Synthesis, characterization & biological activity of Isopropyl Thiazole derivatives of the natural products Distamycin & Proximicin

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عبد الرحمن, امجد عبد الرحمن موسى
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An-Najah National University
Minor groove binders (MGBs) are molecules which bind selectively to the minor groove of DNA. Distamycin and netropsin are naturally occurring MGBs, and are members of the polypyrrole class of compounds. They have potential antiviral, antibacterial, and anticancer properties. However, they also have toxic properties. These biological effects arise from the molecule binding to DNA in regions where there are short runs of A: T base pairs. Much work has been carried out in developing analogues of distamycin and netropsin which have improved their biological activities and reduced their toxicity profile. This project was concerned with developing a novel synthetic pathway of MGBs which allows for more varied substituents at the tail and head position of these molecules and replacing the N-methyl pyrrole with more lipophilic aromatic rings which, to date, has not been fully investigated. Aromatic rings such as benzene, pyridine, morpholine and indole were added to the structure of these compounds, in order to enhance the lipophilicity and membrane permeability to generate biologically active compounds. The tail group is significant as it plays a key role in both DNA binding, and transportation of these compounds to within cells. These structural variations will allow libraries of compounds with small molecular weight to be prepared. In this project, we developed simple and novel routes for the synthesis of potential minor groove binders. The outcome of such a study would be of great importance regarding the development of new analogues of distamycin and netropsin as potential antibacterial and anticancer agents. The synthetic pathway of the compounds started from the preparation of the isopropyl thiazole ring using the Darzen reaction and coupling the epoxide intermediate with thiourea. The second step was reacting the amine terminal of the isopropyl thiazole ring with various acid chlorides to give the second intermediate compounds in the synthetic pathway. After that the intermediate compounds where ether refluxed with an amine directly, or, where hydrolyzed and converted to acyl chlorides to be then reacted with various amines to give the final products. NMR spectroscopy was used to confirm the chemical structures of the investigated compounds, which were tested against different bacterial strains, and showed variable activities among the different compounds with the compound MGB 10 being the most active of the synthesized compounds.