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Journal of Enzyme Inhibition and Medicinal Chemistry Volume 35, 2020 - Issue 1
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Research Paper

Exploring structure-activity relationship of S-substituted 2-mercaptoquinazolin-4(3H)-one including 4-ethylbenzenesulfonamides as human carbonic anhydrase inhibitors

Adel S. El-Azaba Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0001-7197-1515View further author information
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Alaa A.-M. Abdel-Aziza Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaORCID Iconhttps://orcid.org/0000-0002-3362-9337View further author information
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Hany E. A. Ahmedb Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Cairo, Egypt;c Pharmacognosy and Pharmaceutical Chemistry Department, College of Pharmacy, Taibah University, Al-Madinah Al-Munawarah, Saudi ArabiaView further author information
,
Sivia Buad Department of Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Florence, ItalyView further author information
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Alessio Nocentinid Department of Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Florence, ItalyView further author information
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Nawaf A. AlSaifa Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaView further author information
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Ahmad J. Obaidullaha Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaView further author information
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Mohamed M. Hefnawya Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi ArabiaView further author information
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Claudiu T. Supurand Department of Neurofarba, Sezione di Scienze Farmaceutiche e Nutraceutiche, Università degli Studi di Firenze, Florence, ItalyCorrespondence[email protected]
ORCID Iconhttps://orcid.org/0000-0003-4262-0323View further author information
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Pages 598-609 | Received 21 Dec 2019, Accepted 09 Jan 2020, Published online: 02 Feb 2020

Abstract

Inhibitory action of newly synthesised 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides compounds 2–13 against human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII, was evaluated. hCA I was efficiently inhibited by compounds 2–13 with inhibition constants (KIs) ranging from 57.8–740.2 nM. Compounds 2, 3, 4, and 12 showed inhibitory action against hCA II with KIs between 6.4 and 14.2 nM. CA IX exhibited significant sensitivity to inhibition by derivatives 2–13 with KI values ranging from 7.1 to 93.6 nM. Compounds 2, 3, 4, 8, 9, and 12 also exerted potent inhibitory action against hCA XII (KIs ranging from 3.1 to 20.2 nM). Molecular docking studies for the most potent compounds 2 and 3 were conducted to exhibit the binding mode towards hCA isoforms as a promising step for SAR analyses which showed similar interaction with co-crystallized ligands. As such, a subset of these mercaptoquinazolin-4(3H)-one compounds represented interesting leads for developing new efficient and selective carbonic anhydrase inhibitors (CAIs) for the management of a variety of diseases including glaucoma, epilepsy, arthritis and cancer.

Graphical Abstract

1. Introduction

Carbonic anhydrases (CAs; EC 4.2.1.1) constitute the superfamily of metalloenzymes catalysing the CO2 hydration/dehydration reaction. CAs are classified into eight genetically distinct families, named α-, β-, γ-, δ-, ζ-, η-, ɵ-, and ι-CAsCitation1,Citation2. 15 α-class isoenzymes have been detected in humans (h) and are sorted into four different subsets depending on their subcellular localisation: CA I, II, III, VII, VIII, X, XI, XIII are cytosolic proteins, CA VA and VB are present in the mitochondrial matrix, CA VI is a secreted enzyme, CA IV is a glycosylphosphatidylinositol (GPI)-anchored protein and CA IX, XII, and XIV are trans-membrane isoformsCitation1–3. hCAs are spread in the human body and are implicated in a plethora of essential physiological processes. As a result, critical pathological conditions might occur upon their dysregulated expression and/or abnormal activityCitation2. CA II is the most physiologically relevant isoform and is implicated in disorders such as cerebral oedema, glaucoma (such as CA XII), and epilepsy. It is conversely off-target like CA I, when targeting tumours where CA IX and XII are overexpressed and represent validated targets to combat the growth of both primary tumours and metastasisCitation4. Significant similarity exists amongst the active site’s architecture of hCAs making it difficult to produce inhibitors that exhibit net isoform-specificity in action and do not induce side effects as a consequence of CA inhibitionCitation1. Aromatic sulphonamides constitute the main subset of CAIs developed to date and have been clinically used for decades as diuretic, antiglaucoma, antiobesity, and antiepilepsy medications. The ureidobenzenesulfonamide SLC-0111 (), a selective CA IX/XII inhibitor, is currently in Phase II/b clinical trials for the therapy of solid, metastatic tumoursCitation2–6. A wealth of sulphonamide derivatives have been reported as CAIsCitation5,Citation7–19, COX-2 inhibitors, or antitumorCitation13,Citation15,Citation20–22. The quinazolinone scaffold is also widely used in medicinal chemistryCitation23–39, such as COX-1/2 inhibitorsCitation23,Citation24 and antitumorCitation25–29,Citation37–39. 4–(2-(4-Oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)benzenesulfonamide (1, ) showed effective inhibitory activity against a subset of hCA isoforms with subnanomolar inhibition constantsCitation40. Likewise, a series of 2-((3-benzyl-4-oxo-3,4-dihydroquinazolin-2-yl)thio)-N-(4-sulfamoylphenethyl)amides (A, ) showed nanomolar inhibitory action against a panel of hCAsCitation39. Various quinazolin-4-yl-aminobenzenesulfonamide, quinazolin-4-yl-oxy-benzenesulfonamide derivatives (B, ) and 3-(6-iodo-4-oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)benzenesulfonamide, 3-(2-mercapto-7-fluoro-4(3H)quinazolinon-3-yl)-benzenesulfonamide (C, ) were reported to exert potent inhibitory effect against CA I, II, IX and XIICitation41,Citation42. As observed from SAR analysis of the reported C derivatives (), it is thought to add an ethyl linker between sulphonamide part and quinazoline scaffold and alkylation of free SH group to increase the lipophilicity as activity parameter in CA enzyme. Therefore, we report the synthesis of a new series of 4-(2-(2-(substituted-thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide compounds (2–13, ) and evaluated their inhibitory action against four pharmacologically relevant hCA isoforms, I, II, IX, and XII.

