title: Tetrahydro-2H-1,3,5-thiadiazine-5-(4-pyridylcarboxamide)-2-thione derivatives as prodrugs for isoniazid; synthesis, investigations and in vitro antituberculous activity.
abstract: 3-Substituted-5-(4-pyridylcarboxamido)tetrahydro-2H-1,3,5-thiad iazine-2- thione derivatives 5a-e were synthesized as prodrugs for isoniazid (INH) to overcome the resistance developed with its therapeutic use. These prodrugs revealed higher lipophilicity compared with INH. Their degradation kinetics were studied in vitro using aqueous buffer solutions of pH values 1.2 and 7.4 was well as biological media of human plasma and rat liver homogenate at 37 degrees C. They were more stable toward enzymatic degradation in biological than in chemical media. Release of INH from these derivatives was detected as a result of both chemical and enzymatic hydrolysis by HPLC. The antimycobacterial activity of the synthesized compounds and INH was tested in vitro against human type of Mycobacterium tuberculosis. They exhibited a greater antitubercular activity than the parent drug. This result is considered as an indicator for an improved permeation of the synthesized prodrugs through mycobacterial cell membranes relative to INH.
authors.affiliation: Department of Pharmaceutical Medicinal Chemistry, Faculty of Pharmacy, Assiut University, Egypt. Fadl@Aun.Eun.Eg
authors.forename: T
authors.initials: T
authors.lastname: Aboul-Fadl
authors.forename: K
authors.initials: K
authors.lastname: Hassanin
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007538:Isoniazid / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D007700:Kinetics; D008099:Liver / Q000378:metabolism; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000302:isolation & purification; D011355:Prodrugs / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D013829:Thiadiazines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013871:Thiones / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D000995:Antitubercular Agents; D011355:Prodrugs; D013829:Thiadiazines; D013871:Thiones; D007538:Isoniazid