Synthesis and in vitro antimycobacterial activity of some pyridine and pyrazinecarboxylic acid isosteres

Persistent Link:
http://hdl.handle.net/10150/284057
Title:
Synthesis and in vitro antimycobacterial activity of some pyridine and pyrazinecarboxylic acid isosteres
Author:
Gezginci, Mikail Hakan
Issue Date:
1999
Publisher:
The University of Arizona.
Rights:
Copyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.
Abstract:
Tuberculosis has been one of the most commonly encountered infectious diseases of humans throughout history. The discovery and introduction of effective treatments in the 1940s resulted in a decline of the incidence of the disease until the 1980s, which marked a sharp turn in this trend with an increase in the number of reported cases in the world. The prevalence of mycobacterial infections in poorer nations and centers of urban decay, and especially in immunologically compromised patients indicates the need for new and better treatments. In this study, to contribute to the worldwide effort to discover more effective medications against tuberculosis, 26 previously unreported compounds were synthesized and tested against Mycobacterium tuberculosis. The synthesized compounds were designed to act as bioisosteres or prodrugs of pyridine and pyrazinecarboxylic acid derivatives and contained acidic or neutral hetero- or carbocyclic ring systems attached to pyridine or pyrazine rings at different positions. The synthesized ring systems included 1,2,4-oxadiazole-5-ones, 1,2,4-thiadiazole-5-ones, 1,2,4-oxadiazole-5-thiones, 1,3,4-oxathiazoline-2-ones and cyclobutene-1,2-diones, which were documented in the literature to act as carboxylic acid isosteres or could act as prodrugs thereof. Pivaloyloxymethyl derivatives of the compounds were also prepared in order to increase their lipophilicity and therefore improve their bioavailability. The synthesized compounds were expected to be biotransformed by esterases or amidases to the active species after penetration of the mycobacterial cell wan. Biological and pharmacokinetic properties of the compounds were compared with the unmodified polar isosteres of pyrazinoic and nicotinic acids. The majority of the tested compounds exhibited activities ranging from 0.5 to 8 times the activity of pyrazinamide, one of the lead compounds that inspired their design.
Type:
text; Dissertation-Reproduction (electronic)
Keywords:
Health Sciences, Pharmacology.; Chemistry, Pharmaceutical.
Degree Name:
Ph.D.
Degree Level:
doctoral
Degree Program:
Graduate College; Pharmaceutical Sciences
Degree Grantor:
University of Arizona
Advisor:
Martin, Arnold R.

Full metadata record

DC FieldValue Language
dc.language.isoen_USen_US
dc.titleSynthesis and in vitro antimycobacterial activity of some pyridine and pyrazinecarboxylic acid isosteresen_US
dc.creatorGezginci, Mikail Hakanen_US
dc.contributor.authorGezginci, Mikail Hakanen_US
dc.date.issued1999en_US
dc.publisherThe University of Arizona.en_US
dc.rightsCopyright © is held by the author. Digital access to this material is made possible by the University Libraries, University of Arizona. Further transmission, reproduction or presentation (such as public display or performance) of protected items is prohibited except with permission of the author.en_US
dc.description.abstractTuberculosis has been one of the most commonly encountered infectious diseases of humans throughout history. The discovery and introduction of effective treatments in the 1940s resulted in a decline of the incidence of the disease until the 1980s, which marked a sharp turn in this trend with an increase in the number of reported cases in the world. The prevalence of mycobacterial infections in poorer nations and centers of urban decay, and especially in immunologically compromised patients indicates the need for new and better treatments. In this study, to contribute to the worldwide effort to discover more effective medications against tuberculosis, 26 previously unreported compounds were synthesized and tested against Mycobacterium tuberculosis. The synthesized compounds were designed to act as bioisosteres or prodrugs of pyridine and pyrazinecarboxylic acid derivatives and contained acidic or neutral hetero- or carbocyclic ring systems attached to pyridine or pyrazine rings at different positions. The synthesized ring systems included 1,2,4-oxadiazole-5-ones, 1,2,4-thiadiazole-5-ones, 1,2,4-oxadiazole-5-thiones, 1,3,4-oxathiazoline-2-ones and cyclobutene-1,2-diones, which were documented in the literature to act as carboxylic acid isosteres or could act as prodrugs thereof. Pivaloyloxymethyl derivatives of the compounds were also prepared in order to increase their lipophilicity and therefore improve their bioavailability. The synthesized compounds were expected to be biotransformed by esterases or amidases to the active species after penetration of the mycobacterial cell wan. Biological and pharmacokinetic properties of the compounds were compared with the unmodified polar isosteres of pyrazinoic and nicotinic acids. The majority of the tested compounds exhibited activities ranging from 0.5 to 8 times the activity of pyrazinamide, one of the lead compounds that inspired their design.en_US
dc.typetexten_US
dc.typeDissertation-Reproduction (electronic)en_US
dc.subjectHealth Sciences, Pharmacology.en_US
dc.subjectChemistry, Pharmaceutical.en_US
thesis.degree.namePh.D.en_US
thesis.degree.leveldoctoralen_US
thesis.degree.disciplineGraduate Collegeen_US
thesis.degree.disciplinePharmaceutical Sciencesen_US
thesis.degree.grantorUniversity of Arizonaen_US
dc.contributor.advisorMartin, Arnold R.en_US
dc.identifier.proquest9960258en_US
dc.identifier.bibrecord.b40274688en_US
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