title: Synthesis of highly potent novel anti-tubercular isoniazid analogues with preliminary pharmacokinetic evaluation.
abstract: Thirty two novel isoniazid analogues were prepared by one-pot three component condensations of isoniazid (INH), 3-mercaptopropionic acid and various aryl/heteroaryl aldehydes. The synthesized compounds were evaluated for their anti-TB activity against Mycobacterium tuberculosis H37Rv (MTB) and cytotoxicity. Among the compounds, compound N-(2-(4-(benzyloxy) phenyl)-4-oxo-1,3-thiazinan-3-yl) isonicotinamide (17) inhibited MTB with MIC of 0.12 μM and was three times more potent than INH. The main pharmacokinetic parameters after intravenous administration (10 mg/kg body weight) in male Wistar rats viz. t(½), K(el), mean plasma clearance and mean volume of distribution were found to be 1.14±0.20 h, 0.62±0.10 h(-1), 22.48±0.16 mL/kg/min and 1.99±0.49 L, respectively. The systemic absorption was slow after oral administration (50 mg/kg body weight). The peak plasma concentration was found to be 1.31±0.06 μg/mL attained in 3 h. The bioavailability was found to be 16.7%.
authors.affiliation: Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Hyderabad, India.
authors.forename: Addepalli Venkata
authors.initials: AV
authors.lastname: Ramani
authors.forename: Arumalla
authors.initials: A
authors.lastname: Monika
authors.forename: Vadlamani Lakshmi
authors.initials: VL
authors.lastname: Indira
authors.forename: Gopisetti
authors.initials: G
authors.lastname: Karyavardhi
authors.forename: Jangala
authors.initials: J
authors.lastname: Venkatesh
authors.forename: Variam Ullas
authors.initials: VU
authors.lastname: Jeankumar
authors.forename: Thimmappa H
authors.initials: TH
authors.lastname: Manjashetty
authors.forename: Perumal
authors.initials: P
authors.lastname: Yogeeswari
authors.forename: Dharmarajan
authors.initials: D
authors.lastname: Sriram
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D007275:Injections, Intravenous; D007538:Isoniazid / Q000138:chemical synthesis* / Q000493:pharmacokinetics* / Q000494:pharmacology; D008297:Male; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
chemical_list: D000995:Antitubercular Agents; D007538:Isoniazid