title: Design, synthesis, and antimycobacterial property of PEG-bis(INH) conjugates.
abstract: Poly(ethylene glycol) derivatives of isoniazid with varying molecular weight of poly(ethylene glycol) were designed as antimycobacterial agents. Poly(ethylene glycol)-diacrylate of three different molecular weights (MW 258, 575, and 700) was conjugated with isoniazid by the Michael addition approach. The poly(ethylene glycol)-bis(isoniazid) conjugates thus obtained were completely characterized by FT-IR, (1)H and (13)C NMR, and ESI-MS spectroscopic techniques. Comparative MTT assay of the poly(ethylene glycol)-bis(isoniazid) conjugates showed much lower cytotoxicity than the neat isoniazid. MIC studies on Mycobaterium tuberculosis H37Rv showed potential antimycobacterial activity than the free isoniazid on a molar basis. The poly(ethylene glycol)-bis(isoniazid) conjugates were successfully radiolabeled with 99m-Technetium with more than 97% efficiency and stability to assess their in vivo fate. The (99m)Tc labeled poly(ethylene glycol)-bis(isoniazid) conjugates showed higher blood retention time in New Zealand rabbits which increased with increasing molecular weight of poly(ethylene glycol). Biodistribution studies in infection-induced murine models (BALB/c mice) showed significant retention of these conjugates at the site of infection for 72 h. The results of this study illustrate the potential utility of the PEGylated isoniazid conjugates as long circulating carriers for improved antitubercular drug therapy.
authors.affiliation: Division of Cyclotron and Radiopharmaceutical Sciences, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organization, Brig. S.K.Mazumdar Marg, Timarpur, Delhi-110054, India.
authors.forename: Dipti
authors.initials: D
authors.lastname: Kakkar
authors.forename: Anjani K
authors.initials: AK
authors.lastname: Tiwari
authors.forename: Krishna
authors.initials: K
authors.lastname: Chuttani
authors.forename: Alka
authors.initials: A
authors.lastname: Khanna
authors.forename: Anupama
authors.initials: A
authors.lastname: Datta
authors.forename: Harpal
authors.initials: H
authors.lastname: Singh
authors.forename: Anil K
authors.initials: AK
authors.lastname: Mishra
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D005260:Female; D006801:Humans; D007538:Isoniazid / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009169:Mycobacterium tuberculosis / Q000187:drug effects*; D011092:Polyethylene Glycols / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D011817:Rabbits; D014376:Tuberculosis / Q000188:drug therapy
chemical_list: D000995:Antitubercular Agents; C437167:poly(ethylene glycol)diacrylate; D011092:Polyethylene Glycols; D007538:Isoniazid