Design, synthesis and biological evaluation of N-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamides as human carbonic anhydrase isoenzymes I, II, VII and XII inhibitors.
A series of N-(5-methyl-isoxazol-3-yl/1,3,4-thiadiazol-2-yl)-4-(3-substitutedphenylureido) benzenesulfonamide derivatives has been designed, synthesized and screened for their in vitro human carbonic anhydrase (hCA; EC 4.2.1.1) inhibition potential. These newly synthesized sulfonamide compounds were assessed against isoforms hCA I, II, VII and XII, with acetazolamide (AAZ) as a reference compound. The majority of these compounds were found quite weak inhibitor against all tested isoforms. Compound 15 showed a modest inhibition potency against hCA I (Ki=73.7 μM) and hCA VII (Ki=85.8 μM). Compounds 19 and 25 exhibited hCA II inhibition with Kivalues of 96.0 μM and 87.8 μM, respectively. The results of the present study suggest that, although the synthesized derivatives have weak inhibitory potential towards all investigated isoforms, some of them may serve as lead molecules for the further development of selective inhibitors incorporating secondary sulfonamide functionalities, a class of inhibitors for which the inhibition mechanism is poorly understood.
a Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi , Delhi , India.
Chandra Bhushan
CB
Mishra
a Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi , Delhi , India.
Shikha
S
Kumari
b Dipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche e Nutraceutiche , Florence , Italy.
Andrea
A
Angeli
c Istituto di Biostrutture e Bioimmagini (IBB) CNR , via Mezzocannone , Naples , Italy , and.
Simona Maria
SM
Monti
c Istituto di Biostrutture e Bioimmagini (IBB) CNR , via Mezzocannone , Naples , Italy , and.
Martina
M
Buonanno
d School of Computational and Integrative Sciences, Jawaharlal Nehru University , New Delhi , India.
Amresh
A
Prakash
a Bio-Organic Chemistry Laboratory, Dr. B. R. Ambedkar Centre for Biomedical Research, University of Delhi , Delhi , India.
Manisha
M
Tiwari
b Dipartimento Neurofarba, Università degli Studi di Firenze, Sezione di Scienze Farmaceutiche e Nutraceutiche , Florence , Italy.
Claudiu T
CT
Supuran
D024401:Carbonic Anhydrase I / Q000037:antagonists & inhibitors / Q000378:metabolism; D024402:Carbonic Anhydrase II / Q000037:antagonists & inhibitors / Q000378:metabolism; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D015394:Molecular Structure; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000096926:Benzenesulfonamides
D024401:Carbonic Anhydrase I; D024402:Carbonic Anhydrase II; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D013449:Sulfonamides; D000096926:Benzenesulfonamides; C477378:carbonic anhydrase XII
Carbonic anhydrase; inhibitor; sulfonamide; synthesis