From human immunodeficiency virus non-nucleoside reverse transcriptase inhibitors to potent and selective antitrypanosomal compounds

• Published in: Bioorganic & medicinal chemistry 2014-10, Vol.22 (19), p.5241-5248
• Main Authors: Venkatraj, Muthusamy, Ariën, Kevin K., Heeres, Jan, Joossens, Jurgen, Dirié, Bertrand, Lyssens, Sophie, Michiels, Johan, Cos, Paul, Lewi, Paul J., Vanham, Guido, Maes, Louis, Van der Veken, Pieter, Augustyns, Koen
• Format: Article
• Language: English
• Subjects: African trypanosomiasis; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antitrypanosomal activity; Cell Line; Cell Survival - drug effects; Dose-Response Relationship, Drug; HIV Reverse Transcriptase - antagonists & inhibitors; HIV Reverse Transcriptase - metabolism; HIV-1 - drug effects; HIV-1 - enzymology; Humans; Microbial Sensitivity Tests; Molecular Structure; NNRTIs; Parasitic Sensitivity Tests; Reverse Transcriptase Inhibitors - chemical synthesis; Reverse Transcriptase Inhibitors - chemistry; Reverse Transcriptase Inhibitors - pharmacology; Structure-Activity Relationship; Triazines; Trypanocidal Agents - chemical synthesis; Trypanocidal Agents - chemistry; Trypanocidal Agents - pharmacology; Trypanosoma brucei; Trypanosoma brucei brucei - drug effects; Trypanosoma brucei rhodesiense - drug effects
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.08.005

The presence of a structural recognition motif for the nucleoside P2 transporter in a library of pyrimidine and triazine non-nucleoside HIV-1 reverse transcriptase inhibitors, prompted for the evaluation of antitrypanosomal activity. It was demonstrated that the structure–activity relationship for anti-HIV and antitrypanosomal activity was different. Optimization in the diaryl triazine series led to 6-(mesityloxy)-N2-phenyl-1,3,5-triazine-2,4-diamine (69), a compound with potent in vitro and moderate in vivo antitrypanosomal activity.