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.

• Keywords
• Diarylpyrimidine, etravirine, human immunodeficiency virus, non-nucleoside reverse transcriptase inhibitor, rilpivirine,
• MeSH
• Cell Line MeSH
• HIV Reverse Transcriptase antagonists & inhibitors   MeSH
• HIV-1 drug effects   enzymology   MeSH
• Reverse Transcriptase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Crystallography, X-Ray MeSH
• Anti-HIV Agents chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Carbon-13 Magnetic Resonance Spectroscopy MeSH
• Microbial Sensitivity Tests MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Proton Magnetic Resonance Spectroscopy MeSH
• Pyrimidines chemical synthesis   chemistry   pharmacology   MeSH
• Drug Development MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• HIV Reverse Transcriptase MeSH
• Reverse Transcriptase Inhibitors MeSH
• Anti-HIV Agents MeSH
• Pyrimidines MeSH
• reverse transcriptase, Human immunodeficiency virus 1 MeSH Browser