Synthesis and bio-evaluation of alkylaminoaryl phenyl cyclopropyl methanones as antitubercular and antimalarial agents.
A series of 4-alkylaminoaryl phenyl cyclopropyl methanones (6a-6u and 8a-8c) were synthesized from 4-fluorochalcones (3a and 3b) by cyclopropanation of double bond followed by nucleophilic substitution of F with different amines. The compounds were screened for their antitubercular and antimalarial activities against Mycobacterium tuberculosis H37Rv and Plasmodium falciparum 3D7 strains in vitro respectively. Several compounds (6a, 6d-6h, 6p, 6q and 8a-8c) exhibited good in vitro antitubercular activities with MIC values 3.12-12.5μg/mL and preferentially inhibited the growth of P. falciparum in vitro (4a, 4c, 6a-6d, 6f, 6s, 8a and 8c) with IC₅₀ as low as 0.080 and 0.035μg/mL and SI values 4975 and 6948, respectively. Molecular docking studies and in vitro evaluation against FAS-II enzymes using reporter gene assays were carried out to elucidate the mode of action of these molecules. Two compounds 4a and 6g showed significant inhibition at 25μM concentration of the compound.
Central Drug Research Institute Chattar Manzil, Mahatma Gandhi Marg, Lucknow, India.
Arya
A
Ajay
Vandana
V
Singh
Shubhra
S
Singh
Swaroop
S
Pandey
Sarika
S
Gunjan
Divya
D
Dubey
Sudhir Kumar
SK
Sinha
Bhupendra N
BN
Singh
Vinita
V
Chaturvedi
Renu
R
Tripathi
Ravishankar
R
Ramchandran
Rama P
RP
Tripathi
D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D001665:Binding Sites; D047188:Chalcones / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002522:Chlorocebus aethiops; D003198:Computer Simulation; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D010963:Plasmodium falciparum / Q000187:drug effects; D013329:Structure-Activity Relationship; D014709:Vero Cells
C556289:(2-(4-chlorophenyl)cyclopropyl)(4-(3-(dimethylamino)propylamino)phenyl)methanone; C556290:3-(4-chlorophenyl)-1-(4-(3-(dimethylamino)propylamino)phenyl)prop-2-en-1-one; D000962:Antimalarials; D000995:Antitubercular Agents; D047188:Chalcones; D003521:Cyclopropanes