Figure 1. Structures of AAZ, SLC-0111, (A–C), and the herein designed quinazoline derivatives (2–13) as CAIs.

Figure 1. Structures of AAZ, SLC-0111, (A–C), and the herein designed quinazoline derivatives (2–13) as CAIs.

2. Materials and methods

2.1. Chemistry

Melting points were recorded on a Barnstead 9100 electrothermal melting point apparatus (UK). IR spectra (KBr) were recorded on a FT-IR Perkin-Elmer spectrometer (Perkin Elmer Inc., Waltham, MA). Nuclear magnetic resonance (1H and 13C NMR) spectra were recorded with Bruker 500 or 700 MHz spectrometers (Zurich, Switzerland) using DMSO-d6 as the solvent. Micro-analytical data (C, H, and N) were obtained using a Perkin-Elmer 240 analyser (Perkin Elmer Inc., MA) and agreed with the proposed structures within ±0.4% of the theoretical values. Mass spectra were recorded on a Varian TQ 320 GC/MS/MS mass spectrometer (Varian, Palo Alto, CA).

4-(2-(4-Oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)benzenesulfonamide compound 1 was prepared by heating anthranilic acid with 4-(2-isothiocyanatoethyl)benzenesulfonamide in ethanol in the presence of triethylamineCitation40.

2.1.1. General procedure for synthesis of 4-(2-(2-(substituted-thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides (2–13)

A mixture of 4-(2-(4-oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)benzenesulfonamide (1) (1 mmol, 361 mg), appropriate halide (1 mmol) and potassium carbonate (3 mmol, 415 mg) in 7 ml acetone were stirred at room temperature for 8–13 h. The reaction mixture was filtered and the prepared solid was washed with water and dried.

2.1.1.1. 4-(2-(2-(Methylthio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (2)

M.P. 255–257 °C, 91% yield; IR (KBr, cm−1) ν: 3285, 3237 (NH), 1655 (C=O), 1345, 1159 (O=S=O); 1H NMR (700 MHz, DMSO-d6): δ 8.09 (d, 1H, J = 7.78 Hz), 7.89 (d, 3H, J = 8.17 Hz), 7.57 (d, 1H, J = 8.14), 7.48 (dd, 3H, J = 8.24 & 7.70 Hz), 7.35 (s, 2H), 4.27 (t, 2H, J = 15.99 Hz), 3.07 (t, 2H, J = 16.20 Hz), 2.65 (s, 3H); 13C NMR (176 MHz, DMSO-d6): δ 160.89, 157.38, 147.29, 143.07, 142.41, 135.21, 129.65, 126.89, 126.48, 126.43, 126.39, 119.16, 45.42, 33.58, 15.11; MS; m/z (375).

2.1.1.2. 4-(2-(2-(Ethylthio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (3)

M.P. 193–195 °C, 94% yield; 1H NMR (700 MHz, DMSO-d6): δ 8.09 (d, 1H, J = 7.89 Hz), 7.80 (d, 3H, J = 8.12 Hz), 7.55 (d, 1H, J = 8.12 Hz), 7.47 (d, 3H, J = 8.19 Hz), 7.34 (s, 2H), 4.25 (t, 2H, J = 15.96 Hz), 3.27 (q, 2H, J = 7.30 Hz), 3.06 (t, 2H, J = 15.96 Hz), 1.36 (d, 3H, J = 7.32 Hz); 13C NMR (176 MHz, DMSO-d6): δ 160.97, 156.68, 147.33, 143.07, 142.41, 135.22, 129.66, 126.87, 126.46, 126.42, 126.38, 119.22, 45.38, 33.58, 26.49, 14.47; MS: m/z 389.

