Naphthoquinone–thiazole hybrids bearing adamantane: Synthesis, antimicrobial, DNA cleavage, antioxidant activity, acid dissociation constant, and drug-likeness

Abstract

In this study, four novel naphthoquinone–thiazole hybrids bearing adamantane were synthesized by reaction of naphthoquinone–aroylthiourea derivatives with 1-adamantyl bromomethyl ketone in 75-85% yield and were characterized using 1H/13C NMR, FT-IR, and HRMS techniques. Various biological activities of the synthesized compounds, such as antibacterial, antifungal, DNA cleavage, and antioxidant activities, were screened. The compounds showed antibacterial activity against Escherichia coli, Bacillus cereus, Staphylococcus aureus, Pseudomonas aeruginosa, Enterococcus hirae, and Legionella pneumophila subsp. pneumophila strains with MIC values in the range of 4–64 µg/mL and antifungal activity against Candida albicans strains with MIC values in the range of 16–64 µg/mL. The compounds had DNA cleavage activity at 250 and 500 µg/mL. Additionally, the antioxidant activity of the compounds was assessed based on the radical scavenging effect of the stable DPPH (2,2-diphenyl-1-picrylhydrazyl) free radical and the compounds exhibited acceptable antioxidant activity. The acid dissociation constants (pKa) of the compounds were determined potentiometrically in 30% (v/v) dimethyl sulfoxide–water at an ionic background of 0.1 mol L-1 NaCl, at 25 ± 0.1 °C, and the HYPERQUAD computer program was used to calculate the pKa values from the data obtained from potentiometric titrations. Prediction of the drug-likeness properties of the compounds was performed with the use of the MolSoft website, and the compounds had promising drug-likeness model scores within a range of 1.09–1.56.

Keywords

• Naphthoquinone
• thiazole
• adamantane
• antimicrobial
• antioxidant
• DNA cleavage
• acid dissociation constant
• drug-likeness

References

1. [1] Kuete V, Mbaveng AT, Sandjo LP, Zeino M, Efferth T. Cytotoxicity and mode of action of a naturally occurring naphthoquinone, 2-acetyl-7-methoxynaphtho [2, 3-b] furan-4, 9-quinone towards multi-factorial drug-resistant cancer cells. Phytomedicine 2007; 33: 62-68. [CrossRef]
2. [2] Aminin D, Polonik S. 1, 4-Naphthoquinones: Some biological properties and application. Chem Pharm Bull. 2020; 68(1): 46-57. [CrossRef]
3. [3] Alferova VA, Shuvalov MV, Korshun VA, Tyurin AP. Naphthoquinone-derived polyol macrolides from natural sources. Russ Chem Bull. 2019; 68(5): 955-966. [CrossRef]
4. [4] Li K, Wang B, Zheng L, Yang K, Li Y, Hu M, He D. Target ROS to induce apoptosis and cell cycle arrest by 5, 7-dimethoxy-1, 4-naphthoquinone derivative. Bioorg Med Chem Lett. 2018; 28(3): 273-277.[CrossRef]
5. [5] Gemili M, Nural Y, Keleş E, Aydıner B, Seferoğlu N, Ülger M, Şahin E, Erat S, Seferoğlu Z. Novel highly functionalized 1, 4-naphthoquinone 2-iminothiazole hybrids: Synthesis, photophysical properties, crystal structure, DFT studies, and anti(myco)bacterial/antifungal activity. J Mol Struct. 2019; 1196: 536-546.[CrossRef]
6. [6] Sánchez-Calvo JM, Barbero GR, Guerrero-Vásquez G, Durán AG, Macías M, Rodríguez-Iglesias MA, Molinillo JMG, Macías FA. Synthesis, antibacterial and antifungal activities of naphthoquinone derivatives: a structure–activity relationship study. Med Chem Res. 2016; 25(6): 1274-1285. [CrossRef]
7. [7] Nural Y, Ozdemir S, Doluca S, Demir B, Serkan Yalcin M, 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. [CrossRef]
8. [8] Vale VV, Cruz JN, Viana GMR, Póvoa MM, Brasil DDSB, Dolabela MF. Naphthoquinones isolated from Eleutherine plicata herb: In vitro antimalarial activity and molecular modeling to investigate their binding modes. Med Chem Res. 2020; 29(3): 487-494. [CrossRef]

