TY - JOUR
T1 - Flavone-based hydrazones as new tyrosinase inhibitors
T2 - Synthetic imines with emerging biological potential, SAR, molecular docking and drug-likeness studies
AU - Alsantali, Reem I I.
AU - Mughal, Ehsan Ullah U.
AU - Naeem, Nafeesa
AU - Alsharif, Meshari A A.
AU - Sadiq, Amina
AU - Ali, Anser
AU - Jassas, Rabab S
AU - Javed, Qamar
AU - Javid, Asif
AU - Sumrra, Sajjad Hussain
AU - Alsimaree, Abdulrahman A A.
AU - Zafar, Muhammad Naveed N.
AU - Asghar, Basim H H.
AU - Altass, Hatem M M.
AU - Moussa, Ziad
AU - Ahmed, Saleh A A.
N1 - Funding Information:
The authors would like to extend their sincere appreciation to Taif University Researchers Supporting Project number (TURSP-2020/312), Taif University, Taif, Saudi Arabia. The authors are also highly grateful to the Higher Education Commission of Pakistan (HEC) for providing financial assistance under Project No. (NRPU-6484).
Funding Information:
The authors would like to extend their sincere appreciation to Taif University Researchers Supporting Project number (TURSP-2020/312), Taif University, Taif, Saudi Arabia. The authors are also highly grateful to the Higher Education Commission of Pakistan (HEC) for providing financial assistance under Project No. (NRPU-6484).
Publisher Copyright:
© 2021 Elsevier B.V.
PY - 2022/3/5
Y1 - 2022/3/5
N2 - Targeting tyrosinase (TYR), a key enzyme responsible for melanogenesis disorders, is a well-known approach utilized for the development of melanogenesis inhibitor. A variety of dermatological disorders and microbial skin infections can cause hyperpigmentation. Hence, exploring new scaffolds for the treatment of melanogenesis disease is an inspiring goal. In this context, a series of varyingly substituted flavone-based hydrazones have been designed, synthesized and characterized successfully. The present study describes the discovery of novel mushroom tyrosinase inhibitors (TIs) for treating hyperpigmentation. In due course, flavone scaffold has been incorporated into the novel chemotypes that exhibit in vitro inhibitory effects against mushroom tyrosinase for the purpose of discovering anti‐melanogenic agents. Biological investigations of prepared analogs herein demonstrated moderate to excellent activity against most of the fungal-bacterial strains and their activity is comparable to those of commercially available antibiotics i.e., Ciprofloxacin and Ketoconazole. Based on in vitro tyrosinase inhibitory assay, some compounds exhibited potent inhibition particularly, 3g (IC50 = 1.40 ± 0.16 µM), 3j (IC50 = 0.95 ± 0.07 µM), 3o (IC50 = 1.13 ± 0.11 µM), and 3q (IC50 = 1.01 ± 0.1 µM) showed best inhibition i.e., 0.7, 0.5, 0.6 and 0.5 folds, respectively, than kojic acid (IC50 = 1.79 ± 0.6 µM). Lineweaver-Burk plots demonstrated that the most potential derivative 3j tyrosinase inhibition proceeds via non-competitive pathway and the Michaelis-Menton constant (Km) value is 0.0265. Molecular modeling was performed for all tested analogs (3a–3q) using a model of mushroom tyrosinase to find crucial binding modes liable for inhibitory activity. The SARs were preliminarily examined, and the docking study revealed that analogs 3j, 3o and 3p had a strong binding association to tyrosinase (2Y9X). Furthermore, a drug-likeness study was employed and confirmed the favorable activity of the new analogs as a new anti-tyrosinase agent.
AB - Targeting tyrosinase (TYR), a key enzyme responsible for melanogenesis disorders, is a well-known approach utilized for the development of melanogenesis inhibitor. A variety of dermatological disorders and microbial skin infections can cause hyperpigmentation. Hence, exploring new scaffolds for the treatment of melanogenesis disease is an inspiring goal. In this context, a series of varyingly substituted flavone-based hydrazones have been designed, synthesized and characterized successfully. The present study describes the discovery of novel mushroom tyrosinase inhibitors (TIs) for treating hyperpigmentation. In due course, flavone scaffold has been incorporated into the novel chemotypes that exhibit in vitro inhibitory effects against mushroom tyrosinase for the purpose of discovering anti‐melanogenic agents. Biological investigations of prepared analogs herein demonstrated moderate to excellent activity against most of the fungal-bacterial strains and their activity is comparable to those of commercially available antibiotics i.e., Ciprofloxacin and Ketoconazole. Based on in vitro tyrosinase inhibitory assay, some compounds exhibited potent inhibition particularly, 3g (IC50 = 1.40 ± 0.16 µM), 3j (IC50 = 0.95 ± 0.07 µM), 3o (IC50 = 1.13 ± 0.11 µM), and 3q (IC50 = 1.01 ± 0.1 µM) showed best inhibition i.e., 0.7, 0.5, 0.6 and 0.5 folds, respectively, than kojic acid (IC50 = 1.79 ± 0.6 µM). Lineweaver-Burk plots demonstrated that the most potential derivative 3j tyrosinase inhibition proceeds via non-competitive pathway and the Michaelis-Menton constant (Km) value is 0.0265. Molecular modeling was performed for all tested analogs (3a–3q) using a model of mushroom tyrosinase to find crucial binding modes liable for inhibitory activity. The SARs were preliminarily examined, and the docking study revealed that analogs 3j, 3o and 3p had a strong binding association to tyrosinase (2Y9X). Furthermore, a drug-likeness study was employed and confirmed the favorable activity of the new analogs as a new anti-tyrosinase agent.
KW - Antimicrobial evaluation
KW - Drug-likeness
KW - Flavone-based hydrazones
KW - Molecular modeling study
KW - Tyrosinase inhibition
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U2 - 10.1016/j.molstruc.2021.131933
DO - 10.1016/j.molstruc.2021.131933
M3 - Article
AN - SCOPUS:85119922102
SN - 0022-2860
VL - 1251
JO - Journal of Molecular Structure
JF - Journal of Molecular Structure
M1 - 131933
ER -