2.1.1.3. 4-(2-(2-((Cyanomethyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (4)

M.P. 169–170 °C, 90% yield; IR (KBr, cm−1) ν: 3287, 3232 (NH), 2193 (CN), 1700 (C=O), 1333, 1155 (O=S=O); 1H NMR (700 MHz, DMSO-d6): δ 8.13 (d, 1H, J = 7.86 Hz), 7.86 (t, 1H, J = 7.61 Hz), 7.80 (d, 2H, J = 7.78 Hz), 7.63 (d, 1H, J = 8.11 Hz), 7.53 (t, 1H, J = 7.51 Hz), 7.49 (d, 2H, J = 7.82 Hz), 7.35 (s, 2H), 4.42 (s, 2H), 4.24 (t, 2H, J = 15.93 Hz), 3.08 (t, 2H, J = 15.95 Hz); 13C NMR (176 MHz, DMSO-d6): δ 160.76, 154.07, 146.88, 143.14, 142.19, 135.48, 129.69, 127.11, 127.01, 126.62, 126.50, 119.41, 117.91, 45.75, 33.62, 18.20; MS: m/z 400.

2.1.1.4. 4-(2-(2-(Benzylthio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (5)

M.P. 251–252 °C, 95% yield; IR (KBr, cm−1) ν: 3289, 3233 (NH), 1686 (C=O), 1331, 1158 (O=S=O); 1H NMR (500 MHz, DMSO-d6): δ 9.09 (d, 1H, J = 7.40 Hz), 7.28 (s, 1H), 7.78 (d, 2H, J = 6.80 Hz), 7.64 (d, 1H, J = 7.50 Hz), 7.53 (d, 2H, J = 6.10 Hz), 7.48 (d, 1H, J = 7.45 Hz), 7.44 (d, 2H, J = 6.75 Hz), 7.35 (s, 4H), 7.28 (d, 1H, J = 6.55 Hz), 4.57 (s, 2H), 4.25 (s, 2H), 3.04 (s, 2H); 13C NMR (125 MHz, DMSO-d6): δ 160.93, 156.26, 147.18, 143.06, 142.33, 137.12, 135.28, 129.88, 129.65, 128.95, 127.90, 126.90, 126.52, 126.45, 45.41, 36.06, 33.61; MS: 451.

2.1.1.5. 4-(2-(2-((4-Bromobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (6)

M.P. 225–227 °C, 92% yield; IR (KBr, cm−1) ν: 3291, 3226 (NH), 1645 (C=O), 1340, 1155 (O=S=O); 1H NMR (500 MHz, DMSO-d6): δ 8.08 (d, 1H, J = 7.26 Hz), 7.78 (t, 3H, J = 10. 05 & 7.10 Hz), 7.63 (d, 1H, J = 7.37 Hz), 7.48 (dd, 7H, J = 11.70 & 19.80 Hz), 7.36 (s, 2H), 4.52 (s, 2H), 4.23 (s, 2H), 3.04 (s, 2H); 13C NMR (125 MHz, DMSO-d6): δ 160.91, 156.02, 147.11, 143.07, 142.34, 137.00, 135.28, 132.07, 131.74, 129.67, 126.90, 126.56, 126.46, 120.97, 119.27, 45.48, 35.21, 33.61; MS: m/z 530 and 532.

2.1.1.6. 4-(2-(2-((4-Chlorobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (7)

M.P. 244–245 °C, 95% yield; IR (KBr, cm−1) ν: 3282, 3224 (NH), 1655 (C=O), 1333, 1155 (O=S=O); 1H NMR (500 MHz, DMSO-d6): δ 8.04 (s, 1H), 7.78 (d, 3H, J = 6.51 Hz), 7.63 (s, 1H), 7.54 (s, 2H), 7.45 (s, 3H), 7.38 (s, 2H), 7.35 (s, 2H), 4.54 (s, 2H), 4.23 (s, 2H), 3.04 (s, 2H); 13C NMR (125 MHz, DMSO-d6): δ 162.53, 156.04, 147.12, 142.36, 136.56, 135.30, 132.44, 131.71, 129.68, 128.81, 126.89, 126.58, 126.45, 119.26, 116.12, 45.47, 35.15, 33.60; MS; m/z 486 and 487.

2.1.1.7. 4-(2-(2-((4-Cyanobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (8)

M.P. 265–267 °C, 95% yield; IR (KBr, cm−1) ν: 3280, 3222 (NH), 2189 (CN), 1654 (C=O), 1334, 1155 (O=S=O); 1H NMR (700 MHz, DMSO-d6): δ 8.08 (dd, 1H, J = 7.91 & 1.19 Hz), 7.82 (dd, 1H, J = 7.00 & 1.40 Hz), 7.79 (t, 4H, J = 17.70 Hz), 7.73 (d, 2H, J = 8.28 Hz), 7.62 (d, 1H, J = 8.19 Hz), 7.48 (d, 1H, J = 7.28 Hz), 7.45 (d, 2H, J = 8.19 Hz), 7.37 (s, 2H), 4.62 (s, 2H), 4.24 (t, 2H, J = 15.90 Hz), 3.05 (t, 2H, J = 15.87 Hz); 13C NMR (176 MHz, CDCl3/DMSO-d6): δ 160.90, 155.79, 147.05, 143.83, 143.07, 142.35, 135.31, 132.70, 130.81, 129.70, 126.91, 126.63, 126.46, 126.41, 119.28, 119.23, 110.45, 45.58, 35.31, 33.60; MS: m/z 476.

