Synthesis And Evaluation Of Piperazine-Carboxamide Derivatives As Potential Antimalarial /Antimycrobialagents

ABSTRACT Malaria and tuberculosis continue to be endemic in Africa and several other regions across the globe. Malaria is caused by a parasite transmitted by the female anopheles’ mosquito. Plasmodium falciparum is responsible for human malaria in most part of Africa and Plasmodium vivax causes malaria in Asia. Tuberculosis on the other hand is caused by Mycobacterium tuberculosis which is propelled when an infected person coughs, sneezes or even talks. Together, these two diseases are responsible for high mortality in the global population including infants. The current mainstay of malaria chemotherapy are the Artemisinin-based combination therapies (ACTs) while tuberculosis is treated with four main drugs known as the frontline drugs including Isoniazid, rifampicin, ethambutol and pyrazinamide. But the emergence of resistance, partly as a result of patient non-compliance, towards the frontline drugs by all pathogens is rendering the fight more challenging. There are no clinically approved vaccines available for the immunization of both disease and no new drug has been introduced to combat tuberculosis for over 50 years now. Carboxamide and urea compounds are emerging as potential drug candidates and were identified to possess antiproliferative, antimalarial and antitubercular activities. This project focused on the synthesis of aryl carboxamides incorporating urea motif as well as analogues devoid of the urea functionality to establish how critical the urea motif is to observed biological activity based MMV676444. Overall, 26 urea and 9 non-urea derivatives were synthesized. Preliminary antimalarial testing of the compounds showed that six (6) possess antimalarial activity in the submicromolar to micromolar ranges. The most active compound was 102 with in vitro antimalarial activity of 0.574 μM against the 3D7 strain of the malaria parasite. It was generally observed that the compounds containing the urea moiety were more potent than the non-urea compounds. The xviii compounds have also been submitted for anti-tubercular testing, but results were not available at time of compiling the thesis