Novel synthesized SLC-0111 thiazole and thiadiazole analogues: Determination of their carbonic anhydrase inhibitory activity and molecular modeling studies
Affiliation:
1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, P.O. Box 33516, 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 Applied Organic Chemistry, National Research Center, Dokki, Cairo 12622, Egypt;5. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Cairo University, Kasr El-Aini Street, Cairo, P.O. Box 11562, Egypt;1. Department of Biothermodynamics and Drug Design, Institute of Biotechnology, Vilnius University, Saulėtekio al. 7, Vilnius LT-10257, Lithuania;2. Department of Organic Chemistry, Faculty of Chemistry and Geosciences, Vilnius University, Naugarduko 24, Vilnius LT-03225, Lithuania;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey;2. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;3. Department of Pharmacology, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo, 11829, Egypt;2. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Kafrelsheikh University, Kafrelsheikh, 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 NEUROFARBA – Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSAR, University of Firenze, Via U. Schiff 6, Sesto Fiorentino, Firenze, 50019, Italy;5. The Regional Center for Mycology and Biotechnology, Al-Azhar University, Cairo, Egypt;6. Laboratory of Growth Regulators, Palacky University & Institute of Experimental Botany, The Czech Academy of Sciences, Slechtitelu 27, 78371, Olomouc, Czech Republic;7. Pharmaceutical Chemistry Department, Faculty of Pharmacy, Cairo University, El-kasr Elaini Street, Cairo, Egypt;1. Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Adiyaman University, 02040 Adiyaman, Turkey;2. Università degli Studi di Firenze, NEUROFARBA Dept., Sezione di Scienze Farmaceutiche, Via Ugo Schiff 6, 50019 Sesto Fiorentino (Florence), Italy;3. University of Pennsylvania, Perelman School of Medicine, Department of Systems Pharmacology and Translational Therapeutics, 19104 Philadelphia, United States;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
Abstract:
In the presented work, we report the design and synthesis of novel SLC-0111 thiazole and thiadiazole analogues (11a–d, 12a–d, 16a–c and 17a–d). A bioisosteric replacement approach was adopted to replace the 4-fluorophenyl tail of SLC-0111 with thiazole and thiadiazole ones, which were thereafter extended with lipophilic un/substituted phenyl moieties. All the newly synthesized SLC-0111 analogues were evaluated in vitro for their inhibitory activity towards a panel of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) isoforms (hCA I, II, IX and XII), using a stopped-flow CO2 hydrase assay. All the examined isoforms were inhibited by the primary sulfonamide derivatives (11a–d and 12a–d) in variable degrees with the following KI ranges: 162.6–7136 nM for hCA I, 9.0–833.6 nM for hCA II, 7.9–153.0 nM for hCA IX, and 9.4–94.0 nM for hCA XII. In particular, compounds 12b and 12d displayed 5.5-fold more potent inhibitory activity (KIs = 8.3 and 7.9 nM, respectively) than SLC-0111 (KI = 45 nM) towards hCA IX. Molecular docking study was carried out for 12d within the hCA IX (PDB 3IAI) active site, to justify its inhibitory activity.
