Synthesis, Enzyme Inhibition, and Acid Dissociation Constant of 1,4-Naphthoquinone Thiazole Hybrid

Year 2024, , 234 - 243, 01.09.2024

Yahya Nural , Yeliz Demir

https://doi.org/10.52794/hujpharm.1432876

Abstract

In this study, N-((Z)-4-((3r,5r,7r)-adamantan-1-yl)-3-(3-amino-1,4-dioxo-1,4-dihydronaphthalen-2yl)thiazol-2(3H)-ylidene)-2,6-difluorobenzamide 3 was synthesized as a new 1,4-naphthoquinone thiazole hybrid compound by reaction of naphthoquinone acyl thiourea compound 2 with 1-((3r,5r,7r)-adamantan-1-yl)-2-bromoethan-1-one in 74% yield and its molecular structure was characterized by various analytical techniques such as 1H/13C NMR, FT-IR, and HRMS. The inhibition effect of the synthesized compound on butyrylcholinesterase (BChE), acetylcholinesterase (AChE), and human carbonic anhydrase isoenzymes (hCA I and hCA II) was investigated. The product 3 showed varying degrees of inhibition 89.92 ± 10.47 nM (against hCA I), 51.60 ± 5.37 nM (against hCA II), 68.11 ± 6.58 nM (against AChE), and 126.90 ± 10.99 (against BChE). Although 1,4-naphthoquinone thiazole hybrid 3 showed significant enzyme activity against the enzymes tested, it showed a higher inhibition activity against the AChE enzyme than the standard drug Tacrine. Three acid dissociation constants (pKa) values (pKa1= 2.75±0.02, pKa2= 6.79±0.02, pKa3= 10.85±0.02) of the product were determined potentiometrically in 0.1 M NaCl ionic strength at 25.0±0.1 ºC in 25% (v/v) DMSO:water hydro organic medium.

Keywords

Thiazole, Enzyme inhibition, Acid dissociation constant, 1, 4-Naphthoquinone

1,4-Naftokinon Tiyazol Hibritinin Sentezi, Enzim İnhibisyonu ve Asit Ayrışma Sabiti

Abstract

Bu çalışmada, yeni naftokinon tiyazol hibriti 3 1-((3r,5r,7r)-adamantan-1-il)-2-bromoetan-1-on ile naftokinon açil tiyoüre bileşiğinin 2 tepkimesi ile 74% verimle sentezlendi ve moleküler yapısı çeşitli analitik tekniklerle karakterize edildi. Sentezlenen bileşiğin bütirilkolinesteraz (BChE), asetilkolinesteraz (AChE) ve insan karbonik anhidraz izoenzimleri (hCA I ve hCA II) üzerindeki inhibisyon etkisi araştırıldı. Ürün 3, 89,92 ± 10,47 nM (hCA I'e karşı), 51,60 ± 5,37 nM (hCA II'ye karşı), 68,11 ± 6,58 nM (AChE'ye karşı) ve 126,90 ± 10,99 (BChE'ye karşı) gibi değişen değerlerde inhibisyon gösterdi. Ürünün üç asit dissosiyasyon sabiti (pKa) değeri (pKa1= 2,75±0,02, pKa2= 6,79±0,02, pKa3= 10,85±0,02) belirlendi.

