Investigation of the inhibitory effects of isoindoline-1,3-dion derivatives on hCA-I and hCA-II enzyme activities Hayrunnisa Nadaroglu a, b, * , Azize Alaylı Gungor b, c , € Ozlem Gundogdu d , Nurhan Horasan Kishali e, ** , Belgin Kishali f , Mehlika Dilek Altintop f a Ataturk University, Erzurum Vocational School, Department of Food Technology, Erzurum, Turkey b Department of Nano-Science and Nano-Engineering, Institute of Science and Technology, Ataturk University, 25240 Erzurum, Turkey c Ataturk University, Erzurum Vocational Collage, Department of Chemical Technology, Erzurum, Turkey d Ahi Evran University, Kaman Vocational School, Department of Food Technology, Kırsehir, Turkey e Ataturk University, Faculty of Science, Department of Chemistry, 25240 Erzurum, Turkey f Anadolu University, Faculty of Pharmacy, Department of Pharmaceutical Chemistry, Eskis ¸ ehir, Turkey article info Article history: Received 20 May 2019 Received in revised form 12 July 2019 Accepted 16 July 2019 Available online 19 July 2019 Keywords: Carbonic anhydrase Isoindoline-1,3-diones Molecular docking abstract Inhibition of carbonic anhydrase (CA) has emerged as a promising approach for the treatment of a variety of diseases such as glaucoma, epilepsy, obesity and cancer. As a result, the design of CA inhibitors (CAIs) is an outstanding field of medicinal chemistry. Due to the therapeutic potential of isoindoline-1,3-diones as CAIs, herein hCA I and hCA II isozymes were purified from human erythrocytes using affinity chroma- tography and the inhibitory effects of a series of isoindoline-1,3-diones on hydratase activities of these isozymes were investigated. Among these compounds, compound 3a was found to be the most effective compound on hCA I with an IC 50 value of 7.02 mM, whereas compound 3c was the most potent compound on hCA II with an IC 50 value of 6.39 mM. Moreover, molecular docking studies were carried out for all compounds and acetazolamide (AAZ), the reference agent, in the active sites of hCA I and hCA II. Generally, the compounds showed high affinity through salt bridge formation and metal coordination with Zn 2þ ion and p-stacking interaction with His94 residue. According to in silico Absorption, Distri- bution, Metabolism and Excretion (ADME) studies, the pharmacokinetic parameters of all compounds were within the acceptable range. © 2019 Elsevier B.V. All rights reserved. 1. Introduction Carbonic anhydrases (CAs; EC 4.2.1.1) are ubiquitous zinc- containing metalloenzymes and they play a pivotal role in all living metabolism. The CA enzyme is present in 16 isoforms in mammals [1]. These isoforms are found to be specialized in different tissues of the organism. Although CAs are involved in many different reactions, the removal of waste carbon dioxide in the metabolism is their main task (Fig. 1)[2]. Due to their role in the conversion of carbon dioxide to bicarbonate, CAs participate in key biosynthetic reactions such as lipogenesis, gluconeogenesis and ureagenesis. Some CA isoenzymes contain zinc in their active regions, while others catalyze the reaction in the active site without zinc [3]. The regulation and control of enzyme activity is important for all living things. There are many regulations that increase the activity of enzymes, as well as decreasing regulations. In addition, enzyme activity is regulated by covalent modifications, phosphorylation and allosteric effects. One of the most important approaches for the reduction of this type of enzyme activity is the inhibition of CAs [4,5]. Over the past 60 years, heterocyclic and aromatic sulfonamides have been used as CA inhibitors in the treatment of many diseases such as glaucoma, obesity, epilepsy, cancer, altitude sickness. Moreover, in the last years CA inhibitors have emerged as anti- infective agents [6]. In addition to the sulfonamide derivatives such as AAZ, meth- azolamide, ethoxzolamide, aromatic/heteroaromatic sulfonamide- based Schiff bases have also been identified as CA inhibitors [6,7]. Isoindoline-1,3-dione is a prominent compound in organic * Corresponding author. Ataturk University, Erzurum Vocational School, Depart- ment of Food Technology, 25240 Erzurum, Turkey. ** Corresponding author. E-mail addresses: hnisa25@atauni.edu.tr (H. Nadaroglu), nhorasan@atauni.edu. tr (N.H. Kishali). Contents lists available at ScienceDirect Journal of Molecular Structure journal homepage: http://www.elsevier.com/locate/molstruc https://doi.org/10.1016/j.molstruc.2019.07.070 0022-2860/© 2019 Elsevier B.V. All rights reserved. Journal of Molecular Structure 1197 (2019) 386e392