2.1.1.8. 4-(2-(2-((4-Fluorobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (9)

M.P. 267–269 °C, 93% yield; IR (KBr, cm−1) ν: 3285, 3220 (NH), 1663 (C=O), 1336, 1157 (O=S=O); 1H NMR (500 MHz, DMSO-d6): δ 8.08 (d, 1H, J = 7.32 Hz), 7.78 (t, 3H, J = 12.70 & 6.69 Hz), 7.64 (d, 1H, J = 7.68 Hz), 7.57 (s, 2H), 7.44 (t, 3H, J = 9.65 & 6.56 Hz), 7.35 (s, 2H), 7.16 (d, 2H, J = 8.25 Hz), 4.55 (s, 2H), 4.23 (s, 2H), 3.04 (s, 2H);13C NMR (125 MHz, DMSO-d6): δ 160.92, 156.16, 147.15, 143.06, 142.35, 135.28, 133.55, 131.90, 131.83, 129.66, 126.90, 126.54, 126.45, 119.28, 115.76, 115.59, 45.44, 35.16, 33.60; MS: m/z 469.

2.1.1.9. 4-(2-(2-((4-Methylbenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (10)

M.P. 227–228 °C, 92% yield; IR (KBr, cm−1) ν: 3287, 3221 (NH), 1656 (C=O), 1334, 1156 (O=S=O); 1H NMR (700 MHz, DMSO-d6): δ 8.09 (d, 1H, J = 7.84 Hz), 7.81 (d, 1H, J = 6.79 Hz), 7.78 (d, 2H, J = 7.98 Hz), 7.64 (d, 1H, J = 8.12 Hz), 7.47 (t, 1H, J = 8.11 Hz), 7.44 (d, 2H, J = 7.91 Hz), 7.40 (d, 2H, J = 7.70 Hz), 7.35 (s, 2H), 7.14 (d, 2H, J = 7.70 Hz), 4.52 (s, 2H), 4.23 (t, 2H, J = 15.89 Hz), 3.03 (t, 2H, J = 15.92 Hz), 2.27 (s, 3H); 13C NMR (176 MHz, DMSO-d6): δ 160.91, 156.02, 147.11, 143.07, 142.34, 137.00, 135.28, 132.07, 131.74, 129.67, 126.90, 126.56, 126.46, 120.97, 119.27, 45.48, 35.21, 33.61; MS: m/z 465.

2.1.1.10. 4-(2-(2-((4-Nitrobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (11)

M.P. 210–211 °C, 90% yield; IR (KBr, cm−1) ν: 3279, 3226 (NH), 1661 (C=O), 1326, 1161 (O=S=O); 1H NMR (500 MHz, DMSO-d6): δ 8.19 (d, 2H, J = 6.56 Hz), 8.08 (d, 1H, J = 6.10 Hz), 7.80 (t, 5H, J = 8.30 & 8.26 Hz), 7.64b (d, 1H, J = 5.55 Hz), 7.46 (s, 3H), 7.36 (s, 2H), 4.68 (s, 2H), 4.25 (s, 2H), 3.05 (s, 2H); 13C NMR (125 MHz, DMSO-d6): δ 160.90, 155.71, 147.06, 146.06, 143.07, 142.36, 135.31, 131.08, 129.71, 126.89, 126.65, 126.45, 123.86, 119.27, 45.60, 35.02, 33.60; MS: m/z 496.

2.1.1.11. 4-(2-(4-Oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12)

M.P. 198–199 °C, 92% yield; 1H NMR (700 MHz, DMSO-d6): δ 7.08 (dd, 1H, J = 9.18 & 6.64 Hz), 7.79 (d, 3H, J = 8.22 Hz), 7.53 (d, 1H, J = 8.05 Hz), 7.47 (dd, 3H, J = 8.26 & 6.70 Hz), 7.36 (s, 2H), 4.26 (t, 2H, J = 16.04 Hz), 3.41 (t, 2H, J = 14.25 Hz), 3.07 (t, 2H, J = 16.01 Hz), 2.65 (s, 2H), 2.51 (t, 2H, J = 3.55 Hz), 2.48 (d, 2H, J = 6.54 Hz), 1.50 (d, 4H, J = 4.35 Hz), 1.38 (s, 2H); 13C NMR (176 MHz, DMSO-d6): δ 160.95, 156.81, 147.27, 143.08, 142.43, 135.24, 129.65, 126.88, 126.46, 126.38, 126.34, 119.19, 57.48, 54.15, 45.38, 33.59, 31.17, 29.37, 25.93, 24.36; MS: m/z 472.

