Discovery of 4-sulfamoyl-phenyl-b-lactams as a new class of potent carbonic anhydrase isoforms I, II, IV and VII inhibitors: The first example of subnanomolar CA IV inhibitors Srinivas Angapelly a , P.V. Sri Ramya a , Andrea Angeli b , Simona Maria Monti c , Martina Buonanno c , Mallika Alvala d , Cladiu T. Supuran b,⇑ , Mohammed Arifuddin a,⇑ a Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Govt of India, Balanagar, Hyderabad 500037, India b Neurofarba Department, Section of Pharmaceutical and Nutriceutical Sciences, Università degli Studi di Firenze, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy c Istituto di Biostrutture e Bioimmagini-CNR, via Mezzocannone 16, 80134 Napoli, Italy d Molecular Modeling Facility, Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Department of Pharmaceuticals, Ministry of Chemicals & Fertilizers, Govt. of India, Balanagar, Hyderabad 500037, India article info Article history: Received 8 October 2016 Revised 8 November 2016 Accepted 11 November 2016 Available online 19 November 2016 Keywords: Carbonic anhydrase Sulfonamide b-Lactam Isoform CA I, II, IV, VII abstract A series of benzenesulfonamides incorporating 1,3,4-trisubstituted-b-lactam moieties was prepared from sulfanilamide Schiff bases and in situ obtained ketenes, by using the Staudinger cycloaddition reaction. The new compounds were assayed as inhibitors of four human isoforms of the metalloenzyme carbonic anhydrase (hCA, EC 4.2.1.1) involved in various physiological/pathological conditions, hCA I, II, IV and VII. Excellent inhibitory activity was observed against all these isoforms, as follows: hCA I, involved in some eye diseases was inhibited with K I s in the range of 7.3–917 nM; hCA II, an antiglaucoma drug target, with K I s in the range of 0.76–163 nM. hCA IV, an isoform involved in several pathological conditions such as glaucoma, retinitis pigmentosa and edema was potently inhibited by the lactam-sulfonamides, with K I s in the range of 0.53–51.0 nM, whereas hCA VII, a recently validated anti-neuropathic pain target was the most inhibited isoform by these derivatives, with K I s in the range of 0.68–9.1 nM. The struc- ture-activity relationship for inhibiting these CAs with the new lactam-sulfonamides is discussed in detail. Ó 2016 Elsevier Ltd. All rights reserved. 1. Introduction Carbonic anhydrases (CAs, also known as carbonate dehy- dratase, EC 4.2.1.1) are ubiquitous metallo-enzymes, acting as quite efficient catalysts in promoting the hydration of carbon diox- ide to produce bicarbonate and protons, a crucial reaction in all liv- ing organisms. 1 Although the reaction also occurs without a catalyst, the hydration of CO 2 is particularly slow at pH of 7.5 or lower but very effective at higher pH values, being instantaneous at pH > 12. 2 CAs are involved in many physiological processes such as cell differentiation and proliferation, pH and CO 2 homeostasis, transport of CO 2 and bicarbonate in respiration, electrolyte secre- tion, neurotransmission and various biosynthetic pathways (bone resorption, calcification, gluconeogenesis and lipogenesis) and other physiologic or pathologic processes. 3–6 Indeed, seven (a-, b-, c-, d-, f-, g- and h) genetically distinct families are known to date, which contain different metal ions at their active site which includes, Zn(II) (in all classes), Cd(II) (in f-CAs), Fe(II) (for c-CAs, in anaerobic conditions) and Co(II) (in the d class). 7,8 So far, in humans, 15 different a-CAs were described and these are inhibited by various classes of compounds. Currently known CA inhibitors (CAIs) can be divided into several groups: those that coordinate to the active site metal ion 9 and those that do not inter- act with it. 10 Sulfonamides/sulfamates, mercaptophenols, ureates/ hydroxamates and metal complexing anion inhibitors are coordi- nating to the Zn +2 metal ion from the active site to elicit their inhi- bitory activity. 9,10 The sulfonamides and their bioisosters such as sulfamates and sulfamides are well known CAIs and are in clinical use for the treat- ment of various diseases such as glaucoma, epilepsy, obesity and as diuretics. The wide use of CAIs relies on the structural diversity and subcellular localization of the 15 human (h) CA isoforms as well as http://dx.doi.org/10.1016/j.bmc.2016.11.027 0968-0896/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding authors. E-mail addresses: claudiu.supuran@unifi.it (C.T. Supuran), arif@niperhyd.ac.in (M. Arifuddin). Bioorganic & Medicinal Chemistry 25 (2017) 539–544 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry journal homepage: www.elsevier.com/locate/bmc