Synthesis, in silico modelling, and in vitro biological evaluation of substituted pyrazole derivatives as potential anti-skin cancer, anti-tyrosinase, and antioxidant agents

• Main Authors: Samuel T. Boateng (Author), Tithi Roy (Author), Kara Torrey (Author), Uchechi Owunna (Author), Sergette Banang-Mbeumi (Author), David Basnet (Author), Eleonora Niedda (Author), Alexis D. Alexander (Author), Denzel El Hage (Author), Siriki Atchimnaidu (Author), Bolni Marius Nagalo (Author), Dinesh Aryal (Author), Ann Findley (Author), Navindra P. Seeram (Author), Tatiana Efimova (Author), Mario Sechi (Author), Ronald A. Hill (Author), Hang Ma (Author), Jean Christopher Chamcheu (Author), Siva Murru (Author)
• Format: Book
• Published: Taylor & Francis Group, 2023-12-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.
• Notes: 10.1080/14756366.2023.2205042; 1475-6374; 1475-6366
• Keywords: Antitumor agents; apoptosis; tyrosinase inhibition; antioxidant; molecular docking and ADMET; Therapeutics. Pharmacology; RM1-950
• Source: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 38, Iss 1 (2023)

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.