Organic Synthesis of Novel Compounds for the Inhibition of the SARS-CoV-2 Main Protease

"COVID-19 is a highly contagious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and has resulted in an international pandemic and economic crisis following its emergence in late 2019. The Drugs for Neglected Diseases initiative (DNDi) is an international not-for-profit organization exploring novel therapeutic agents for diseases that possess limited economic incentive for pharmaceutical research, and in early 2020 they initiated the COVID Moonshot project to contribute toward the global efforts of designing an effective antiviral therapeutic for COVID-19. Having collaborated with the DNDi since 2018, Williams College was offered the opportunity to work on the COVID Moonshot project by developing methods for synthesizing and purifying a set of target compounds that were computationally estimated to demonstrate antiviral activity against SARS-CoV-2. This thesis focuses on the synthesis of two groups of compounds from the COVID Moonshot project’s Work Packages A Abstract C. Work Package A target compounds were classified as amidopyrimidines, and their synthesis was achieved through an amide coupling reaction between a pyrimidinamine and a carboxylic acid reagent. We successfully synthesized and purified three target compounds from Work Package A and packaged these molecules for testing as inhibitors against SARS-CoV-2. Work Package C target compounds were synthesized through a two-step process utilizing an aminopyridine, chloroacetyl chloride, and a piperazine compound. We successfully synthesized an intermediate for the Work Package C target and will continue to refine the methods for purifying this intermediate so that the target molecule can be produced. The work of this thesis has contributed to the DNDi’s efforts in providing a treatment for COVID-19 for communities around the world."

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