2.1.1.12. 4-(2-(2-((3-(1,3-Dioxoisoindolin-2-yl)propyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (13)

M.P. 205–207 °C, 91% yield; IR (KBr, cm−1) ν: 3277, 3228 (NH), 1701 (C=O), 1328, 1159 (O=S=O); 1H NMR (700 MHz, DMSO-d6): δ 8.05 (d, 1H, J = 7.84 Hz), 7.88–7.83 (m, 4H), 7.79 (d, 2H, J = 7.91 Hz), 7.68 (p, 1H, J = 8.15, 14.14 Hz), 7.54 (d, 2H, J = 8.26 Hz), 7.42 (p, 1H, J = 17.15 & 7.03 Hz), 7.36 (s, 2H), 7.20 (d, 1H, J = 8.12 Hz), 4.21 (t, 2H, J = 15.86 Hz), 3.75 (t, 2H, J = 6.49 Hz), 3.31 (t, 2H, J = 7.18 Hz), 3.03 (t, 2H, J = 16.07 Hz), 2.10–2.06 (m, 2H); 13C NMR (176 MHz, DMSO-d6): δ 168.52, 160.88, 156.36, 147.11, 143.05, 142.37, 135.05, 134.87, 132.14, 129.62, 127.74, 126.84, 126.47, 126.36, 126.14, 123.51, 119.17, 45.28, 37.00, 33.54, 29.22, 28.21; MS: m/z 547.

2.2. CA inhibition

The hCA I, II, IX, and XII isoenzyme inhibition assay was performed according to the reported method using SX.18 MV-R stopped-flow instrument (Applied Photophysics, Oxford, UK)Citation43–45. All CA isoforms were recombinant isoforms obtained in-house, as reported earlierCitation46,Citation47.

2.3. Molecular docking method

Molecular docking was carried out according to the previously reported methodsCitation24,Citation28,Citation29,Citation37–39,Citation48–52 using MOE 2008.10 from the Chemical Computing Group IncCitation53.

3. Results and discussion

3.1. Chemistry

4-(2-(4-Oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)benzenesulfonamide (1) was obtained through the reaction between anthranilic acid, 4-(2-isothiocyanatoethyl)benzenesulfonamide and triethylamine in ethanolCitation40,Citation54 (Scheme 1). Its yield was 93%. Stirring of compound 1 with potassium carbonate in acetone and different alkyl-halides or aralkyl-halides produced the corresponding 4-(2-(2-(substituted-thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides 2–13 with 90–95% yield. Various spectral analyses were performed to confirm the structures of compounds 2–13. The formation of target compounds was assessed by the disappearance of thioamide proton (NH–C = S) at 13.03 ppm in 1H NMR and thione moiety (NH–C = S) at 175.29 ppm in the 13C NMR spectra, together with presence of the new thio-substituted moieties (S–R), that were confirmed by 1H NMR and 13C NMR spectra.

Scheme 1. Synthesis of 4–(2–(2-(substituted-thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides 2–13.

Scheme 1. Synthesis of 4–(2–(2-(substituted-thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides 2–13.

3.2. CA inhibitory activity

The CAI activity of newly produced 4-(2-(2-(substituted-thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamides 2-13 against hCA I, II, IV, and IX isoforms was measured by a Stopped-Flow kinetic assayCitation48 and compared to acetazolamide (AAZ), a standard sulphonamide inhibitor (, ). The hCA I was effectively inhibited by compounds 2–13 with inhibition constant (KI) values in the range of 57.8–740.2 nM, (AAZ: KI, 250.0 nM). Compounds 2, 3, 4, and 12 showed to be potent hCA II inhibitors, with KI values between 6.4 and 14.2 nM, which were greater than or nearly identical to that of AAZ (KI, 12.0 nM). Compounds 7–11 and 13 showed modest hCA II inhibitory activity with KIs ranging between 66.5 and 86.6 nM, whereas compounds 5 and 6 showed a weak inhibitory activity with KIs values of 115.3 and 173.4 nM, respectively. Compounds 2–13 displayed potent hCA IX inhibitory activity with KI values ranging from 7.1 to 93.6 nM (AAZ KI, 25.0 nM). Quinazoline derivatives 2, 3, 4, 8, 9, and 12 possessed potent hCA XII inhibitory activities with KI values ranging between 3.1–20.2 nM (AAZ KI, 5.7 nM). On the other hand, compounds 5, 10, and 11 exerted moderate hCA XII inhibitory activities with KI values between 25.6–38.4 nM, whereas compounds 6, 7, and 13 had weak hCA XII inhibitory activities with KI values in the range of 57.6–71.4 nM (, ).

