Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Tri-Aryl Imidazole-Benzene Sulfonamide Hybrids as Promising Selective Carbonic Anhydrase IX and XII Inhibitors

Lamya H Al-Wahaibi; Bahaa G M Youssif; Ehab S Taher; Ahmed H Abdelazeem; Antar A Abdelhamid; Adel A Marzouk

doi:10.3390/molecules26164718

Design, Synthesis, Biological Evaluation, and Computational Studies of Novel Tri-Aryl Imidazole-Benzene Sulfonamide Hybrids as Promising Selective Carbonic Anhydrase IX and XII Inhibitors

Molecules. 2021 Aug 4;26(16):4718. doi: 10.3390/molecules26164718.

Authors

Lamya H Al-Wahaibi¹, Bahaa G M Youssif², Ehab S Taher³, Ahmed H Abdelazeem^{4

5}, Antar A Abdelhamid^{6

7}, Adel A Marzouk⁸

Affiliations

¹ Department of Chemistry, College of Sciences, Princess Nourah Bint Abdulrahman University, P.O. Box 84428, Riyadh 11564, Saudi Arabia.
² Pharmaceutical Organic Chemistry Department, Faculty of Pharmacy, Assiut University, Assiut 71526, Egypt.
³ Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.
⁴ Department of Medicinal Chemistry, Faculty of Pharmacy, Beni-Suef University, Beni-Suef 62514, Egypt.
⁵ Department of Pharmaceutical Sciences, College of Pharmacy, Riyadh Elm University, Riyadh 11681, Saudi Arabia.
⁶ Department of Chemistry, Faculty of Science, Sohag University, Sohag 82524, Egypt.
⁷ Chemistry Department, Faculty of Science, Albaha University, P.O. Box 1988, Albaha 65731, Saudi Arabia.
⁸ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Al-Azhar University, Assiut 71524, Egypt.

Abstract

A novel series of tri-aryl imidazole derivatives 5a-n carrying benzene sulfonamide moiety has been designed for their selective inhibitory against hCA IX and XII activity. Six compounds were found to be potent and selective CA IX inhibitors with the order of 5g > 5b > 5d > 5e > 5g > 5n (Ki = 0.3-1.3 μM, and selectivity ratio for hCA IX over hCA XII = 5-12) relative to acetazolamide (Ki = 0.03 μM, and selectivity ratio for hCA IX over hCA XII = 0.20). The previous sixth inhibitors have been further investigated for their anti-proliferative activity against four different cancer cell lines using MTT assay. Compounds 5g and 5b demonstrated higher antiproliferative activity than other tested compounds (with GI₅₀ = 2.3 and 2.8 M, respectively) in comparison to doxorubicin (GI₅₀ = 1.1 M). Docking studies of these two compounds adopted orientation and binding interactions with a higher liability to enter the active side pocket CA-IX selectively similar to that of ligand 9FK. Molecular modelling simulation showed good agreement with the acquired biological evaluation.

Keywords: XII; benzene sulfonamide; carbonic anhydrase IX; imidazole.

MeSH terms

Antineoplastic Agents / pharmacology
Carbonic Anhydrase IX / metabolism*
Carbonic Anhydrase Inhibitors / chemistry
Carbonic Anhydrase Inhibitors / pharmacology*
Carbonic Anhydrases / metabolism*
Cell Line, Tumor
Cell Proliferation / drug effects
Cell Survival / drug effects
Computational Biology*
Doxorubicin / pharmacology
Drug Design*
Humans
Imidazoles / chemical synthesis*
Imidazoles / chemistry
Imidazoles / pharmacology*
Molecular Docking Simulation
Structure-Activity Relationship
Sulfonamides / chemical synthesis*
Sulfonamides / chemistry
Sulfonamides / pharmacology

Substances

Antineoplastic Agents
Carbonic Anhydrase Inhibitors
Imidazoles
Sulfonamides
imidazole
Doxorubicin
Carbonic Anhydrase IX
Carbonic Anhydrases
carbonic anhydrase XII

Grants and funding

Fast Track System/Princess Nourah Bint Abdulrahman University