Design and development of novel series of indole‐3‐sulfonamide ureido derivatives as selective carbonic anhydrase II inhibitors

• Published in: Archiv der Pharmazie (Weinheim) 2022-01, Vol.355 (1), p.e2100333-n/a
• Main Authors: Singh, Priti, Choli, Abhishek, Swain, Baijayantimala, Angeli, Andrea, Sahoo, Santosh K., Yaddanapudi, Venkata M., Supuran, Claudiu T., Arifuddin, Mohammed
• Format: Article
• Language: English
• Subjects: acetazolamide; Antibiotics; carbonic anhydrase; Carbonic Anhydrase Inhibitors - chemical synthesis; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase Inhibitors - pharmacology; Drug Design; Drug Development; Humans; Indoles - chemical synthesis; Indoles - chemistry; Indoles - pharmacology; indole‐3‐sulfonamide; Isoenzymes; selective hCA II inhibition; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Urea - chemical synthesis; Urea - chemistry; Urea - pharmacology
• ISSN: 0365-6233; 1521-4184
• DOI: 10.1002/ardp.202100333

Indole is a privileged moiety with a wide range of bioactivities, making it a popular scaffold in drug design and development studies as well as in synthetic chemistry. Here, novel urea derivatives of indole, containing sulfonamide at position‐3 of indole, were synthesized using a well‐known tail approach, as carbonic anhydrases (CAs; EC 4.2.1.1) inhibitors. All the newly synthesized molecules were screened for their CA‐inhibitory activity against four clinically relevant isoforms of human‐origin carbonic anhydrase (hCA), that is, hCA I, hCA II, hCA IX, and hCA XII. These compounds were specifically active against hCA II, more than against hCA I, hCA IX, and hCA XII. Derivative 6l was found to be most active, with a Ki value of 7.7 µM against hCA II. Novel urea derivatives of indole‐containing sulfonamide at position‐3 of indole were synthesized and tested for their activity as inhibitors of the clinically relevant human carbonic anhydrases: hCA I, hCA II, hCA IX, and hCA XII. These compounds were specifically more active on hCA II than on hCA I, hCA IX, and hCA XII, with derivative 6l being the most active one, with Ki = 7.7 µM against hCA II.