Natural inspired piperine-based sulfonamides and carboxylic acids as carbonic anhydrase inhibitors: Design, synthesis and biological evaluation

The natural product piperine, the major bioactive alkaloid present in black pepper fruits, has the ability to modulate the functional activity of several biological targets. In this study, we have utilized the natural piperine as a tail moiety to develop new SLC-0111 analogues (6a-d, 8 and 9) as pot...

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Bibliographic Details
Published in:European journal of medicinal chemistry 2021-12, Vol.225, p.113800-113800, Article 113800
Main Authors: Elimam, Diaaeldin M., Elgazar, Abdullah A., Bonardi, Alessandro, Abdelfadil, Mohamed, Nocentini, Alessio, El-Domany, Ramadan A., Abdel-Aziz, Hatem A., Badria, Farid A., Supuran, Claudiu T., Eldehna, Wagdy M.
Format: Article
Language:English
Subjects:
Anticancer
Antineoplastic Agents - chemical synthesis
Antineoplastic Agents - chemistry
Antineoplastic Agents - pharmacology
Benzenesulfonamide
Biological Products - chemical synthesis
Biological Products - chemistry
Biological Products - pharmacology
Carbonic Anhydrase Inhibitors - chemical synthesis
Carbonic Anhydrase Inhibitors - chemistry
Carbonic Anhydrase Inhibitors - pharmacology
Carbonic Anhydrases - metabolism
Carboxylic Acids - chemical synthesis
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Cell Cycle - drug effects
Cell Proliferation - drug effects
Dose-Response Relationship, Drug
Drug Design
hCA IX inhibitors
Humans
MCF-7 Cells
Molecular Structure
Piperic acid
SLC-0111 analogues
Structure-Activity Relationship
Sulfonamides - chemical synthesis
Sulfonamides - chemistry
Sulfonamides - pharmacology
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Summary:The natural product piperine, the major bioactive alkaloid present in black pepper fruits, has the ability to modulate the functional activity of several biological targets. In this study, we have utilized the natural piperine as a tail moiety to develop new SLC-0111 analogues (6a-d, 8 and 9) as potential carbonic anhydrase inhibitors. Thereafter, different functionalities, free carboxylic acid (11a-c), acetyl (13a) and ethyl ester (13b-c), were exploited as bioisosteres of the sulfamoyl functionality. All piperine-based derivatives were assessed for their inhibitory actions against four human (h) CA isoforms: hCA I, II, IX and XII. The best hCA inhibitory activity was observed for the synthesized primary piperine-sulfonamides (6a-d and 8). In particular, both para-regioisomers (6c and 8) emerged as the most potent hCA inhibitors in this study with two-digit nanomolar activity against hCA II (KIs = 93.4 and 88.6 nM, respectively), hCA IX (KIs = 38.7 and 68.2 nM, respectively), and hCA XII (KIs = 57.5 and 45.6 nM, respectively). Moreover, piperine-sulfonamide 6c was examined for its anti-cancer and pro-apoptotic actions towards breast MCF-7 cancer cell line. Collectively, piperine-based sulfonamides could be considered as a promising scaffold for development of efficient anticancer candidates with potent CA inhibitory activities. [Display omitted] •New series of piperine-based sulfonamides and carboxylic acids were designed and synthesized.•Inhibitory activities of all derivatives were evaluated toward hCA I, II, IX and XII isoforms.•Compounds 6c and 8 displayed two-digit nanomolar CA II, IX and XII inhibitory activities.•Compound 6c was examined for its potential anticancer and pro-apoptotic activities.
ISSN:0223-5234
1768-3254
DOI:10.1016/j.ejmech.2021.113800