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In this study, two series of novel 1,4-benzothiazine-3-one derivatives with alkyl substitution (series 1: 4a-4f) and aryl substitution (series 2: 4g-4l) were designed and synthesized based on the chemical scaffolds of perampanel, hydantoins, progabide and etifoxine as anti-convulsant agents. The chemical structures of the synthesized compounds were confirmed by FT-IR, 1H NMR and 13C NMR spectroscopy. Anti-convulsant effect of the compounds was examined through intraperitoneal pentylenetetrazol (i.p. PTZ) induced epilepsy mouse models. Compound 4h (4-(4-bromo-benzyl)− 4 H-benzo[ b ] [1,4] thiazin-3(4 H)-one) demonstrated a promising activity toward chemically-induced seizure experiment. Molecular dynamics simulation on GABA-Aergic receptors as a plausible mechanism were also done to achieve the binding and orientation of compounds in the active site of the target to evaluate the results of docking and experimental studies. The computational results were confirmed the biological activity. DFT study of 4c and 4h was performed on B3LYP/6–311 G** level of theory. Reactivity descriptors such as HOMO, LUMO, electron affinity, ionization potential, chemical potential, hardness and softness were studied in detail and show that 4h has higher activity than 4c. Also, the frequency calculations were performed on the same level of theory and the results are in line with experimental data. Moreover, in silico ADMET properties were done to establish a relationship between the physiochemical data of the designed compounds and their in-vivo activity. Appropriate plasma protein binding and high blood-brain barrier penetration are the main features of desired in -vivo performance. [Display omitted] • 1,4 benzothiazine 3-one derivatives were synthesized as anticonvulsant agents. • The benzothiazine containing 4-bromo-benzyl substitution, increased the latency of convulsions. • The computational studies and biology assay indicated that compound 4h might had a good inhibitory effect on GABA-A receptor. • The results of the computational study and experimental methods about compound 4h were agreement together. [ABSTRACT FROM AUTHOR]

• A new set of imidazole derivatives were synthesized and characterized. • The synthesized compounds (7a-f) were screened for their in vitro antifungal activities against several fungal strains. • Compounds 7c, 7d and 7f exhibited excellent activities against tested fungi species with MIC 90 values in the range of 0.5-16 µg/ml. • Molecular modelling studies and molecular dynamic simulation were carried out to predict the possible interaction mode of these compounds in the binding site of lanosterol 14α-demethylase (CYP51). • These compounds can be considered as antifungal candidates for further development. Fungal infections have become a serious threat to human health due to their high incidence and mortality. In this study, a new set of imidazole derivatives (7a-f) were synthesized and their chemical structures were characterized using spectroscopic techniques including IR, 1H-NMR, 13C-NMR and Mass. In the following, the antifungal activities of these derivatives were evaluated against several yeasts, aspergillus and dermatophyte species using the CLSI method. In addition, to check the safety of the synthesized compounds, the in vitro cytotoxicity activity of these compounds was investigated towards normal human fibroblasts cell line (MRC-5) using MTT assay. The obtained biological results indicated that these compounds acted as the most potential antifungal agents. In particular, compounds 7c, 7d and 7f exhibited excellent activity against Candida albicans, Candida tropicalis, Candida glabrata, Candida krusei, Candida dubliniensis, Candida parapsilosis , and Cryptococcus neoformans species with MIC 50 values in the range of 0.5-16 µg/ml. The cytotoxicity results showed that these compounds have low toxicity against normal human fibroblasts cell line (MRC-5). Additionally, molecular modelling studies and molecular dynamic simulation were carried out to predict the binding energy and possible interaction mode of these compounds in the binding site of lanosterol 14α-demethylase (CYP51) as a conventional target for azole derivatives. In silico ADME study was also performed to investigate the physicochemical features of the synthesized imidazole derivatives. According to the results, these compounds can be considered as promising antifungal candidates for further development. [Display omitted] [ABSTRACT FROM AUTHOR]