Keywords

1,4-Naftokinon, Tiyazol, Enzim inhibisyonu, Asit dissosiyasyon sabiti

References

• 1. Osmaniye D, Türkeş C, Demir Y, Özkay Y, Beydemir Ş, Kaplancıklı ZA. Design, synthesis, and biological activity of novel dithiocarbamate-methylsulfonyl hybrids as carbonic anhydrase inhibitors. Arch Pharm (Weinheim). 2022;355(8):2200132. https://doi: 10.1002/ardp.202200132.
• 2. Kakakhan C, Türkeş C, Güleç Ö, Demir Y, Arslan M, Özkemahlı G, Beydemir Ş. Exploration of 1, 2, 3-triazole linked benzenesulfonamide derivatives as isoform selective inhibitors of human carbonic anhydrase. Bioorg Med Chem. 2023;77:117111. https://doi.org/10.1016/j.bmc.2022.117111
• 3. Hoff E, Zou D, Schiza S, Demir Yeliz, Grote L, Bouloukaki I, Beydemir Ş, Eskandari D, Stenlöf K, Hedner J. Carbonic anhydrase, obstructive sleep apnea and hypertension: effects of intervention. J Sleep Res. 2020;29(2):e12956. https://doi. org/10.1111/jsr.12956
• 4. Buza A, Türkeş C, Arslan M, Demir Y, Dincer B, Nixha AR, Beydemir Ş. Discovery of novel benzenesulfonamides incorporating 1, 2, 3-triazole scaffold as carbonic anhydrase I, II, IX, and XII inhibitors. Int J Biol Macromol. 2023;239:124232. https://doi.org/10.1016/j.ijbiomac.2023.124232
• 5. Oztaskin N, Goksu S, Demir Y, Maras A, Gulcin İ. Synthesis of novel bromophenol with diaryl methanes—determination of their inhibition effects on carbonic anhydrase and acetylcholinesterase. Molecules. 2022;27(21):7426. https://doi. org/10.3390/molecules27217426
• 6. Türkeş C. Carbonic anhydrase inhibition by antiviral drugs in vitro and in silico. J Mol Recognit. 2023;36(12):e3063. https:// doi.org/10.1002/jmr.3063
• 7. Akocak S, Lolak N, Duran HE, Işık M, Türkeş C, Durgun M, Beydemir Ş. Synthesis and characterization of novel 1, 3-diaryltriazene-substituted sulfaguanidine derivatives as selective carbonic anhydrase inhibitors: Biological evaluation, in silico ADME/T and molecular docking study. Chem Biodivers. 2023;20(8):e202300611. https://doi.org/10.1002/ cbdv.202300611
• 8. Güven L, Can H, Ertürk A, Miloğlu F. D, Koca M, İnce F, Gülçin İ. Comprehensive metabolic profiling of Thymus canoviridis (endemic) and Thymus pubescens var. pubescens using UPLC-MS/MS and evaluation of their antioxidant activities, enzyme inhibition abilities, and molecular docking studies. South African J Bot. 2024;165:478–493. https://doi. org/10.1016/j.sajb.2023.12.015
• 9. Lolak N, Akocak S, Türkeş C, Taslimi P, Işık M, Beydemir Ş, Gülçin İ, Durgun M. Synthesis, characterization, inhibition effects, and molecular docking studies as acetylcholinesterase, α-glycosidase, and carbonic anhydrase inhibitors of novel benzenesulfonamides incorporating 1, 3, 5-triazine structural motifs. Bioorg Chem. 2020;100:103897. https://doi. org/10.1016/j.bioorg.2020.103897
• 10. Akocak S, Taslimi P, Lolak N, Işık M, Durgun M, Budak Y, Türkeş C, Gülçin İ, Beydemir Ş. Synthesis, characterization, and inhibition study of novel substituted phenylureido sulfaguanidine derivatives as α-glycosidase and cholinesterase inhibitors. Chem Biodivers. 2021;18(4):e2000958. https://doi. org/10.1002/cbdv.202000958
• 11. Türkeş C, Akocak S, Işık M, Taslimi PGülçin İ, Budak Y, Beydemir Ş. Novel inhibitors with sulfamethazine backbone: synthesis and biological study of multi-target cholinesterases and α-glucosidase inhibitors. J Biomol Struct Dyn. 2022;40(19):8752–8764. https://doi.org/10.1080/07391102.2 021.1916599
• 12. Soliman AM, Abd El-wahab HAA, Akincioglu H, Gülçin İ, Omar FA. Piperazine-2-carboxylic acid derivatives as MTDLs anti-Alzheimer agents: Anticholinesterase activity, mechanistic aspect, and molecular modeling studies. Bioorg Chem. 2024;142:106916. https://doi.org/10.1016/j. bioorg.2023.106916
