Pyrimidine nucleotides are essential for a wide variety of cellular processes and are synthesized either via a salvage pathway or through de novo biosynthesis. The latter is particularly important in proliferating cells, such as infectious diseases and cancer cells. Aspartate transcarbamoylase (ATCase) catalyzes the first committed and rate-limiting step in the de novo pyrimidine biosynthesis pathway, making it an attractive therapeutic target for various diseases. This review summarizes the development of a series of allosteric ATCase inhibitors, advancing them as potential candidates for malarial, tuberculosis and cancer therapies. Furthermore, it explores the potential for these compounds to be expanded into drugs targeting neglected tropical diseases, antimicrobial-resistant infections caused by the ESKAPE pathogens, and their possible application as herbicides. We identify the likely equivalent allosteric pocket in these systems and perform a structure and sequence-based analysis of the residues comprising it, providing a rationale for continued exploration of this compound series as both specific and broad-range inhibitors. The review concludes by emphasizing the importance of continued research into ATCase inhibitors, given their potential broad applicability in treating diverse diseases to enhance both human health and agricultural practices.

Czech Advanced Technology and Research Institute and Institute of Molecular and Translational Medicine (IMTM Faculty of Medicine and Dentistry Palacky University Šlechtitelů 27 779 00 Olomouc Czech Republic

Department of Chemical and Pharmaceutical Biology University of Groningen Antonius Deusinglaan 1 9731AV Groningen The Netherlands

Genomics for Health in Africa

National Institute for Theoretical and Computational Sciences South Africa

Neurobiology MRC Laboratory of Molecular Biology Cambridge Biomedical Campus Francis Crick Ave Trumpington Cambridge CB2 0QH

Research Unit in Bioinformatics Department of Biochemistry Microbiology and Biochemistry Rhodes University

Unit for Drug Discovery Department of Parasitology Institute of Biomedical Sciences University of São Paulo Avenida Professor Lineu Prestes 1374 05508 000 São Paulo SP Brazil

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