Temephos is an organophosphorothioate (OPT) larvicide used for controlling vectors of diseases such as dengue, chikungunya, and Zika. OPTs require a metabolic activation mediated by cytochrome P540 (CYP) to cause toxic effects, such as acetylcholinesterase (AChE) activity inhibition. There is no information about temephos biotransformation in humans, and it is considered to have low toxicity in mammals. Recent studies have reported that temephos-oxidized derivatives cause AChE inhibition. The aim of this study was to propose the human biotransformation pathway of temephos using in silico tools. The metabolic pathway was proposed using the MetaUltra program of MultiCase software as well as the Way2Drug and Xenosite web servers. The results show the following three essential reactions of phase I metabolism: (1) S-oxidation, (2) oxidative desulfurization, and (3) dephosphorylation, as well as the formation of 19 possible intermediary metabolites. Temephos dephosphorylation is the most likely reaction, and it enables phase II metabolism for glucuronidation to be excreted. However, the CYP-dependent metabolism showed that temephos oxon can be formed, which could lead to toxic effects in mammals. CYP2B6, 2C9, and 2C19 are the main isoforms involved in temephos metabolism, and CYP3A4 and 2D6 have minor contributions. According to computational predictions, the highest probability of temephos metabolism is dephosphorylation and phase II reactions that do not produce cholinergic toxic effects; nonetheless, the participation of CYPs is highly possible if the primary reaction is depleted.

Background: The rapidly widespread SARS-CoV-2 infection has affected millions worldwide, thus becoming a global health emergency. Although vaccines are already available, there are still new COVID-19 cases daily worldwide, mainly due to low immunization coverage and the advent of new strains. Therefore, there is an utmost need for the discovery of lead compounds to treat COVID-19. Objective: Considering the relevance of the SARS-CoV-2 MPRO in viral replication and the role of the isoquinoline moiety as a core part of several biologically relevant compounds, this study aimed to identify isoquinoline-based molecules as new drug-like compounds, aiming to develop an effective coronavirus inhibitor. Method: 274 isoquinoline derivatives were submitted to molecular docking interactions with SARS-CoV-2 MPRO (PDB ID: 7L0D) and drug-likeness analysis. The five best-docked isoquinoline derivatives that did not violate any of Lipinski's or Veber's parameters were submitted to ADMET analysis and molecular dynamics (MD) simulations. Results < Discussion: The selected compounds exhibited docking scores similar to or better than chloroquine and other isoquinolines previously reported. The fact that the compounds interact with residues that are pivotal for the enzyme's catalytic activity, and show the potential to be orally administered makes them promising drugs for treating COVID-19. Conclusion: Ultimately, MD simulation was performed to verify ligand-protein complex stability during the simulation period.