The discovery of novel diarylpyri(mi)dine derivatives with high level activity against a wide variety of HIV-1 strains as well as against HIV-2. Issue 8 (1st May 2018)

• Record Type: Journal Article
• Authors: Lu, Xueyi; Yang, Jiapei; Kang, Dongwei; Gao, Ping; Daelemans, Dirk; De Clercq, Erik; Pannecouque, Christophe; Zhan, Peng; Liu, Xinyong
• Is Part Of: Bioorganic & medicinal chemistry. Volume 26:Issue 8(2018)
• Page Start: 2051
• Page End: 2060
• Publication Date: 2018-05-01
• Subjects: HIV-1 -- HIV-2 -- NNRTIs -- DAPY -- Drug design -- Entrance channel; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2018.03.003
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: By means of structure-based molecular hybridization strategy, a series of novel diarylpyridine and diarylpyrimidine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were identified as potent NNRTIs. Highlights: All diarylpyri(mi)dines exhibited robust activities against wild-type (WT) HIV-1 with EC50 ranging from 1.36 nM to 29 nM. Most compounds displayed significant activity against a wide variety of HIV-1 mutated strains. Unexpectedly, four diarylpyrimidines demonstrate moderate anti-HIV-2 activities. Preliminary SARs and molecular modeling analysis were detailed. Abstract: By means of structure-based molecular hybridization strategy, a series of novel diarylpyri(mi)dine derivatives targeting the entrance channel of HIV-1 reverse transcriptase (RT) were designed, synthesized and evaluated as potent non-nucleoside reverse transcriptase inhibitors (NNRTIs). Encouragingly, all the tested compounds showed good activities against wild-type (WT) HIV-1 (IIIB) with EC50 in the range of 1.36 nM–29 nM, which is much better than those of nevirapine (NVP, EC50 = 125.42 nM) and azidothymidine (AZT, EC50 = 11.36 nM). Remarkably, these compounds also displayed effective activity against the most of the single and double-mutated HIV-1 strains with low EC50 values, which is comparable to the control drugs. Besides, these compounds were also exhibited favorable enzymatic inhibitory activity. Moreover, preliminary structure-activity relationships (SARs) and molecular modeling study were investigated and discussed in detail. Unexpectedly, four diarylpyrimidines yielded moderate anti-HIV-2 activities. To our knowledge, this is rarely reported that diarylpyrimidine-based NNRTIs have potent activity against both HIV-1 and HIV-2 in cell culture.