Molecular Design,synthesis And Anti-HIV Activity Of Diarylpyrimidines As HIV-1 Inhibitors

Diarylpyrimidine（DAPY）as the second generation NNRTIs has attracted wide attention of medicinal chemists due to its extremely potent activities against both wild-type（WT）strain and many mutant strains.Based on the strategy of molecular hybridization,diketo acid fragment as a classical phamacophore of integrase inhibitors was introduced to reverse transcriptase inhibitors diarylpyrimidines to design a series of diketo acid-diarylpyrimidine hybrids（DAPY-DKAs）.The docking results verified the rationality of molecular deign.Targets molecules DAPY-DKAs were prepared according to synthetic proedures as follows:XP1a-b were obtained via a nucleophilic substitution reaction of 4 with6a-b using Cs₂CO₃ as base.XP1a-b were subject to a simple hydrolysis to afford the corresponding compounds XP1c-d.The intermediate 4 was synthesized through a three-step reaction from 2-thiouracil as starting material.And intermediates 6a-b were prepared from corresponding hydroxyacetophenone and diethyl oxalate in the presence of NaH.Finally,the structures of all target compounds were confirmed by ¹H NMR,¹³C NMR,and MS.All target molecules were evaluated for activities against wild-type human immunodeficiency virus type 1（WT HIV-1）,HIV-1 mutants,and reverse transcriptase in vitro.The results of anti-HIV-1 activities displayed that all hybrid molecules showed moderate activities against WT HIV-1 strain.Among them,the most potent compound XP1b displayed good activity with an EC₅₀ of 0.14μM.Compound XP1a revealed conspicuous potency against the mutant strain K103N(EC₅₀=10μM),which is superior to nevirapine(EC₅₀>15μM).All hybrid molecules showed moderate activities against HIV-1 RT with IC₅₀ values ranged from 5.9 to 25μM.To sum up,based on the strategy of molecular hybridization,a series of novel DAPYs were designed and synthesized as HIV-1 inhibitors.It provides a reference for future modification of DAPYs.