• Design and synthesis of a novel series of 1,2,4-triazole derivatives. • The antifungal activity of these compounds were investigated against several yeasts (candida species), filamentous and clinical strains using the CLSI method. • Compounds 7g and 7h were found to be more potent against yeast strains and clinical strain of fluconazole-resistant and fluconazole-sensitive with MIC values of 0.5 µg/mL compared to the Fluconazole as control drug. • Molecular docking study was performed to elucidate the binding mode of these ligands in the active site of 14α-demethylase enzyme as plausible target of azole compounds. Fungal infections are still threatening human health due to resistance to existing drugs, therefore, the design and development of novel antifungal agents is to be necessary and also, is interesting topic for medicinal chemist. Azole derivatives are one of the promising antifungal agents, which exert their activities through inhibition of cytochrome P450 14α-demethylase (CYP51). In this regard, a new series of 1,2,4-triazole derivatives (7a-i) were designed, synthesized and confirmed with IR, 1HNMR, 13CNMR and Mass spectrum. The antifungal activity of these compounds were investigated against several yeasts (candida species), filamentous and clinical strains using the CLSI method. Furthermore, to measure the cytotoxic activity, MTT assay was also done against MRC-5 as normal human fibroblasts cell line. Our results represented that most of the compounds had appropriate activity ranging from 0.5-256 µg/mL, especially, compounds 7g and 7h were found to be more potent against yeast strains and clinical strain of Fluconazole-resistant and Fluconazole-sensitive with MIC values of 0.5 µg/mL compared to the Fluconazole as control drug. Subsequently, molecular docking studies were performed to find the binding energy and interaction mode of these compounds in the active site of 14α-demethylase enzyme as plausible target of azole compounds. According to in vitro antifungal assay and in silico ADME predictions, compounds 7g and 7h can be considered as potent candidates for further studies. [Display omitted] [ABSTRACT FROM AUTHOR]

[Display omitted] • Indole-carbohydrazide moieties with different aryl substitutions were designed, synthesized, and screened as tyrosinase inhibitors. • Compounds bearing para -hydroxybenzyl moiety exhibited superior tyrosinase inhibitory activities with IC 50 values of 0.007, 0.072, and 0.19 µM. • Molecular docking analyses and molecular dynamic simulations were also performed to anticipate critical interaction between potent derivatives and the binding site of tyrosinase. In the current study, twenty-five indole-carbohydrazide derivatives linked to different aryl substitutions were rationally designed and synthesized. The structures of all derivatives were confirmed using different spectroscopic techniques including 1H NMR, 13C NMR, Mass spectrometry, and elemental analysis. The tyrosinase inhibitory activities of all synthetic compounds exhibited IC 50 values in the range of 0.070 to > 100 μM. Structure-activity relationships showed that compounds 4f (R = 4-OH, IC 50 = 0.070 μM), 8f (R = 4-OH, IC 50 = 0.072 μM), and 19e (IC 50 = 0.19 μM) with para -OH substituent at the R position was found to be the most active members of all three tested series. Kinetic studies exhibited that compounds 4f, 8f, and 19e are mixed-type inhibitors. Furthermore, toxicity and cell-based anti-melanogenesis assessments were performed on the most potent derivatives and it was shown that 4f, 8f, and 19e had no toxicity at 8 µM and reduced the percent of melanin content to 68.43, 72.61, 73.47 at 8 μM, respectively. In silico analyses of absorption, distribution, metabolism, and excretion (ADME) profile of synthesized compounds showed that these molecules followed drug-likeness rules and acceptable predictive ADMET features. Results of the docking study were almost in line with biological results with ChemPLP values of 53.56 to 79.33. Also, the docking study showed the critical interactions of potent inhibitors with the active site of the enzyme which affects the potency of the synthesized hybrids. Based on molecular dynamic simulations, compound 4f exhibited pronounced interaction with the critical residues of the tyrosinase active site so that the indole ring participated in H-bond interaction with Gly281 and 4-hydroxy benzylidene recorded another H-bond interaction with Asp289 plus hydrophobic interactions with Phe292. Hydrazide linker also exhibited three H-bond interactions with His263 and Gly281. [ABSTRACT FROM AUTHOR]