A comprehensive review of synthetic strategies and SAR studies for the discovery of PfDHODH inhibitors as antimalarial agents. Part 2: Non-DSM compounds.

Malaria remains a severe global health concern, with 249 million cases reported in 2022, according to the World Health Organization (WHO) [1]. PfDHODH is an essential enzyme in malaria parasites that helps to synthesize certain building blocks for their growth and development. It has been confirmed that targeting Plasmodium falciparum dihydroorotate dehydrogenase (PfDHODH) enzyme could lead to new and effective antimalarial drugs. Inhibitors of PfDHODH have shown potential for slowing down parasite growth during both the blood and liver stages. Over the last two decades, many species selective PfDHODH inhibitors have been designed, including DSM compounds and other non-DSM compounds. In the first chapter [2] of this review, we have reviewed all synthetic schemes and structure-activity relationship (SAR) studies of DSM compounds. In this second chapter, we have compiled all the other non-DSM PfDHODH inhibitors based on dihydrothiophenones, thiazoles, hydroxyazoles, and N-alkyl-thiophene-2-carboxamides. The review not only offers an insightful overview of the synthetic methods employed but also explores into alternative routes and innovative strategies involving different catalysts and chemical reagents. A critical aspect covered in the review is the SAR studies, which provide a comprehensive understanding of how structural modifications impact the efficacy of PfDHODH inhibitors and challenges related to the discovery of PfDHODH inhibitors. This information is invaluable for scientists engaged in the development of new antimalarial drugs, offering insights into the most promising scaffolds and their synthetic techniques.