Figure 2. Carbonic anhydrase inhibition of 2-substituted-mercapto-4(3H|)-quinazolinone derivatives 2–13.

Figure 2. Carbonic anhydrase inhibition of 2-substituted-mercapto-4(3H|)-quinazolinone derivatives 2–13.

Table 1. Inhibition constant values of 2-ethylquinazoline derivatives 2–13 and standard sulphonamide inhibitor acetazolamide (AAZ) against human CA isoforms hCA I, II, IX, and XII as determined by a stopped flow, CO2 hydrase assay48.

The following structure-activity relationship (SAR) can be drawn on the basis of the inhibition data shown in .

  1. SAR analysis for hCA I inhibition indicated that: (1) 2-(aliphatic-thio)quinazolin-4(3H)-one like compounds 2–4 (KI values between 57.8 and 85.5 nM) were more active than the corresponding 2-(benzylthio)quinazolin-4(3H)-ones (KI values between 229.4 and 740.2 nM) 5–11, 4–(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) (KI, 532.2 nM) and 4–(2-(2-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (13) (KI, 320.5 nM); (2) 2-(benzylthio)quinazolin-4(3H)-one (5) (KI, 229.4 nM) was more potent than the corresponding 4-substituted-2-(benzylthio)quinazolin-4(3H)-ones such as compounds 6–11 and 13 (KI values ranging from 256.8 to 740.2 nM); (3) 4-(2-(2-((4-cyanobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (8) (KI, 256.8 nM) was more effective than other 2-((4-substituted-benzyl)thio)quinazolin-4(3H)-ones 6, 7, 9, 10 and 11 (KI values between 370.1 and 740.2 nM); (4) 4-(2-(2-(ethylthio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (2) with KI of 57.8 nM was more potent than 4-(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) with KI of 532.2 nM; (5) hCA I inhibitory activity (KI, 85.5 nM) of 4-(2-(2-((cyanomethyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (4) was more potent than 4-(2-(2-((4-cyanobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (8) with KI of 256.8 nM; (6) substitution of benzyl group of compound 5 (KI of 229.4 nM) by propylphthalimide moiety produced compound 13 with significant decrease of CA I activity (KI, 320.5 nM).

  2. SAR analysis for hCA II inhibition indicated that: (1) 2-(aliphatic-thio)quinazolin-4(3H)-one compounds such as compounds 2, 3, 4 and 12 (KI values ranging from 6.4 to 14.2 nM) were more active than the corresponding 2-(benzylthio)quinazolin-4(3H)-ones 5–11 and 4-(2-(2-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (13) with KI values between 66.5 and 173.4 nM; (2) the introduction of electron withdrawing groups such as 4-Cl, 4-CN, 4-F, 4-NO2 or electron donating group such as 4-CH3 at the benzyl moiety of compound 5 (KI, 115.3 nM) produced compounds 7–11 with moderate increase in the CA I activity (KI values ranging between 66.5 and 84.2 nM); (3) 4-(2-(2-(ethylthio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (2) with KI, 11.6 nM was more potent than 4-(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) with KI, 14.2 nM; (4) For hCA I, inhibitory activity (KI, 13.5 nM) of 4-(2-(2-((cyanomethyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (4) was more potent than 4-(2-(2-((4-cyanobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (8) with KI, 74.1 nM; (5) substitution of benzyl group in compound 5 (KI, 115.3 nM) by propylphthalimide moiety produced compound 13 with significant increase in the CA activity (KI, 86.6 nM).

  3. SAR analysis for hCA IX inhibition indicated that: (1) 2-(aliphatic-thio)quinazolin-4(3H)-one such as compounds 2–4 (KI values ranging between 7.1 and 12.6 nM) were more active than the corresponding 2-(benzylthio)quinazolin-4(3H)-one 5–11, 4-(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) and 4-(2-(2-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (13) (KI values in the range of 19.3–93.6 nM); (2) the introduction of electron withdrawing groups such as 4-Cl, 4-F, or 4-NO2 at the benzyl moiety in compound 5 (KI, 50.7 nM) produced compounds 7, 9, and 11 with significant increase in the CA I activity (KI values ranging between 19.3 and 34.2 nM); (3) 4-(2-(2-(ethylthio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (2) with KI of 7.1 nM was more potent than 4-(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) with KI value of 22.2 nM; (4) hCA I inhibitory activity of 4-(2-(2-((cyanomethyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (4) (KI, 12.6 nM) was more potent than 4-(2-(2-((4-cyanobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (8) with KI value of 47.3 nM; (5) substitution of benzyl group in compound 5 (KI, 50.7 nM) by propylphthalimide moiety produced compound 13 with significant increase in the CA activity (KI, 93.6 nM).

