İlhami GÜLÇİN, Barış ANIL, Halise İnci GÜL, Mehtap TUĞRAK

Synthesis and pharmacological effects of novel benzenesulfonamides carrying benzamide moiety as carbonic anhydrase and acetylcholinesterase inhibitors

N-(1-(4-Methoxyphenyl)-3-oxo-3-((4-(N-(substituted)sulfamoyl)phenyl)amino)prop-1-en-1-yl)benzamides 3a – g were designed since sulfonamide and benzamide pharmacophores draw great attention in novel drug design due to their wide range of bioactivities including acetylcholinesterase (AChE) and human carbonic anhydrase I and II (hCA I and hCA II) inhibitory potencies. Structure elucidation of the compounds was carried out by 1 H NMR, $^{13}C NMR$, and HRMS spectra. In vitro enzyme assays showed that the compounds had significant inhibitory potential against hCA I, hCA II, and AChE enzymes at nanomolar levels. Ki values were in the range of 4.07 ± 0.38 – 29.70 ± 3.18 nM for hCA I and 10.68 ± 0.98 – 37.16 ± 7.55 nM for hCA II while Ki values for AChE were in the range of 8.91 ± 1.65 – 34.02 ± 5.90 nM. The most potent inhibitors 3g (Ki = 4.07 ± 0.38 nM, hCA I), 3c (Ki = 10.68 ± 0.98 nM, hCA II), and 3f (Ki = 8.91 ± 1.65 nM, AChE) can be considered as lead compounds of this study with their promising bioactivity results. Secondary sulfonamides showed promising enzyme inhibitory effects on AChE while primary sulfonamide derivative was generally effective on hCA I and hCA II isoenzymes.

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1. Akı-Şener E, Bingöl KK, Temiz-Arpacı Ö, Yalçın İ, Altanlar N. Synthesis and microbiological activity of some N-(2-hydroxy-4-substituted phenylbenzamides, phenylacetamides and furamides as the possible metabolites of antimicrobial active benzoxazoles. Il Farmaco 2002; 57 (6): 451-456. doi: 10.1016/s0014-827x(02)01226-0
2. Akı Şener E, Bingöl KK, Ören İ, Temiz Arpacı Ö, Yalçın İ et al. Synthesis and microbiological activity of some N-(o-hydroxyphenyl) benzamides and phenylacetamides as the possible metabolites of antimicrobial active benzoxazoles: part II. Il Farmaco 2000; 55 (6-7): 469-476. doi: 10.1016/s0014-827x(00)00070-7
3. Pau A, Boatto G, Palomba M, Asproni B, Cerri R et al. Synthesis of N-[4-(alkyl)cyclohexyl]-substituted benzamides with antiinflammatory and analgesic activities. Il Farmaco 1999; 54 (8): 524-532. doi: 10.1016/s0014-827x(99)00057-9
4. Asif M. Pharmacological potential of benzamide analogues and their uses in medicinal chemistry. Modern Chemistry Applications 2016; 4 (4): 1-10. doi: 10.4172/2329-6798.1000194
5. Bondi MW, Edmonds EC, Salmon DP. Alzheimer’s disease: past, present, and future. Journal of the International Neuropsychological Society 2017; 23 (9-10): 818-831. doi: 10.1017/S135561771700100X
6. Karlawish J, Jack CR, Rocca WA, Snyder HM, Carrillo MC. Alzheimer’s disease: the next frontier-special report 2017. Alzheimers Dement 2017; 13 (4): 374-380. doi: 10.1016/j.jalz.2017.02.006
7. Realdon O, Rossetto F, Nalin M, Baroni I, Cabinio M et al. Technology-enhanced multi-domain at home continuum of care program with respect to usual care for people with cognitive impairment: the Ability-TelerehABILITation study protocol for a randomized controlled trial. BMC Psychiatry 2016; 16: 425-433. doi: 10.1186/s12888-016-1132-y
8. Sobolova K, Hrabinova M, Hepranova V, Kucera T, Tereza Kobrlova T et al. Discovery of novel berberine derivatives with balanced cholinesterase and prolyl oligopeptidase inhibition profile. European Journal of Medicinal Chemistry 2020; 203: 112593. doi: 10.1016/j. ejmech.2020.112593
9. Sawatzky E, Wehle S, Kling B, Wendrich J, Bringmann G et al. Discovery of highly selective and nanomolar carbamate-based butyrylcholinesterase inhibitors by rational investigation into their inhibition mode. Journal of Medicinal Chemistry 2016; 59 (5): 2067- 2082. doi: 10.1021/acs.jmedchem.5b01674
