Enaminone-based carboxylic acids as novel non-classical carbonic anhydrases inhibitors: design, synthesis and in vitro biological assessment

Mahmoud F Abo-Ashour; Hadia Almahli; Alessandro Bonardia; Amira Khalil; Tarfah Al-Warhi; Sara T Al-Rashood; Hatem A Abdel-Aziz; Alessio Nocentini; Claudiu T Supuran; Wagdy M Eldehna

doi:10.1080/14756366.2022.2114079

Enaminone-based carboxylic acids as novel non-classical carbonic anhydrases inhibitors: design, synthesis and in vitro biological assessment

J Enzyme Inhib Med Chem. 2022 Dec;37(1):2256-2264. doi: 10.1080/14756366.2022.2114079.

Affiliations

¹ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, El saleheya El Gadida University, Cambridge, Egypt.
² Department of Chemistry, University of Cambridge, Cambridge, United Kingdom.
³ Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Firenze, Italy.
⁴ Pharmaceutical Chemistry Department, Faculty of Pharmacy, The British University in Egypt (BUE), Cairo, Egypt.
⁵ Department of Chemistry, College of Science, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia.
⁶ Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
⁷ Department of Applied Organic Chemistry, National Research Center, Dokki, Egypt.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt.

Abstract

In searching for new molecular drug targets, Carbonic Anhydrases (CAs) have emerged as valuable targets in diverse diseases. CAs play critical functions in maintaining pH and CO₂ homeostasis, metabolic pathways, and much more. So, it is becoming attractive for medicinal chemists to design novel inhibitors for this class of enzymes with improved potency and selectivity towards the different isoforms. In the present study, three sets of carboxylic acid derivatives 5a-q, 7a-b and 12a-c were designed, developed and evaluated for the hCA inhibitory effects against hCA I, II, IX and XII. Compounds 5l, 5m, and 5q elicited the highest inhibitory activities against hCA II, IX and XII. In summary, structural rigidification, regioisomerism and structural extension, all played obvious roles in the degree of hCA inhibition. This present work could be a good starting point for the design of more non-classical selective hCA inhibitors as potential targets for several diseases.

Keywords: Carbonic anhydrase; H-NMR; enaminone; stopped-flow assay.

MeSH terms

Antigens, Neoplasm / metabolism
Carbonic Anhydrase IX / metabolism
Carbonic Anhydrase Inhibitors* / chemistry
Carbonic Anhydrases* / metabolism
Carboxylic Acids / pharmacology
Molecular Structure
Structure-Activity Relationship

Substances

Antigens, Neoplasm
Carbonic Anhydrase Inhibitors
Carboxylic Acids
Carbonic Anhydrase IX
Carbonic Anhydrases

Grants and funding

The authors extend their appreciation to the Princess Nourah bint Abdulrahman University Researchers Supporting Project number (PNURSP2022R25), Princess Nourah bint Abdulrahman University, Riyadh, Saudi Arabia. The authors acknowledge financial support from the Researchers Supporting Project number (RSP-2021/103), King Saud University, Riyadh, Saudi Arabia.