Synthesis and anti-human immunodeficiency virus activity of substituted (o,o-difluorophenyl)-linked-pyrimidines as potent non‐nucleoside reverse transcriptase inhibitors

Abstract

With the worldwide number of human immunodeficiency virus positive patients stagnant and the increasing emergence of viral strains resistant to current treatment, the development of novel anti-human immunodeficiency virus drug candidates is a perpetual quest of medicinal chemists. Herein, we report a novel group of diarylpyrimidines, non-nucleoside reverse transcriptase inhibitors, which represents an important class of current anti-human immunodeficiency virus therapy. Series of diarylpyrimidines containing o,o-difluorophenyl (A-arm), 4-cyanophenylamino (B-arm), and a small substituent (e.g. NH2, OMe) at positions 2, 4, and 6 of the pyrimidine ring were prepared. The A-arm was modified in the para position (F or OMe) and linked to the central pyrimidine core with a variable spacer (CO, O, NH). Antiviral activities of 20 compounds were measured against wild type human immunodeficiency virus-1 and mutant reverse transcriptase strains (K103N, Y181C) using a cytoprotection assay. To the most promising structural motives belong the o,o-difluoro-p-methoxy A-arm in position 4, and the amino group in position 6 of pyrimidine. Single digit nanomolar activities with no significant toxicity (CC50 > 17,000 nM) were found for compounds 35 (EC50 = 2 nM), 37 (EC50 = 3 nM), and 13 (EC50 = 4 nM) having O, NH, and CO linkers, respectively.

Pharmacological Potential of Pyrmidine Derivatives: A Review With Emphasis on Antiviral Effects and Virtual Screening Against Sars‐Cov‐2 Molecular Targets

“…In the study reported by Cechová et al ., a new group of diarylpyrimidine reverse transcriptase inhibitors was synthesized [27] . The 20 compounds in the series were tested for cytoprotection against reverse transcriptase mutant strains (K103N, Y181C) and wild‐type Human Immunodeficiency Virus‐1.…”

“…synthesized. [27] The 20 compounds in the series were tested for cytoprotection against reverse transcriptase mutant strains (K103N, Y181C) and wild-type Human Immunodeficiency Virus-1. Among the compounds tested, the ones that showed the most promise were compounds 9, with EC 50 = 2 nM, 10 with EC 50 = 3 nM and 11 with EC 50 = 4 nM (Figure 6).…”