10. Darvesh S. Butyrylcholinesterase as a diagnostic and therapeutic target for Alzheimer’s disease. Current Alzheimer Research 2016; 13 (10): 1173-1177. doi: 10.2174/1567205013666160404120542
11. Kratky M, Stepankova S, Houngbedji NH, Vosatka R, Vorcakova K et al. 2-Hydroxy-N-phenylbenzamides and their esters inhibit acetylcholinesterase and butyrylcholinesterase. Biomolecules 2019; 9 (11): 698-714. doi: 10.3390/biom9110698
12. Gul HI, Tugrak M, Sakagami H, Taslimi P, Gulcin I et al. Synthesis and bioactivity studies on new 4-(3-(4-Substitutedphenyl)-3a,4- dihydro-3H-indeno[1,2-c]pyrazol-2-yl) benzenesulfonamides. Journal of Enzyme Inhibition Medicinal Chemistry 2016; 31 (6): 1619- 1624. doi: 10.3109/14756366.2016.1160077
13. Tugrak M, Gul HI, Sakagami H, Gulcin I, Supuran CT. New azafluorenones with cytotoxic and carbonic anhydrase inhibitory properties: 2-Aryl-4-(4-hydroxyphenyl)-5H-indeno[1,2-b]pyridin-5-ones. Bioorganic Chemistry 2018; 81: 433-439. doi: 10.1016/j. bioorg.2018.09.013
14. Supuran CT. Carbonic anhydrases: novel therapeutic applications for inhibitors and activators. Nature Reviews Drug Discovery 2008; 7 (2): 168-181. doi: 10.1038/nrd2467
15. Supuran CT. Structure and function of carbonic anhydrases. Biochemistry Journal 2016; 473 (14): 2023-2032. doi: 10.1042/BCJ20160115
16. Supuran CT. Carbonic anhydrases and metabolism. Metabolites 2018; 8 (2): 25-30. doi: 10.3390/metabo8020025
17. Manasa KL, Pujitha S, Sethi A, Mohammed A, Alvala M et al. Synthesis and biological evaluation of imidazo[2 ,1-b] thiazole based sulfonyl piperazines as novel carbonic anhydrase II inhibitors. Metabolites 2020; 10 (4): 136-144. doi: 10.3390/metabo10040136
18. Supuran CT. Carbonic anhydrase inhibitors. Bioorganic and Medicinal Chemistry Letters 2010; 20 (12): 3467-3474. doi: 10.1016/j. bmcl.2010.05.009
19. Soliman AM, Ghorab MM, Bua S, Supuran CT. Iodoquinazolinones bearing benzenesulfonamide as human carbonic anhydrase I, II, IX and XII inhibitors: Synthesis, biological evaluation and radiosensitizing activity. Europan Journal of Medicinal Chemistry 2020; 200: 112449. doi: 10.1016/j.ejmech.2020.112449
20. Supuran CT. How many carbonic anhydrase inhibition mechanisms exist? Journal of Enzyme Inhibition and Medicinal Chemistry 2016; 31 (3): 345-360. doi: 10.3109/14756366.2015.1122001
21. Saleem M, Saeed A, Atia-tul-Wahab, Khan A, Abbasi S et al. Benzamide sulfonamide derivatives: potent inhibitors of carbonic anhydraseII. Medicinal Chemistry Research 2016; 25 (3): 438-448. doi: 10.1007/s00044-015-1493-7
22. Wani TV, Bua S, Khude PS, Chowdhary AH, Supuran CT et al. Evaluation of sulphonamide derivatives acting as inhibitors of human carbonic anhydrase isoforms I, II and Mycobacterium tuberculosis beta-class enzyme Rv3273. Journal of Enzyme Inhibition Medicinal Chemistry 2018; 33 (1): 962-971. doi: 10.1080/14756366.2018.1471475
23. Georgey HH, Manhi FM, Mahmoud WR, Mohamed NA, Berrino E et al. 1,2,4-Trisubstituted imidazolinones with dual carbonic anhydrase and p38 mitogen-activated protein kinase inhibitory activity. Bioorganic Chemistry 2019; 82: 109-116. doi: 10.1016/j. bioorg.2018.09.037
24. Sağlık BN, Osmaniye D, Çevik UA, Levent S, Kaya Çavuşoğlu B et al. Synthesis, characterization and carbonic anhydrase I and II inhibitory evaluation of new sulfonamide derivatives bearing dithiocarbamate. Europan Journal of Medicinal Chemistry 2020; 198:112392. doi: 10.1016/j.ejmech.2020.112392
25. Ulus R, Aday B, Tanç M, Supuran CT, Kaya M. Microwave assisted synthesis of novel acridine-acetazolamide conjugates and investigation of their inhibition effects on human carbonic anhydrase isoforms hCA I, II, IV and VII. Bioorganic and Medicinal Chemistry 2016; 24 (16): 3548-3555. doi: 10.1016/j.bmc.2016.05.064
