title: Novel phthalazinyl derivatives: synthesis, antimycobacterial activities, and inhibition of Mycobacterium tuberculosis isocitrate lyase enzyme.
abstract: Novel 2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-3,4-dihydro-1-phthalazinyl]acetic acid hydrazones were synthesized from phthalic anhydride by a six step synthesis and evaluated for in vitro, in vivo activities against eight mycobacterial species and Mycobacterium tuberculosis (MTB) isocitrate lyase (ICL) enzyme inhibition studies. Among twenty six compounds N'1-[(4-nitrophenyl)methylene]-2-[3-(4-bromo-2-fluorobenzyl)-4-oxo-1,2,3,4-tetrahydro-1-phthalazinyl]ethanohydrazide (7j) was found to be the most active compound in-vitro with MIC's of 0.18 and <0.09 microM against log-phase cultures of MTB and multi-drug resistant MTB respectively. Compound 7j inhibited all the eight mycobacterial species with MIC ranging from <0.09-12.25 microM and was not toxic to Vero cell lines till 122.5 microM. Seven compounds were tested against starved culture of MTB and they inhibited with MIC's ranging from 2.88-8.91 microM. Some compounds showed 45-61% inhibition against MTB ICL enzyme at 10 microM. In the in vivo animal model 7j decreased the bacterial load in lung and spleen tissues with 1.87 and 3.03-log10 protections respectively at 25 mg/kg body weight dose.
authors.affiliation: Medicinal Chemistry & Antimycobacterial Research Laboratory, Pharmacy Group, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad-500 078, Andhra Pradesh, India. drdsriram@yahoo.com
authors.forename: D
authors.initials: D
authors.lastname: Sriram
authors.forename: P
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: P
authors.initials: P
authors.lastname: Senthilkumar
authors.forename: S
authors.initials: S
authors.lastname: Dewakar
authors.forename: N
authors.initials: N
authors.lastname: Rohit
authors.forename: B
authors.initials: B
authors.lastname: Debjani
authors.forename: Pritesh
authors.initials: P
authors.lastname: Bhat
authors.forename: B
authors.initials: B
authors.lastname: Veugopal
authors.forename: V V S
authors.initials: VV
authors.lastname: Pavan
authors.forename: H M
authors.initials: HM
authors.lastname: Thimmappa
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D005260:Female; D006801:Humans; D007522:Isocitrate Lyase / Q000037:antagonists & inhibitors*; D051379:Mice; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D010793:Phthalazines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D010793:Phthalazines; D007522:Isocitrate Lyase