9. [9] Mathiyazhagan K, Kumaran A, Arjun P. Isolation of natural naphthoquinones from juglans regia and in vitro antioxidant and cytotoxic studies of naphthoquinones and the synthetic naphthofuran derivatives. Russ J Bioorg Chem. 2018; 44(3): 346-353. [CrossRef]
10. [10] Abbas G, Hassan Z, Al-Harrasi A, Al-Adawi A, Ali M. Synthesis, biological evaluation, molecular docking and structure-activity relationship studies of halogenated quinone and naphthoquinone derivatives. J Mol Struct. 2019; 1195: 462-469. [CrossRef]
11. [11] Mohamady S, Gibriel AA, Ahmed MS, Hendy MS, Naguib BH. Design and novel synthetic approach supported with molecular docking and biological evidence for naphthoquinone-hydrazinotriazolothiadiazine analogs as potential anticancer inhibiting topoisomerase-IIB. Bioorg Chem. 2020; 96: 103641. [CrossRef]
12. [12] Alimohammadi A, Mostafavi H, Mahdavi M. Thiourea Derivatives Based on the Dapsone‐Naphthoquinone Hybrid as Anticancer and Antimicrobial Agents: In Vitro Screening and Molecular Docking Studies. ChemistrySelect. 2020; 5(2): 847-852.[CrossRef]
13. [13] Manickam M, Boggu PR, Cho J, Nam YJ, Lee SJ, Jung SH. Investigation of chemical reactivity of 2-alkoxy-1, 4-naphthoquinones and their anticancer activity. Bioorg Med Chem Lett. 2018; 28(11): 2023-2028.[CrossRef]
14. [14] Ullah S, Akter J, Kim SJ, Yang J, Park Y, Chun P, Moon HR. The tyrosinase-inhibitory effects of 2-phenyl-1, 4-naphthoquinone analogs: importance of the (E)-β-phenyl-α, β-unsaturated carbonyl scaffold of an endomethylene type. Med Chem Res. 2019; 28(1): 95-103. [CrossRef]
15. [15] González A, Becerra N, Kashif M, González M, Cerecetto H, Aguilera E, Nogueda-Torres B, Chacón-Vargas KF, Zarate-Ramos JJ, Castillo-Velázquez U, Salas CO, Gildardo Rivera G, Vázquez K. In vitro and in silico evaluations of new aryloxy-1, 4-naphthoquinones as anti-Trypanosoma cruzi agents. Med Chem Res. 2020; 29: 665-674. [CrossRef]
16. [16] Wu Q, Er‐bu, A, Liang X, Luan S, Wang Y, Yin Z, He C, Yin L, Zou Y, Li L, Song, X. Evaluation of antioxidant and anticancer activities of naphthoquinones‐enriched ethanol extracts from the roots of Onosma hookeri Clarke. var. longiforum Duthie. Food Sci Nutr. 2020; 8(8): 4320-4329. [CrossRef]
17. [17] Sharma PC, Bansal KK, Sharma A, Sharma D, Deep A. Thiazole-containing compounds as therapeutic targets for cancer therapy. Eur J Med Chem. 2020; 188: 112016. [CrossRef]
18. [18] Arshadi S, Vessally E, Edjlali L, Hosseinzadeh-Khanmiri R, Ghorbani-Kalhor E. N-Propargylamines: versatile building blocks in the construction of thiazole cores. Beilstein J Org Chem. 2017; 13(1): 625-638. [CrossRef]
19. [19] Arora P, Narang R, Nayak SK, Singh SK, Judge V. 2, 4-Disubstituted thiazoles as multitargated bioactive molecules. Med Chem Res. 2016; 25(9): 1717-1743. [CrossRef]
20. [20] Ayati A, Emami S, Asadipour A, Shafiee A, Foroumadi A. Recent applications of 1, 3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur J Med Chem. 2015; 97: 699-718. [CrossRef]
