Synthesis and antimycobacterial evaluation of novel Phthalazin-4-ylacetamides against log- and starved phase cultures.
Twenty four novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid amides were synthesized from phthalic anhydride and were subjected to in vitro and in vivo evaluation against log- and starved phase of mycobacterial species and Mycobacterium tuberculosis isocitrate lyase enzyme inhibition studies. Among the compounds screened, 2-(2-(4-bromo-2-fluorobenzyl)-1,2-dihydro-1-oxophthalazin-4-yl)-N-(2,6-dimethylphenyl)acetamide (5j) inhibited all eight mycobacterial species with MIC's ranging from 0.08 to 5.05 microm and was non-toxic to Vero cells till 126.43 microm. Four compounds were tested against starved culture of Mycobacterium tuberculosis and they inhibited with MIC's ranging from 3.78 to 23.2 microm. Some compounds showed 40-66% inhibition against Mycobacterium tuberculosis isocitrate lyase enzyme at 10 microm. The docking studies also confirmed the binding potential of the compounds at the isocitrate lyase active site. In the in vivo animal model, 5j reduced the mycobacterial load in lung and spleen tissues with 1.38 and 2.9-log10 protections, respectively, at 25 mg/kg body weight dose.
Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science - Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad - 500 078, Andhra Pradesh, India. dsriram@bits-pilani.ac.in
Dharmarajan
D
Sriram
Perumal
P
Yogeeswari
Palaniappan
P
Senthilkumar
Dewakar
D
Sangaraju
Rohit
R
Nelli
Debjani
D
Banerjee
Pritesh
P
Bhat
Thimmappa H
TH
Manjashetty
D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000633:toxicity; D001665:Binding Sites; D020134:Catalytic Domain; D003198:Computer Simulation; D007522:Isocitrate Lyase / Q000737:chemistry; D008826:Microbial Sensitivity Tests; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
C550216:2-(2-(4-bromo-2-fluorobenzyl)-1,2-dihydro-1-oxophthalazin-4-yl)-N-(2,6-dimethylphenyl)acetamide; D000081:Acetamides; D000995:Antitubercular Agents; D010793:Phthalazines; D007522:Isocitrate Lyase