• 13. Çomaklı V, Aygül İ, Sağlamtaş R, Kuzu M, Demirdağ R, Akincioğlu H, Adem Ş, Gülçin İ. Assessment of anticholinergic and antidiabetic properties of some natural and synthetic molecules: an in vitro and in silico approach. Curr Comput Aided Drug Des. 2024;20:441-451. https://doi.org/10.2174/15 73409919666230518151414
• 14. Gök Y, Taslimi P, Şen B, Bal S, Aktaş A, Aygün M, Sadeghi M, Gülçin İ. Design, synthesis, characterization, crystal structure, in silico studies, and inhibitory properties of the PEPPSI type Pd (II) NHC complexes bearing chloro/fluorobenzyl group. Bioorg Chem. 2023;135:106513. https://doi.org/10.1016/j. bioorg.2023.106513
• 15. Singh A, Malhotra D, Singh K, Chadha R, Bedi PMS. Thiazole derivatives in medicinal chemistry: Recent advancements in synthetic strategies, structure activity relationship and pharmacological outcomes. J Mol Struct. 2022;1266:133479. https://doi.org/10.1016/j.molstruc.2022.133479
• 16. Nural Y. Synthesis, antimycobacterial activity, and acid dissociation constants of polyfunctionalized 3-[2-(pyrrolidin- 1-yl)thiazole-5-carbonyl]-2 H-chromen-2-one derivatives. Monatsh Chem. 2018;149:1905–1918. https://doi. org/10.1007/s00706-018-2250-7
• 17. Jagadale SM, Abhale YK, Pawar HR, Shinde A, Bobade VD, Chavan AP, Sarkar D, Mhaske PC. Synthesis of new thiazole and pyrazole clubbed 1, 2, 3-triazol derivatives as potential antimycobacterial and antibacterial agents. Polycycl Aromat Compd. 2022;42(6):3216–3237. https://doi.org/10.1080/1040 6638.2020.1857272
• 18. Al-Shemary RK, Mohapatra RK, Kumar M, Sarangi AK, Azam M, Tuli HS, Ansari A, Mohapatra PK, Dhama K. Synthesis, structural investigations, XRD, DFT, anticancer and molecular docking study of a series of thiazole based Schiff base metal complexes. J Mol Struct. 2023;1275:134676. https:// doi.org/10.1016/j.molstruc.2022.134676
• 19. Alfi AA, Alharbi A, Qurban J, Abualnaja MM, Abumelha HM, Saad FA, El-Metwaly NM. Molecular modeling and docking studies of new antioxidant pyrazole-thiazole hybrids. J Mol Struct. 2022;1267:133582. https://doi.org/10.1016/j.molstruc. 2022.133582
• 20. Doğan A, Özdemir S, Yalcin M, Sari H, Nural Y. Naphthoquinone- thiazole hybrids bearing adamantane: Synthesis, antimicrobial, DNA cleavage, antioxidant activity, acid dissociation constant, and drug-likeness. J Res Pharm. 2021;25(3):292- 304. https://doi.org/10.29228/jrp.20
• 21. Efeoglu C, Selcuk O, Demir B, Sahin E, Sari H, Türkeş C, Demir Y, Nural Y, Beydemir Ş. New naphthoquinone thiazole hybrids as carbonic anhydrase and cholinesterase inhibitors: Synthesis, crystal structure, molecular docking, and acid dissociation constant. J Mol Struct. 2024;1301:137365. https:// doi.org/10.1016/j.molstruc.2023.137365
• 22. Sever B, Türkeş C, Altıntop MD, Demir Y, Akalın Çiftçi G, Beydemir Ş. Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds. Arch Pharm (Weinheim). 2021;354(12):2100294. https://doi.org/10.1002/ardp.202100294
• 23. Taha M, Hayat S, Rahim F, Uddin N, Wadood A, Nawaz M, Gollapalli M, Ur Rehman A, Khan KM, Farooq RK. Exploring thiazole-based Schiff base analogs as potent α-glucosidase and α-amylase inhibitor: their synthesis and in-silico study. J Mol Struct. 2023;1287:135672. https://doi.org/10.1016/j.molstruc. 2023.135672
• 24. Khan S, Ullah H, Taha M, Rahim F, Sarfraz M, Iqbal R, Iqbal N, Hussain R, Shah SAA, Ayub K, Albalawi MA, Abdelaziz MA, Alatawi FS, Khan KM. Synthesis, DFT studies, molecular docking and biological activity evaluation of thiazole-sulfon-amide derivatives as potent Alzheimer’s inhibitors. Molecules. 2023;28(2):559. https://doi.org/10.3390/molecules28020559
