Synthesis and anti-tubercular activity of novel alkyl substituted riminophenazine derivatives.
A series of novel riminophenazine derivatives bearing an alkyl substituent attached to N-5 and imino nitrogen at C-3 position of the phenazine ring were obtained through rational drug design, aiming to maintain high anti-tubercular activity, lower toxicity and reduce lipophilicity. All target compounds were prepared by utilizing simple and flexible synthetic route and evaluated against Mycobacterium tuberculosis H37Rv and screened for mammalian cytotoxicity. The results demonstrated that compounds with a cyclopropyl substituent at N-5 position were more active than the reference compound clofazimine. In particular, 2-(4-chloroanilino)-5-cyclopropyl-3-(4-methoxycyclohexyl) imino-3, 5-dihydrophenazine (25) was found to be the most potent compound with low cytotoxicity and lipophilicity. This compound could serve as a valuable lead molecule for further optimization.
Beijing Key Laboratory of Active Substances Discovery and Druggability Evaluation, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
Yu-Li
YL
Li
Chun-Lin
CL
Zhang
Dong-Feng
DF
Zhang
Yu
Y
Lu
Bin
B
Wang
Mei-Qin
MQ
Zheng
Chun
C
Li
Da-Li
DL
Yin
Hai-Hong
HH
Huang
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D002522:Chlorocebus aethiops; D015195:Drug Design; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D010619:Phenazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D014709:Vero Cells
C583583:2-(4-chloroanilino)-5-cyclopropyl-3-(4-methoxycyclohexyl)imino-3,5-dihydrophenazine; D000995:Antitubercular Agents; D010619:Phenazines