Synthesis, antitubercular activity and pharmacokinetic studies of some Schiff bases derived from 1-alkylisatin and isonicotinic acid hydrazide (INH).
N'-(1-alkyl-2,3-dihydro-2-oxo-1H-3-indolyliden)-4-pyridinecarboxylic acid hydrazide derivatives, 3(a-g), were synthesized in a trial to overcome the resistance developed with the therapeutic uses of isoniazid (INH). The lipophilicity of the synthesized derivatives supersedes that of the INH as expressed by Clog p values. The synthesized compounds and INH were tested against bovin, human sensitive and human resist strains of Mycobacterium tuberculosis. Compounds 3a, 3d, 3f and 3g with 1-unsubstituted, 1-propyl, 1-propynyl and 1-benzyl groups respectively exhibited equipotent growth inhibitory activity (MIC 10 micromol) against the tested strains as compared with INH however the later has no activity against human resist strain. Pharmacokinetic study revealed that the rate and extent of absorption of the tested derivatives (3d and 3f) significantly higher than that of INH (p < 0.05). The relative bioavailabilities (F(R)%) were 183.15 and 443.25 for 3f and 3d respectively as compared to INH. These results preliminary indicate the possible use of the prepared derivatives for treatment of tuberculosis infections in order to overcome the resistance developed with INH.
Aboul-Fadl
Tarek
T
Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt. Fadl@acc.aun.edu.eg
Mohammed
Faragany Abdel-Hamid
FA
Hassan
Ehsan Abdel-Saboor
EA
D000284:Administration, Oral; D000818:Animals; D000995:Antitubercular Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D004353:Drug Evaluation, Preclinical / Q000379:methods; D007510:Isatin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics*; D007538:Isoniazid / Q000008:administration & dosage / Q000737:chemistry* / Q000493:pharmacokinetics*; D009169:Mycobacterium tuberculosis / Q000187:drug effects; D011817:Rabbits; D012545:Schiff Bases / Q000737:chemistry*
D000995:Antitubercular Agents; D012545:Schiff Bases; D007510:Isatin; D007538:Isoniazid