• 25. Hussain R, Ullah H, Rahim F, Sarfraz M, Taha M, Iqbal R, Rehman W, Khan S, Shah SAA, Hyder S, Alhomrani M, Alamri AS, Abdulaziz O, Abdelaziz, MA. Multipotent cholinesterase inhibitors for the treatment of Alzheimer’s disease: Synthesis, biological analysis and molecular docking study of benzimidazole- based thiazole derivatives. Molecules. 2022;27(18):6087. https://doi.org/10.3390/molecules27186087
• 26. Mor S, Khatri M. Synthesis, antimicrobial evaluation, α-amylase inhibitory ability and molecular docking studies of 3-alkyl-1-(4-(aryl/heteroaryl) thiazol-2-yl) indeno [1, 2-c] pyrazol-4(1H)-ones. J Mol Struct. 2022;1249:131526. https:// doi.org/10.1016/j.molstruc.2021.131526
• 27. Devi M, Kumar P, Singh R, Narayan L, Kumar A, Sindhu J, Lal S, Hussain K, Singh D. A comprehensive review on synthesis, biological profile and photophysical studies of heterocyclic compounds derived from 2, 3-diamino-1, 4-naphthoquinone. J Mol Struct. 2022;1269:133786. https://doi.org/10.1016/j.molstruc. 2022.133786
• 28. Qin T, Ma Y-Y, Dong C-E, Wu W-L, Feng Y-Y, Yang S, Su J-B, Si X-X, Wang X-J, Shi D-H. Design, synthesis, cytotoxicity evaluation and molecular docking studies of 1, 4-naphthoquinone derivatives. J Mol Struct. 2022;1263:133067. https://doi. org/10.1016/j.molstruc.2022.133067
• 29. Chaves-Carballo K, Lamoureux G V, Perez AL, Cruz AB, Cechinel Filho V. Novel one-pot synthesis of a library of 2-aryloxy-1, 4-naphthoquinone derivatives. Determination of antifungal and antibacterial activity. RSC Adv. 2022;12(29):18507–18523. https://doi.org/10.1039/ D2RA01814D
• 30. Nural Y, Gemili M, Yabalak E, De Coen L, Ulger M. Green synthesis of highly functionalized octahydropyrrolo [3, 4-c] pyrrole derivatives using subcritical water, and their anti(myco) bacterial and antifungal activity. Arkivoc. 2018;(5):51–64. https://doi.org/10.24820/ark.5550190.p010.573
• 31. Gholivand K, Faraghi M, Fallah N, Vahabirad M, Malekshah RE, Salimi F, Pournasir-roudbaneh M. New phosphoramides containing 2-amino-1, 4-naphthaquinone moiety as anticancer and antibacterial agents: Experimental and theoretical evaluations. Process Biochem. 2023;132:97–109. https://doi. org/10.1016/j.procbio.2023.06.015
• 32. Efeoglu C, Yetkin D, Nural Y, Ece A, Seferoğlu Z, Ayaz F. Novel urea-thiourea hybrids bearing 1, 4-naphthoquinone moiety: Anti-inflammatory activity on mammalian macrophages by regulating intracellular PI3K pathway, and molecular docking study. J Mol Struct. 2022;1264:133284. https:// doi.org/10.1016/j.molstruc.2022.133284
• 33. Canatar C, Türkben H, Efeoglu C, Sari H, Karasu E, Nural Y, Ayaz F. Anti-inflammatory potential of 1, 4-naphthoquinone acyl thiourea hybrids on lipopolysaccharide-activated mammalian macrophages, and their acid dissociation constants. ChemistrySelect. 2023;8(20):e202301258. https://doi. org/10.1002/slct.202301258
• 34. Nural Y, Ozdemir S, Doluca O, Demir B, Yalcin MS, Atabey H, Kanat B, Erat S, Sari H, Seferoglu Z. Synthesis, biological properties, and acid dissociation constant of novel naphthoquinone– triazole hybrids. Bioorg Chem. 2020;105:104441. https://doi.org/10.1016/j.bioorg.2020.104441
• 35. Hosseini S, Pourmousavi SA, Mahdavi M, Taslimi P. Synthesis, and in vitro biological evaluations of novel naphthoquinone conjugated to aryl triazole acetamide derivatives as potential anti-Alzheimer agents. J Mol Struct. 2022;1255:132229. https://doi.org/10.1016/j.molstruc.2021.132229
