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Synthesis, in silico modelling, and in vitro biological evaluation of substituted pyrazole derivatives as potential anti-skin cancer, anti-tyrosinase, and antioxidant agents
- Source :
- Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 38, Iss 1 (2023)
- Publication Year :
- 2023
- Publisher :
- Taylor & Francis Group, 2023.
-
Abstract
- Twenty-five azole compounds (P1–P25) were synthesised using regioselective base-metal catalysed and microwave-assisted approaches, fully characterised by high-resolution mass spectrometry (HRMS), nuclear magnetic resonance (NMR), and infrared spectra (IR) analyses, and evaluated for anticancer, anti-tyrosinase, and anti-oxidant activities in silico and in vitro. P25 exhibited potent anticancer activity against cells of four skin cancer (SC) lines, with selectivity for melanoma (A375, SK-Mel-28) or non-melanoma (A431, SCC-12) SC cells over non-cancerous HaCaT-keratinocytes. Clonogenic, scratch-wound, and immunoblotting assay data were consistent with anti-proliferative results, expression profiling therewith implicating intrinsic and extrinsic apoptosis activation. In a mushroom tyrosinase inhibition assay, P14 was most potent among the compounds (half-maximal inhibitory concentration where 50% of cells are dead, IC50 15.9 μM), with activity greater than arbutin and kojic acid. Also, P6 exhibited noteworthy free radical-scavenging activity. Furthermore, in silico docking and absorption, distribution, metabolism, excretion, and toxicity (ADMET) simulations predicted prominent-phenotypic actives to engage diverse cancer/hyperpigmentation-related targets with relatively high affinities. Altogether, promising early-stage hits were identified – some with multiple activities – warranting further hit-to-lead optimisation chemistry with further biological evaluations, towards identifying new skin-cancer and skin-pigmentation renormalising agents.
Details
- Language :
- English
- ISSN :
- 14756366 and 14756374
- Volume :
- 38
- Issue :
- 1
- Database :
- Directory of Open Access Journals
- Journal :
- Journal of Enzyme Inhibition and Medicinal Chemistry
- Publication Type :
- Academic Journal
- Accession number :
- edsdoj.6723a7780c15410686963a027f101484
- Document Type :
- article
- Full Text :
- https://doi.org/10.1080/14756366.2023.2205042