26. Abdoli M, Bozdag M, Angeli A, Supuran CT. Benzamide-4-sulfonamides are effective human carbonic anhydrase I, II, VII, and IX inhibitors. Metabolites 2018; 8 (2): 37-48. doi: 10.3390/metabo8020037
27. Başar E, Tunca E, Bülbül M, Kaya M. Synthesis of novel sulfonamides under mild conditions with effective inhibitory activity against the carbonic anhydrase isoforms I and II. Journal of Enzyme Inhibition and Medicinal Chemistry 2016; 31 (6): 1356-1361. doi: 10.3109/14756366.2015.1134524
28. Bozdag M, Alafeefy AM, Altamimi AM, Vullo D, Carta F et al. Coumarins and other fused bicyclic heterocycles with selective tumorassociated carbonic anhydrase isoforms inhibitory activity. Bioorganic and Medicinal Chemistry 2017; 25 (2): 677-683. doi: 10.1016/j. bmc.2016.11.039
29. Rodriguez-Lavado J, Gallardo-Garrido C, Mallea M, Bustos V, Osorio R et al. Synthesis, in vitro evaluation and molecular docking of a new class of indolylpropyl benzamidopiperazines as dual AChE and SERT ligands for Alzheimer’s disease. European Journal of Medicinal Chemistry 2020; 198: 112368. doi: 10.1016/j.ejmech.2020.112368
30. Chirra S, Jupally VR. Anti-inflammatory and antioxidant activity of novel dehydro peptides. World Journal of Pharmacy and Pharmaceutical Sciences 2016; 5 (2): 1015-1022.
31. Vanghelovici M, Lupsa I, Bilegan C, Muste A. Studies in the oxazolone group. V. Condensation of oxazolones with paminobenzenesulfonamide, ethanolamine, and anesthesine. Acad. rep. populare Romine Baza cercetari stiint. Timisoara Studii cercetari stiint. Ser. stiint. chim 1960; 6: 103-110 (in Romani).
32. Akbaba Y, Akıncıoglu A, Göçer H, Göksu S, Gülçin İ et al. Carbonic anhydrase inhibitory properties of novel sulfonamide derivatives of aminoindanes and aminotetralins. Journal of Enzyme Inhibition and Medicinal Chemistry 2014; 29 (1): 35-42. doi: 10.3109/14756366.2012.750311
33. Verpoorte JA, Mehta S, Edsall JT. Esterase activities of human carbonic anhydrases B and C. Journal of Biological Chemistry 1967; 242 (18): 4221-4229.
34. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analitical Biochemistry 1976; 72: 248-254. doi: 10.1016/0003-2697(76)90527-3
35. Tugrak M, Gul HI, Sakagami H, Gulcin I. Synthesis, cytotoxic, and carbonic anhydrase inhibitory effects of new 2-(3-(4-methoxyphenyl)- 5-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)benzo[d]thiazole derivatives. Journal of Heterocyclic Chemistry 2020; 57 (7): 2762-2768. doi: 10.1002/jhet.3985
36. Gul HI, Tugrak M, Gul M, Mazlumoglu S, Sakagami H et al. New phenolic Mannich bases with piperazines and their bioactivities. Bioorganic Chemistry 2019; 90: 103057. doi: 10.1016/j.bioorg.2019.103057
37. Tugrak M, Gul HI, Bandow K, Sakagami H, Gulcin I et al. Synthesis and biological evaluation of some new mono Mannich bases with piperazines as possible anticancer agents and carbonic anhydrase inhibitors. Bioorganic Chemistry 2019; 90: 103095. doi: 10.1016/j. bioorg.2019.103095
38. Ellman GL, Courtney KD, Andres V. Feather-Stone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochemical Pharmacology 1961; 7: 88-95. doi: 10.1016/0006-2952(61)90145-9
39. Yamali C, Gul HI, Kazaz C, Levent S, Gulcin I. Synthesis, structure elucidation, and in vitro pharmacological evaluation of novel polyfluoro substituted pyrazoline type sulfonamides as multi-target agents for inhibition of acetylcholinesterase and carbonic anhydrase I and II enzymes. Bioorganic Chemistry 2020; 96: 103627. doi: 10.1016/j.bioorg.2020.103627
40. Lineweaver H, Burk D. The determination of enzyme dissociation constants. Journal of American Chemical Society 1934; 56: 658-666. doi: 10.1021/ja01318a036
41. Yiğit B, Kaya R, Taslimi P, Işık Y, Karaman M et al. Imidazolinium chloride salts bearing wingtip groups: synthesis, molecular docking and metabolic enzymes inhibition. Journal of Molecular Structure 2019; 1179: 709-718. doi: 10.1016/j.molstruc.2018.11.038