Synthesis and optimization of antitubercular activities in a series of 4-(aryloxy)phenyl cyclopropyl methanols.
A series of [4-(aryloxy)phenyl]cyclopropyl methanones were synthesized by reaction of different benzyl alcohols with 4-chloro-4'-fluorobutyrophenone in DMF in the presence of NaH/TBAB. The methanones were further reduced to respective methanols. The antitubercular activity of these compounds was evaluated in vitro against Mycobacterium tuberculosis H37Rv. Compounds 19, 21, 35, 36 and 37 have shown minimum inhibitory concentration (MIC) of 3.12 μg/mL, while compounds 14, 25 and 18 have shown MIC of 1.56 μg/mL and 0.78 μg/mL respectively. One of the compounds, cyclopropyl-4-[4-(2-piperidin-1-yl-ethoxy)benzyloxy]phenyl}methanol (36) showed 98% killing of intracellular bacilli in mouse bone marrow derived macrophages and was active against MDR, XDR and rifampicin clinical isolates resistant strains with MIC 12.5 μg/mL. Compound 36 was orally active in vivo in mice against M. tuberculosis H37Rv with an increase in MST by 6 days with 1 log reduction in the bacillary density in lungs as compared to control on 30th day after infection.
Medicinal and Process Chemistry Division, CSIR, Lucknow-226001, India.
Surendra S
SS
Bisht
Namrata
N
Dwivedi
Vinita
V
Chaturvedi
Namrata
N
Anand
Mridul
M
Misra
Rahul
R
Sharma
Brijesh
B
Kumar
Richa
R
Dwivedi
Shyam
S
Singh
Sudhir Kumar
SK
Sinha
Versha
V
Gupta
P R
PR
Mishra
Anil K
AK
Dwivedi
Rama P
RP
Tripathi
D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D003521:Cyclopropanes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D008264:Macrophages / Q000187:drug effects; D000432:Methanol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D051379:Mice; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014709:Vero Cells
D000995:Antitubercular Agents; D003521:Cyclopropanes; D000432:Methanol