21. [21] Pawar CD, Sarkate AP, Karnik KS, Bahekar SS, Pansare DN, Shelke RN, Jawale CS, Shinde DB. Synthesis and antimicrobial evaluation of novel ethyl 2-(2-(4-substituted) acetamido)-4-subtituted-thiazole-5-carboxylate derivatives. Bioorg Med Chem Lett. (2016); 26(15): 3525-3528. [CrossRef]
22. [22] Nural Y, Gemili M, Ulger M, Sari H, De Coen LM, Sahin E. Synthesis, antimicrobial activity and acid dissociation constants of methyl 5, 5-diphenyl-1-(thiazol-2-yl) pyrrolidine-2-carboxylate derivatives. Bioorg Med Chem Lett. 2018; 28(5): 942-946. [CrossRef]
23. [23] Nural Y, Gemili M, Yabalak E, De Coen LM, 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. [CrossRef]
24. [24] Nural, Y. Synthesis, antimycobacterial activity, and acid dissociation constants of polyfunctionalized 3-[2-(pyrrolidin-1-yl) thiazole-5-carbonyl]-2H-chromen-2-one derivatives. Monatsh Chem. 2018; 149(10): 1905-1918. [CrossRef]
25. [10] Abbas G, Hassan Z, Al-Harrasi A, Al-Adawi A, Ali M. Synthesis, biological evaluation, molecular docking and structure-activity relationship studies of halogenated quinone and naphthoquinone derivatives. J Mol Struct. 2019; 1195: 462-469. [CrossRef]
26. [11] Mohamady S, Gibriel AA, Ahmed MS, Hendy MS, Naguib BH. Design and novel synthetic approach supported with molecular docking and biological evidence for naphthoquinone-hydrazinotriazolothiadiazine analogs as potential anticancer inhibiting topoisomerase-IIB. Bioorg Chem. 2020; 96: 103641. [CrossRef]
27. [12] Alimohammadi A, Mostafavi H, Mahdavi M. Thiourea Derivatives Based on the Dapsone‐Naphthoquinone Hybrid as Anticancer and Antimicrobial Agents: In Vitro Screening and Molecular Docking Studies. ChemistrySelect. 2020; 5(2): 847-852. [CrossRef]
28. [13] Manickam M, Boggu PR, Cho J, Nam YJ, Lee SJ, Jung SH. Investigation of chemical reactivity of 2-alkoxy-1, 4-naphthoquinones and their anticancer activity. Bioorg Med Chem Lett. 2018; 28(11): 2023-2028.[CrossRef]
29. [14] Ullah S, Akter J, Kim SJ, Yang J, Park Y, Chun P, Moon HR. The tyrosinase-inhibitory effects of 2-phenyl-1, 4-naphthoquinone analogs: importance of the (E)-β-phenyl-α, β-unsaturated carbonyl scaffold of an endomethylene type. Med Chem Res. 2019; 28(1): 95-103. [CrossRef]
30. [15] González A, Becerra N, Kashif M, González M, Cerecetto H, Aguilera E, Nogueda-Torres B, Chacón-Vargas KF, Zarate-Ramos JJ, Castillo-Velázquez U, Salas CO, Gildardo Rivera G, Vázquez K. In vitro and in silico evaluations of new aryloxy-1, 4-naphthoquinones as anti-Trypanosoma cruzi agents. Med Chem Res. 2020; 29: 665-674. [CrossRef]
31. [16] Wu Q, Er‐bu, A, Liang X, Luan S, Wang Y, Yin Z, He C, Yin L, Zou Y, Li L, Song, X. Evaluation of antioxidant and anticancer activities of naphthoquinones‐enriched ethanol extracts from the roots of Onosma hookeri Clarke. var. longiforum Duthie. Food Sci Nutr. 2020; 8(8): 4320-4329. [CrossRef]
32. [17] Sharma PC, Bansal KK, Sharma A, Sharma D, Deep A. Thiazole-containing compounds as therapeutic targets for cancer therapy. Eur J Med Chem. 2020; 188: 112016. [CrossRef]
33. [18] Arshadi S, Vessally E, Edjlali L, Hosseinzadeh-Khanmiri R, Ghorbani-Kalhor E. N-Propargylamines: versatile building blocks in the construction of thiazole cores. Beilstein J Org Chem. 2017; 13(1): 625-638. [CrossRef]
