Isoxazole analogues of dibenzazepine as possible leads against ulcers and skin disease: In vitro and in silico exploration.

Autor: Khan M; Department of Biochemistry, University of Malakand, Chakdara, KPK 18800, Pakistan.; Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman., Halim SA; Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman., Shah L; Department of Biochemistry, Faculty of Biological and Health Sciences, Hazara University, Mansehra 21120, Pakistan., Khan A; Natural and Medical Sciences Research Center, University of Nizwa, PO Box 33, 616 Birkat Al Mauz, Nizwa, Oman., Ahmed IE; Department of Internal Medicine, Faculty of Medicine, University of Tabuk, P.O Box 741, Tabuk 71491, Saudi Arabia., Abdalla AN; Department of Pharmacology and Toxicology, College of Pharmacy, Umm Al-Qura University, Makkah 21955, Saudi Arabia., Jan A; Umm Al-Qura University, Faculty of Medicine, Department of Biochemistry, Makkah, Kingdom of Saudi Arabia., Khalid A; Substance Abuse and Toxicology Research Center, Jazan University, P.O. Box: 114, Jazan 45142, Saudi Arabia., Mushtaque A; Institute of Microbiology, University of Veterinary & Animal Sciences, Lahore 54000, Pakistan., Al-Harrasi A; Department of Internal Medicine, Faculty of Medicine, University of Tabuk, P.O Box 741, Tabuk 71491, Saudi Arabia.
Jazyk: angličtina
Zdroj: Saudi pharmaceutical journal : SPJ : the official publication of the Saudi Pharmaceutical Society [Saudi Pharm J] 2023 Dec; Vol. 31 (12), pp. 101877. Date of Electronic Publication: 2023 Nov 16.
DOI: 10.1016/j.jsps.2023.101877
Abstrakt: Utilizing multi-target drugs shows great promise as an effective strategy against polygenic diseases characterized by intricate patho-mechanisms, such as ulcers, skin dermatitis, and cancers. The current research centers around the creation of hybrid compounds, connecting dibenzazepine and isoxazole, with the aim of exploring their potential as inhibitors for urease and tyrosinase enzymes. Analogs 6a, 6b, 6d, 6 h-6j, and 6 l demonstrated strong inhibitory potential against tyrosinase enzyme with IC 50 values of 4.32 ± 0.31-12.36 ± 0.48. Whereas analogs 6a, 6c, 6e, 6f, 6h-6m, and 6r exhibited potent inhibitory activities against urease enzyme with IC 50 values of 3.67 ± 0.91-15.60 ± 0.18 μM. Furthermore, compounds 6i, 6n, and 6r showed weak toxic effect in BJ-cell line, whereas the remaining compounds were found non-toxic to normal cell line. The mechanistic studies of potent inhibitors of both the enzymes showed competitive mode of inhibition. Molecular docking was employed to establish the relationship between structure and activity and to elucidate the interaction mechanism. This analysis revealed that the active analogs exhibited crucial interactions with the active site residues of urease and tyrosinase, thus corroborating our experimental results. Hence, the generated derivatives of dibenzazepine-linked isoxazoles present intriguing starting points for further investigations into their potential as inhibitors of urease and tyrosinase, with the potential for future modification and enhancement.
Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2023 The Authors.)
Databáze: MEDLINE
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