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dc.contributor.advisorNorth, Jeffrey
dc.contributor.authorSethiya, Jigar Paras
dc.date.accessioned2021-07-21T22:53:40Z
dc.date.available2021-07-21T22:53:40Z
dc.date.issued2021-05-24
dc.identifier.urihttp://hdl.handle.net/10504/133561
dc.description.abstractTuberculosis (TB) is a top killer infectious disease worldwide, caused by Mycobacterium tuberculosis (M. tb). Despite several efforts in finding new effective treatment options, TB remains a public threat. Moreover, drug-resistant TB and the HIV pandemic makes treatment options more challenging. The COVID-19 pandemic is predicted to exacerbate the situation. TB treatment consists of multidrug regimens for a lengthy duration of time and elicit various toxicities. Nontuberculous mycobacteria (NTM) are environmental pathogens found in soil, dust, biofilms, and water resources which targets immunocompromised patients or those with underlying structural lung diseases. Current therapy of NTM infections include commonly used clinical antibiotics, which are already resistant to bacteria. Therefore, newer agents which are selective against mycobacteria are required to treat tuberculosis. FadD32 is a fatty-acyl AMP ligase which activates and transfers fatty acids in the process of mycolic acids biosynthesis. FadD32 is a putative drug target as its blockage inhibits the growth of mycobacteria. Inhibition of FadD32 function through coumarin derivatives showed to be effective against drug-susceptible and drug-resistant TB, as well as on slow-growing NTM species. However, this class of agents undergo rapid metabolism in mouse liver microsomes likely leading to short half-lives in vivo. We employed scaffold hopping methodologies to replace the metabolically labile coumarin core with a 2-quinolone core. The 2-quinolone series achieved high antimycobacterial activity, with a lead compound 250 eliciting a MIC value of 0.5 µg/mL against M. tb. Moreover, our lead compound 250 exhibited inhibitory activity against rapid-growing NTM species (M. abscessus MIC = 8 µg/mL) whereas the coumarin class was inactive. Furthermore, compound 250 achieved 27-fold aqueous solubility and 2-fold improved metabolic stability than the lead coumarin derivative. Thus, further pharmacokinetic and biochemical studies on the 2-quinolone class, particularly compound 250, are warranted.en_US
dc.language.isoen_USen_US
dc.publisherCreighton Universityen_US
dc.rightsCopyright is retained by the Author. A non-exclusive distribution right is granted to Creighton University and to ProQuest following the publishing model selected above.en_US
dc.titleDesign and Synthesis of Novel Antimycobacterial FadD32 Inhibitors With Improved Drug Propertiesen_US
dc.typeDissertation
dc.rights.holderJigar Paras Sethiyaen_US
dc.publisher.locationOmaha, Nebraskaen_US
dc.description.noteProQuest Traditional Publishing Optionen_US
dc.contributor.cuauthorSethiya, Jigar Paras
dc.degree.levelMS (Master of Science)en_US
dc.degree.disciplinePharmaceutical Science (graduate program)en_US
dc.degree.nameM.S. in Pharmaceutical Sciencesen_US
dc.degree.grantorGraduate Schoolen_US
dc.degree.committeeNorth, Jeffrey


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