  4. SAR analysis for hCA XII inhibition indicated that: (1) 2-(aliphatic-thio)quinazolin-4(3H)-one compounds such as compounds 2-4 (KI values between 3.1 and 8.6 nM) were more active than the corresponding 2-(benzylthio)quinazolin-4(3H)-one 5–11, 4-(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) and 4-(2-(2-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (13) (KI values ranging from 17.2 to 71.4 nM); (2) the introduction of electron withdrawing groups such as 4-CN, 4-F, 4-NO2 or electron donating group such as 4-CH3 at the benzyl moiety in compound 5 (KI, 115.3 nM) produced compounds 8–11 which significantly increased the CAI activity (KI, 17.2–28.2 nM), while introduction of 4-Br and 4-Cl groups at the benzyl moiety in compound 5 gave compounds 6 and 7 which significantly increased the CAI activity (KI values, 57.0 and 65.6 nM, respectively); 3) 4-(2-(2-(ethylthio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (2) with KI of 3.9 nM was more potent than 4-(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) with KI of 20.2 nM; (4) hCA XII inhibitory activity of 4-(2-(2-((cyanomethyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (4) (KI, 8.6 nM) was more potent than 4-(2-(2-((4-cyanobenzyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (8) with KI of 14.6 nM; (5) substitution of benzyl group in compound 5 (KI of 38.4 nM) by propylphthalimide moiety produced compound 13 with a significant decrease in CAI activity (KI, 71.4 nM).

3.3. Molecular docking studies

The docking simulations between the hCAs targets, and the most active compounds such as 2 and 3, as well as least active compound such as 6 compared with the prototype 1 lead compound were performed using MOE SuiteCitation53.

3.3.1. Docking of compounds 2, 3, and 6 with hCA isoenzymes

The most active methyl derivative 2 was docked with the binding pockets of the hCA isoforms II and XII, utilising the different protein crystal structures; 5ULN and 1JD0 downloaded from Protein Data Bank storeCitation55,Citation56. As shown in , and , the results suggested that the compound 2 displayed similar patterns to the co-crystallized ligands. Firstly, the docking pose of compound 2 in the complex with isoform II formed bidentate chelate with SO2NH2 fragment with zinc metal at a distance range of 2.45–2.01 Å. The sulphonyl part was stabilised by three strong hydrogen bonds through the residues, Thr199 and Leu198 at average bond distance of 2.35–2.22 Å. Moreover, the carbonyl moiety of 4(3H)quinazolinone was stabilised by direct and indirect hydrogen bonding between water and polar residues Gln92 and Asn67 at distance of 2.25 Å as co-crystallized inhibitor S-atom does. In addition, hydrophobic interactions were experienced with methylthioether fragment through Phe131 residue. Secondly, the docking poses of compound 2 in the complex with isoform XII exhibited interactions like the co-crystallized inhibitor especially the SO2NH2 part with Zinc metal and stabilising Thr199 and Thr200 residues. In addition, hydrophobic interactions were experienced with methylthioether fragment through Leu141 residue. The compound 3 was docked with the binding pockets in the hCA isoforms I and IX, utilising the different protein crystal structures; 4WR7 and 5FL4 downloaded from Protein Data Bank storeCitation57,Citation58. As shown in and , the results suggested that the compound 3 interacted with both active sites in a similar fashion to the co-crystallized ligands in the pockets. Firstly, the docking pose of compound 3 in the complex with isoform I, consisted of a long, narrow tunnel, leading to a cavity that contained the catalytic Zn2+ ion chelated with SO2NH2 fragment (2.45–2.01 Å) and a sulphonyl part stabilised by two strong hydrogen bonds through the residues, Thr199 and His200 (2.38-2.41 Å). Moreover, different hydrophobic aromatic interactions were also formed with ethylthioether, phenethyl, and 4(3H)quinazolinone moieties through pockets of Leu131, Leu198, Pro202, Leu141, Trp209, Ala135, and Ala132 residues. Secondly, the docking pose of compound 3 in the complex with isoform IX, revealed that the cavity contained the catalytic Zn2+ ion forming bidentate chelate with SO2NH2 fragment (2.32-2.12 Å) and the sulphonyl part was stabilised by three hydrogen bonds through the residues, Thr200, His96 and His94 (2.44-1.99 Å). Different hydrophobic aromatic interactions were formed with ethylthioether, phenethyl, and 4(3H)quinazolinone moieties through pockets of Val130, Leu134, and Leu91 residues. The 4(3H)quinazolinone was modulated through molecules of H2O in the pocket by polar interactions. In addition, the aryl moiety of benzene sulphonamide formed a H2O-mediated π-π interactions with certain aromatic amino acids. Thr201 might also play an important role in increasing their binding affinity for the enzyme. In addition, the lease active compound 6 was placed in the hCA I binding cavity (, right panel) and results showed that certain factors affecting the incorrect placement like the insertion of S-bromophenyl ring among polar Gln92 and Asn69 residues and disorienting of planer quinazolinone to Leu131 residue. Moreover, the docking of the least active compound 6 into the hCA-II pocket (, left panel) revealed the intolerance of S side chain bromophenyl moiety into the His119 polar part leading to protrusion out of the pocket and so appeared incompatible with pocket residue that makes it low active.