34. [19] Arora P, Narang R, Nayak SK, Singh SK, Judge V. 2, 4-Disubstituted thiazoles as multitargated bioactive molecules. Med Chem Res. 2016; 25(9): 1717-1743. [CrossRef]
35. [20] Ayati A, Emami S, Asadipour A, Shafiee A, Foroumadi A. Recent applications of 1, 3-thiazole core structure in the identification of new lead compounds and drug discovery. Eur J Med Chem. 2015; 97: 699-718. [CrossRef]
36. [21] Pawar CD, Sarkate AP, Karnik KS, Bahekar SS, Pansare DN, Shelke RN, Jawale CS, Shinde DB. Synthesis and antimicrobial evaluation of novel ethyl 2-(2-(4-substituted) acetamido)-4-subtituted-thiazole-5-carboxylate derivatives. Bioorg Med Chem Lett. (2016); 26(15): 3525-3528. [CrossRef]
37. [22] Nural Y, Gemili M, Ulger M, Sari H, De Coen LM, Sahin E. Synthesis, antimicrobial activity and acid dissociation constants of methyl 5, 5-diphenyl-1-(thiazol-2-yl) pyrrolidine-2-carboxylate derivatives. Bioorg Med Chem Lett. 2018; 28(5): 942-946. [CrossRef]
38. [23] Nural Y, Gemili M, Yabalak E, De Coen LM, 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. [CrossRef] [24] Nural, Y. Synthesis, antimycobacterial activity, and acid dissociation constants of polyfunctionalized 3-[2-(pyrrolidin-1-yl) thiazole-5-carbonyl]-2H-chromen-2-one derivatives. Monatsh Chem. 2018; 149(10): 1905-1918. [CrossRef]
39. [42] Nural Y, Gemili M, Seferoglu N, Sahin E, Ulger M, Sari H. Synthesis, crystal structure, DFT studies, acid dissociation constant, and antimicrobial activity of methyl 2-(4-chlorophenyl)-7a-((4-chlorophenyl) carbamothioyl)-1-oxo-5,5-diphenyl-3-thioxo-hexahydro-1H-pyrrolo[1, 2-e]imidazole-6-carboxylate. J Mol Struct. 2018; 1160: 375-382. [CrossRef]
40. [43] El-Sherif AA, Shoukry MM, Abd-Elgawad MM. Protonation equilibria of some selected α-amino acids in DMSO–water mixture and their Cu (II)-complexes. J Solution Chem. 2013; 42(2): 412-427. [CrossRef]
41. [44] 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(2): 299-308. [CrossRef]
42. [45] Jia CY, Li JY, Hao GF, Yang GF. A drug-likeness toolbox facilitates ADMET study in drug discovery. Drug Discovery Today 2020; 25(1): 248-258. [CrossRef]
43. [46] Tian S, Wang J, Li Y, Li D, Xu L, Hou T. The application of in silico drug-likeness predictions in pharmaceutical research. Adv Drug Delivery Rev. 2015; 86: 2-10. [CrossRef]
44. [47] L.L.C. MolSoft. MolSoft Molecules in Silico (2020) http://molsoft.com/mprop/, Accessed 26th August 2020.
45. [48] Desai NC, Kotadiya GM, Trivedi AR. Studies on molecular properties prediction, antitubercular and antimicrobial activities of novel quinoline based pyrimidine motifs. Bioorg Med Chem Lett. 2014; 24(14): 3126-3130. [CrossRef]
46. [49] Dinis TCP, Madeira VMC, Almeida LM. Action of phenolic derivatives (acetaminophen, salicylate, and 5-aminosalicylate) as inhibitors of membrane lipid peroxidation and as peroxyl radical scavengers. Arch Biochem Biophy. 1994; 315(1): 161-169. [CrossRef] [50] Pettit LD. (1992) Academic Software, Sourby Farm, Timble, Otley, LS21 2PW, UK.