Synthesis and Antiviral Evaluation of 6‐(Trifluoromethylbenzyl) and 6‐(Fluorobenzyl) Analogues of HIV Drugs Emivirine and GCA‐186

The present study describes the synthesis and antiviral evaluation of a series of novel 6‐(3‐trifluoromethylbenzyl) and 6‐(fluorobenzyl) analogues of the HIV drugs emivirine and GCA‐186. The objective was to investigate whether the fluoro or trifluoromethyl substituents could lead to an improved antiviral activity against HIV‐1 wild type and mutants resistant to non‐nucleoside RT inhibitors. The biological test results showed that the most of theses compounds showed good activity against wild type HIV‐1. Among them, compound 1‐(ethoxymethyl)‐6‐(3‐fluorobenzyl)‐5‐isopropyluracil (9i) showed the largest inhibitory potency (EC50 = 0.02 μM), resulting equally potent than emivirine against wild type HIV‐1. Furthermore, compound 9i showed marginal better activity against resistant mutants than emivirine. The key steps in the synthesis of the target compounds were either reaction of an appropriate β‐keto ester with thiourea or a cross‐coupling reaction of 6‐chloro‐2,4‐dimethoxypyrimidines with benzylic Grignard reagents.

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