Figure 3. Docking modes of compound 2 in the binding pockets of CA isoenzymes II and XII. Interactions between the protein (PDB IDs: 5ULN and 1JD0). Predicted binding modes of co-crystallized inhibitor (upper left panel) and compound 2 (upper right panel) with hCA-II target as well as co-crystallized inhibitor (lower left panel) and compound 2 (lower right panel) with hCA-XII target.

Figure 3. Docking modes of compound 2 in the binding pockets of CA isoenzymes II and XII. Interactions between the protein (PDB IDs: 5ULN and 1JD0). Predicted binding modes of co-crystallized inhibitor (upper left panel) and compound 2 (upper right panel) with hCA-II target as well as co-crystallized inhibitor (lower left panel) and compound 2 (lower right panel) with hCA-XII target.

Figure 4. Docking modes of compound 3 in the binding pockets of CA isoenzymes I and IX. Interactions between the protein (PDB IDs: 4WR7, 5FL4). Predicted binding modes of co-crystallized inhibitor (upper left panel) and compound 3 (upper right panel) with hCA-I target as well as co-crystallized inhibitor (lower left panel) and compound 3 (lower right panel) with hCA-IX target.

Figure 4. Docking modes of compound 3 in the binding pockets of CA isoenzymes I and IX. Interactions between the protein (PDB IDs: 4WR7, 5FL4). Predicted binding modes of co-crystallized inhibitor (upper left panel) and compound 3 (upper right panel) with hCA-I target as well as co-crystallized inhibitor (lower left panel) and compound 3 (lower right panel) with hCA-IX target.

Figure 5. Docking modes of compound 6 as the least active example in the binding pockets of CA isoenzymes I and II. Interactions between the protein (PDB IDs: 4WR7, 5ULN). Predicted binding modes of compound 6 with CA-I; right panel, and CA-II; left panel.

Figure 5. Docking modes of compound 6 as the least active example in the binding pockets of CA isoenzymes I and II. Interactions between the protein (PDB IDs: 4WR7, 5ULN). Predicted binding modes of compound 6 with CA-I; right panel, and CA-II; left panel.

Table 2. Description of the docking data of selected target compounds 2 and 3.

However, the lead compound 1 was docked into the pockets of hCA II and XII (, ) for comparing its behaviour that showed the loss of SH role in the interactions compared to the potent active 2 and 3 derivatives. These overall docking findings proved that the S-alkylated derivatives exhibited good binding interactions better than the lead compound 1.

Figure 6. Docking modes of the lead compound 1 in the binding pockets of CA isoenzymes II (Right) and XII (Left) with (PDB IDs: 5ULN and 1JD0) respectively.

Figure 6. Docking modes of the lead compound 1 in the binding pockets of CA isoenzymes II (Right) and XII (Left) with (PDB IDs: 5ULN and 1JD0) respectively.

4. Conclusions

A new series of 4-(2-(2-substituted-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide derivatives 2–13 were synthesised and assessed in vitro for CA inhibition in comparison to AAZ as reference drug. 4–(2-(2-Aliphatic-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide derivatives 2–4 showed efficient inhibitory activity against hCA I, hCA II, h IX and hCA XII with KI values ranging between 57.8–85.5, 6.4–13.5, 7.1–12.6, and 3.1–8.6 nM, respectively, which were better or had the same activity as AAZ as standard drug with KI values of 250, 12.0, 25.0, and 5.7 nM, respectively. 4–(2-(2-Aliphatic-thio-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide derivatives 2–4 were more active than the corresponding 2-(benzylthio)quinazolin-4(3H)-ones 5–11, 4–(2-(4-oxo-2-((2-(piperidin-1-yl)ethyl)thio)quinazolin-3(4H)-yl)ethyl)benzenesulfonamide (12) and 4-(2-(2-((3-(1,3-dioxoisoindolin-2-yl)propyl)thio)-4-oxoquinazolin-3(4H)-yl)ethyl)benzenesulfonamide (13) but lower than 4-(2-(4-Oxo-2-thioxo-1,4-dihydroquinazolin-3(2H)-yl)ethyl)benzenesulfonamide (1) as parent compound. Molecular docking studies for compounds 2 and 3 were done and exhibited specific binding modes for hCA isoforms as comparable interaction with lead compound 1.

Acknowledgements

The authors thank the Deanship of Scientific Research and RSSU at King Saud University for their technical support

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The authors extend their appreciation to the Deanship of Scientific Research at King Saud University for funding the work through the research group project No. RG-1435-046.

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