and safety: From Isopropyl-HEPTs to Cyclopropyl-HEPTs.

Members of the HEPT class are potential non-nucleoside inhibitors of HIV-1 reverse transcriptase. Our previously disclosed one representative HEPT analog 2 produced potent inhibitory activity against wild-type HIV-1 (EC50 = 63.0 nM), but its high cytotoxicity and low selectivity index still needs to be improved (CC50 = 34.0 µM, SI = 565). In this work, a series of novel cyclopropyl-substituted HEPT analogs were developed by substituting a cyclopropyl ring for the isopropyl group at the C-5 position of 2 with the purpose of improving its potency and safety. Of this series, the most potent compound 9h featuring a 2,5-fluoro substitution on the C-6 benzene ring exerted significantly increased inhibitory activity toward wild-type HIV-1 (EC50 = 0.017 µM), which was 4-fold more active than the lead compound 2. The cytotoxicity of 9h was also reduced with much higher selectivity index (SI > 2328). This compound possessed good pharmacokinetics profiles and potential safety: (1) No obvious in vitro inhibition effect toward CYP enzyme and hERG was observed in 9h; (2) The single-dose acute toxicity test did not induce mice death and obvious pathological damage; (3) Excellent oral bioavailability of 9h (F= 86%) in rats was unveiled. These results provide valuable guidance for further development of HEPT anti-HIV-1 drugs.