Publication Date
2023
Document Type
Dissertation/Thesis
First Advisor
Hagen, Timothy
Degree Name
Ph.D. (Doctor of Philosophy)
Legacy Department
Department of Chemistry and Biochemistry
Abstract
Phosphodiesterase-4 (PDE4) enzyme mainly present in immune cells, epithelial cells, and brain cells that regulate inflammation and epithelial integrity in cells. Inhibition of PDE4 enzyme leads to regulation of various inflammatory mechanisms by elevation of cyclic adenosine monophosposphate (cAMP) levels in the cells. PDE4 enzyme is promising target for treatment of pulmonary, dermatological, and neurological inflammatory diseases. Several PDE4 inhibitor drugs Roflumilast, Apremilast, and Crisaborole were approved and marketed as Dalsirep, Otezla and Eucrisa for the treatment of inflammatory pulmonary diseases, psoriatic arthritis, and atopic dermatitis. However, these drugs have adverse effects such as nausea, emesis, and gastrointestinal effects. Benzothiazole compounds selective for PDE4 isoforms have the potential for reduced side effects including nausea, emesis, etc. Benzothiazole PDE4 inhibitors selective for PDE4 isoforms can lead to new PDE4 inhibitor drugs in the future for treatment of inflammatory diseases. Acetyl CoA synthetases (ACSs) are key component of central carbon metabolism in eukaryotes and prokaryotes. Mammalian cells are not dependent on ACS enzyme, while fungi rely on ACS enzyme for carbon metabolism. Therefore, ACSs have emerged as a potential drug target for anti-fungal drugs. MV019721 and MMV084978 compounds were reported to inhibit the Plasmodium falciparum acetyl-coenzyme A synthetase (PfACS) enzyme. Homology modeling indicated high degree conservation between ACS1 enzymes of P. falciparum and C. neoformans. MMV019721 and MMV084978 analogues were synthesized to determine inhibitory activity against fungal ACS1 enzyme. Infectious diseases are a major cause of morbidity and mortality around the world. New therapeutic strategies must be developed for the prevention and control of infectious diseases. In this study Seven Kenyan medicinal plants Artemisia annua, Ajuga remota, Bridelia micrantha, Cordia africana, Physalis peruviana, Prunus africana and Senna didymobotrya were explored for their potential activity against Schistosoma mansoni worms and Escherichia coli, Pseudomonas aeruginosa, Bacillus cereus, and Mycobacterium smegmatis bacteria. Phytochemical analysis of plant extracts identified various compounds in different extracts of the plants. Isolation of bioactive compounds from the plants can lead to new drugs against infectious bacteria and parasitic worms. Ajuga remota, a member of the Lamiaceae family, mainly distributed throughout Africa used in traditional medicines for rheumatic fevers, malaria, hypertension, diabetes, and gastrointestinal disorders. Ajugarin – I, a neo-clerodane diterpene was isolated from leaves of Ajuga remota. The structure of the isolated Ajugarin – I was elucidated based on extensive Nuclear Magnetic Resonance spectral studies (1D and 2D). The activity of Ajugarin – I against schistosome worm was studied in collaboration with Rush University Medical center.
Recommended Citation
Kondam, Chaitanya, "I. design, Synthesis, and Evaluation of The Human Phoshodiesterase-4 and Fungal acetyl Coa Synthetase Enzyme Inhibitors Ii. evaluation of Biological activity of Kenyan Medicinal Plants" (2023). Graduate Research Theses & Dissertations. 7332.
https://huskiecommons.lib.niu.edu/allgraduate-thesesdissertations/7332
Extent
299 pages
Language
eng
Publisher
Northern Illinois University
Rights Statement
In Copyright
Rights Statement 2
NIU theses are protected by copyright. They may be viewed from Huskie Commons for any purpose, but reproduction or distribution in any format is prohibited without the written permission of the authors.
Media Type
Text