• 36. Chuanqian D, Baohua X, Ming H, Zhiye H, Yu L, Xue H, Fanyu L, Chen C, Hai-Bing Z, Shengtang H, Chun’e D. Design, synthesis and biological evaluation of pyrano [2, 3-b]- naphthoquinone derivatives as acetylcholinesterase inhibitors. Chinese J Org Chem. 2020;40(7):2035-2044. https://doi. org/10.6023/cjoc202002039
• 37. Riaz MT, Yaqub M, Shafiq Z, Ashraf A, Khalid M, Taslimi P, Tas R, Tuzun B, Gulcin I. Synthesis, biological activity and docking calculations of bis-naphthoquinone derivatives from Lawsone. Bioorg Chem. 2021;114:105069. https://doi. org/10.1016/j.bioorg.2021.105069
• 38. Estolano-Cobián A, Noriega-Iribe E, Díaz-Rubio L, Padrón JM, Brito-Perea M, Cornejo-Bravo JM, Chávez D, Rivera RR, Quintana-Melgoza JM, Cruz-Reyes J, Córdova-Guerrero I. Antioxidant, antiproliferative, and acetylcholinesterase inhibition activity of amino alcohol derivatives from 1,4-naphthoquinone. Med Chem Res. 2020;29:1986–1999. https://doi. org/10.1007/s00044-020-02617-1
• 39. Yu Y, Liu A, Dhawan G, Mei H, Zhang W, Izawa K, Soloshonok VA, Han, J. Fluorine-containing pharmaceuticals approved by the FDA in 2020: Synthesis and biological activity. Chinese Chem Lett. 2021; 32(11), 3342-3354. https://doi. org/10.1016/j.cclet.2021.05.042
• 40. Štimac A, Šekutor M, Mlinarić-Majerski K, Frkanec L, Frkanec R. Adamantane in Drug Delivery Systems and Surface Recognition. Molecules. 2017; 22(2):297. https://doi. org/10.3390/molecules22020297
• 41. Nural Y, Karasu E, Keleş E, Aydıner B, Seferoğlu N, Efeoğlu Ç. Şahin E, Seferoğlu Z. Synthesis of novel acylthioureas bearing naphthoquinone moiety as dual sensor for high-performance naked-eye colorimetric and fluorescence detection of CN− and F− ions and its application in water and food samples. Dye Pigment. 2022;198:110006. https://doi.org/10.1016/j. dyepig.2021.110006
• 42. Verpoorte JA, Mehta S, Edsall JT. Esterase activities of human carbonic anhydrases B and C. J Biol Chem. 1967;242(18):4221–4229. https://doi.org/10.1016/S0021- 9258(18)95800-X
• 43. Ellman GL, Courtney KD, Andres Jr V, Featherstone RM. A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol. 1961;7(2):88–95. https:// doi.org/10.1016/0006-2952(61)90145-9
• 44. Kirici M, Demir Y, Beydemir S, Atamanalp M. The effect of Al3+ and Hg2+ on glucose 6-phosphate dehydrogenase from capoeta umbla kidney. Appl Ecol Environ Res. 2016;14(2):253– 264.
• 45. Alım Z, Kılıç D, Demir Y. Some indazoles reduced the activity of human serum paraoxonase 1, an antioxidant enzyme: in vitro inhibition and molecular modeling studies. Arch Physiol Biochem. 2019;125(5):387–395. https://doi.org/10.1080/1381 3455.2018.1470646
• 46. Nural Y, Ozdemir S, Yalcin MS, Demir B, Atabey H, Seferoglu Z, Ece A. New bis-and tetrakis-1,2,3-triazole derivatives: Synthesis, DNA cleavage, molecular docking, antimicrobial, antioxidant activity and acid dissociation constants. Bioorg Med Chem Lett. 2022;55:128453. https://doi.org/10.1016/j. bmcl.2021.128453
• 47. Altun Y, Köseoğlu F, Demirelli H, Yılmaz İ, Çukurovalı A, Kavak N. Potentiometric studies on nickel (II), copper (II) and zinc (II) metal complexes with new schiff bases containing cyclobutane and thiazole groups in 60% dioxane-water mixture. J Braz Chem Soc. 2009;20:299–308. https://doi.org/10.1590/ S0103-50532009000200015
• 48. Ogretir C, Demirayak S, Duran M. Spectroscopic determination and evaluation of acidity constants for some drug precursor 2-amino-4-(3-or 4-substituted phenyl) thiazole derivatives. J Chem Eng Data. 2010;55(3):1137–1142. https://doi. org/10.1021/je9005739