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• Machine learning models were built from a potential in house database. • Multistep virtual screening method were used to identify a novel dual acetylcholinesterase and butyrylcholinesterase inhibitor from the Maybridge database. • In silico drug likeliness properties were evaluated for top hit compounds. • CD05692 was proposed as a potential novel dual acetylcholinesterase and butyrylcholinesterase inhibitors. • Synthesis and in vitro ChE (hAChE and hBChE) inhibition estimation of top hit CD05692. Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) are crucial targets that catalyse the breakdown of acetylcholine (ACh) and are implicated in the pathogenesis of Alzheimer's disease (AD). Thus, the development of cholinesterase (AChE and BChE) inhibitors with a novel scaffold is an effective way to intervene in the pathogenesis of AD. This study used a multistep virtual screening method combined with machine learning (ML) models and structural bioinformatics to identify a novel dual acetylcholinesterase and butyrylcholinesterase inhibitor from the Maybridge database. Finally, five common hits (AW00462, AW00794, MWP01235, SCR00709, CD05692) were found after a consensus analysis of classification models and multistep screening protocol which showed their potential against AChE and BChE enzymes. Further, MM/GBSA free energy calculation and MD simulation studies predicted CD05692 as a potential inhibitor, which formed stable interactions with the active site residues compared with the other compounds. The docking score of CD05692 was found maximum negative (AChE= -15.03 Kcal/mole; BChE= -7.07 Kcal/mole) compared with the other identified hits. The MM/GBSA binding free energy ∆G (AChE= -76.34 Kcal/mole; BChE= -74.72 Kcal/mole) and the HOMO orbital energy (-0.352,410 eV) was also predicted to be in favour of CD05692. The in silico pharmacokinetic investigations also ascertained its drug likeliness properties. Finally, compound CD05692 was synthesised, characterized and evaluated in vitro for ChE (hAChE and hBChE) inhibitory potential. The IC 50 value of the lead CD05692 has shown good hAChE inhibition (IC 50 = 0.927 ± 0.019 µM) and moderate hBChE inhibition (IC 50 = 6.377 ± 0.038 µM). Thus, based on this study, we proposed that CD05692 could further be optimized as a lead to design potential cholinesterase inhibitors to combat AD. [ABSTRACT FROM AUTHOR]

[Display omitted] • Novel 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives were designed and synthesized. • Derivatives 6c and 6k have displayed antioxidant properties. • Derivative 6k was devoid of ulcerogenic and cardiotoxic liabilities. • Derivative 6k molecular docking and dynamic simulations study affirmed consentient interaction with COX-2/5-LOX. A novel series of 5,6-diphenyl-1,2,4-triazine-3-thiol derivatives were designed, synthesized, and screened for their inhibitory potential against COX-2 and 5-LOX enzymes. The compounds from the series have shown moderate to excellent inhibitory potential against both targets. Compound 6k showed the inhibitions against COX-2 (IC 50 = 0.33 ± 0.02 μM) and 5-LOX inhibition (IC 50 = 4.90 ± 0.22 μM) which was better than the standard celecoxib (IC 50 = 1.81 ± 0.13 μM) for COX-2 and zileuton (IC 50 = 15.04 ± 0.18 μM) for 5-LOX respectively. Further investigation on the selected derivative 6k in rat paw edema models revealed significant anti-inflammatory efficacy. Compound 6k has also shown negligible ulcerogenic liability as compared to indomethacin. Moreover, in vivo biochemical analysis also established the compound's antioxidant properties. Compounds 6c and 6k were also observed to be devoid of cardiotoxicity post-myocardial infarction in rats. The molecular docking and dynamics simulation studies of the most active derivative 6k affirmed their consentient binding interactions with COX-2 specific ravine and cleft of 5-LOX. [ABSTRACT FROM AUTHOR]