Synthesis,biological evaluation and in silico modelling studies of 1,3,5-trisubstituted pyrazoles carrying benzenesulfonamide as potential anticancer agents and selective cancer-associated hCA IX isoenzyme inhibitors |
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| Affiliation: | 1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Biruni University, Istanbul, Turkey;3. Neurofarba Department, Sezione di Scienza Farmaceutiche e Nutraceutiche, Universita degli Studi di Firenze, Via U. Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;4. Meikai University Research Institute of Odontology (M-RIO), Sakado, Saitama 350-0283, Japan;5. Department of Chemistry, Faculty of Science, Ataturk University, Erzurum, Turkey;1. Medicinal Chemistry and Biotechnology Division, CSIR-Indian Institute of Chemical Technology (IICT), Hyderabad 500007, India;2. Academy of Scientific and Innovative Research, New Delhi 110 025, India;3. Centre for Chemical Biology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India;1. Department of Chemistry, Kurukshetra University, Kurukshetra 136119, India;2. Università degli Studi di Firenze, Laboratorio di Chimica Bioinorganica, Rm 188, and Neurofarba Department, Sezione di Scienze Farmaceutiche, Via U. Schiff 6, I-50019 Sesto Fiorentino (Firenze), Italy;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt;3. Università degli Studi di Firenze, Department NEUROFARBA – Pharmaceutical and Nutraceutical section, University of Firenze, via Ugo Schiff 6, I-50019, Sesto Fiorentino, Firenze, Italy;4. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019, Sesto Fiorentino, Firenze, Italy;5. Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Cairo, 11562, Egypt;6. Department of Applied Organic Chemistry, National Research Center, Dokki, Giza, P.O. Box 12622, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, P.O. Box 11829, Badr City, Cairo, Egypt;3. Department of NEUROFARBA, Section of Pharmaceutical and Nutraceutical Sciences, University of Florence, Polo Scientifico, Via U. Schiff 6, 50019 Sesto Fiorentino, Firenze, Italy;4. Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt;5. Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia;6. Department of Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt;1. Department of Chemistry, Faculty of Arts and Sciences, Dumlupinar University, 43100 Kutahya, Turkey;2. Department of Chemistry, Faculty of Arts and Sciences, Ahi Evran University, 40000 Kırşehir, Turkey;3. Department of Biochemistry, Faculty of Veterinary Sciences, Mustafa Kemal University, 31000 Hatay, Turkey;4. Department of Chemistry, Faculty of Sciences, Atatürk University, 25240 Erzurum, Turkey;5. Department of Chemistry, Faculty of Natural Sciences, Architecture and Engineering, Bursa Technical University, Osmangazi, 16200 Bursa, Turkey;1. Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Balanagar, Hyderabad 500037, India;2. Università degli Studi di Firenze, Neurofarba Dept., Sezione di Scienze Farmaceutiche e Nutraceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino, Florence, Italy;3. G. Pulla Reddy College of Pharmacy, Mehdipatnam, Hyderabad, India;4. Department of Chemistry, Anwarul Uloom College, 11-3-918, New Malleypally, Hyderabad 500001, T. S., India;5. School of Pharmacy & Technology Management, SVKM''S NMIMS (Deemed to be University), Hyderabad Campus, Plot No. B4, Green Industrial Park, Polepally SEZ, TSIIC, Jadcherla, Telangana 509 301, India |
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| Abstract: | Inhibition of carbonic anhydrases (CAs, EC 4.2.1.1) has clinical importance for the treatment of several diseases. They participate in crucial regulatory mechanisms for balancing intracellular and extracellular pH of the cells. Among CA isoforms, selective inhibition of hCA IX has been linked to decreasing of cell growth for both primary tumors and metastases. The discovery of novel CA inhibitors as anticancer drug candidates is a current topic in medicinal chemistry. 1,3,5-Trisubstituted pyrazoles carrying benzenesulfonamide were evaluated against physiologically abundant cytosolic hCA I and hCA II and trans-membrane, tumor-associated hCA IX isoforms by a stopped-flow CO2 hydrase method. Their in vitro cytotoxicities were screened against human oral squamous cell carcinoma (OSCC) cell lines (HSC-2) and human mesenchymal normal oral cells (HGF) via 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) test. Compounds 6, 8, 9, 11, and 12 showed low nanomolar hCA II inhibitory potency with Ki < 10 nM, whereas compounds 9 and 12 displayed Ki < 10 nM against hCA IX isoenzyme when compared with reference Acetazolamide (AZA). Compound 9, 4-(3-(hydrazinecarbonyl)-5-(4-nitrophenyl)-1H-pyrazol-1-yl)benzenesulfonamide, can be considered as the most selective hCA IX inhibitor over off-target cytosolic isoenzymes hCA I and hCA II with the lowest Ki value of 2.3 nM and selectivity ratios of 3217 (hCA I/hCA IX) and 3.9 (hCA II/hCA IX). Isoform selectivity profiles were also discussed using in silico modelling. Cytotoxicity results pointed out that compounds 5 (CC50 = 37.7 μM) and 11 (CC50 = 58.1 μM) can be considered as lead cytotoxic compounds since they were more cytotoxic than 5-Fluorouracil (5-FU) and Methotrexate (MTX). |
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| Keywords: | Pyrazole Carbonic anhydrase hCA IX Cytotoxicity Anticancer Sulfonamide Molecular modelling |
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