Dithiocarbamates effectively inhibit the α-carbonic anhydrase from Neisseria gonorrhoeae

Simone Giovannuzzi; Nader S Abutaleb; Chad S Hewitt; Fabrizio Carta; Alessio Nocentini; Mohamed N Seleem; Daniel P Flaherty; Claudiu T Supuran

doi:10.1080/14756366.2021.1988945

Dithiocarbamates effectively inhibit the α-carbonic anhydrase from Neisseria gonorrhoeae

J Enzyme Inhib Med Chem. 2022 Dec;37(1):1-8. doi: 10.1080/14756366.2021.1988945.

Authors

Simone Giovannuzzi¹, Nader S Abutaleb², Chad S Hewitt³, Fabrizio Carta¹, Alessio Nocentini¹, Mohamed N Seleem^{2

4}, Daniel P Flaherty^{3

5

6}, Claudiu T Supuran¹

Affiliations

¹ Neurofarba Department, Pharmaceutical and Nutraceutical Section, University of Florence, Sesto Fiorentino, Italy.
² Department of Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
³ Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, Purdue University, West Lafayette, IN, USA.
⁴ Center for Emerging Zoonotic and Arthropod-borne Pathogens, Virginia Polytechnic Institute and State University, Blacksburg, VA, USA.
⁵ Purdue Institute for Drug Discovery, West Lafayette, IN, USA.
⁶ Purdue Institute of Inflammation, Immunology and Infectious Disease, West Lafayette, IN, USA.

Abstract

Recently, inorganic anions and sulphonamides, two of the main classes of zinc-binding carbonic anhydrase inhibitors (CAIs), were investigated for inhibition of the α-class carbonic anhydrase (CA, EC 4.2.1.1) from Neisseria gonorrhoeae, NgCA. As an extension to our previous studies, we report that dithiocarbamates (DTCs) derived from primary or secondary amines constitute a class of efficient inhibitors of NgCA. K_Is ranging between 83.7 and 827 nM were measured for a series of 31 DTCs that incorporated various aliphatic, aromatic, and heterocyclic scaffolds. A subset of DTCs were selected for antimicrobial testing against N. gonorrhoeae, and three molecules displayed minimum inhibitory concentration (MIC) values less than or equal to 8 µg/mL. As NgCA was recently validated as an antibacterial drug target, the DTCs may lead to development of novel antigonococcal agents.

Keywords: Carbonic anhydrase; Neisseria gonorrhoeae; antibacterials; dithiocarbamate; inhibitor.

MeSH terms

Anti-Bacterial Agents / chemical synthesis
Anti-Bacterial Agents / chemistry
Anti-Bacterial Agents / pharmacology*
Carbonic Anhydrase Inhibitors / chemical synthesis
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Dose-Response Relationship, Drug
Microbial Sensitivity Tests
Molecular Structure
Neisseria gonorrhoeae / drug effects*
Neisseria gonorrhoeae / enzymology
Structure-Activity Relationship
Thiocarbamates / chemical synthesis
Thiocarbamates / chemistry
Thiocarbamates / pharmacology*

Substances

Anti-Bacterial Agents
Carbonic Anhydrase Inhibitors
Thiocarbamates
Carbonic Anhydrases

Grants and funding

R01 AI148523/AI/NIAID NIH HHS/United States