Synthesis and In Silico Study of Some New bis-[1,3,4]thiadiazolimines and bis-Thiazolimines as Potential Inhibitors for SARS-CoV-2 Main Protease.

A novel series of bis-[1,3,4]thiadiazolimines, and bis-thiazolimines, with alkyl linker, were synthesized through general routes from cyclization of 1,1'-(hexane-1,6-diyl)bis(3-phenylthiourea) and hydrazonoyl halides or α-haloketones, respectively. Docking studies were applied to test the binding affinity of the synthesized products against the Mpro of SARS-CoV-2. The best compound, 5h, has average binding energy (-7.50 ± 0.58 kcal/mol) better than that of the positive controls O6K and N3 (-7.36 ± 0.34 and -6.36 ± 0.31 kcal/mol). Additionally, the docking poses (H-bonds and hydrophobic contacts) of the tested compounds against the Mpro using the PLIP web server were analyzed.

In silico study to identify novel potential thiadiazole-based molecules as anti-Covid-19 candidates by hierarchical virtual screening and molecular dynamics simulations.

In the present study, a new category of 1,3,4-thiadiazoles was developed by submitting methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate to react with the appropriate hydrazonoyl halides in presence of few drops of diisopropyl ethyl amine. The chemical structures of the newly synthesized derivatives were inferred by means of their micro-analytical and spectral data. Utilizing combined molecular docking and molecular dynamics techniques, the binding affinities and features of the synthesized compounds were evaluated against four SARS-CoV-2 target enzymes, namely, main protease (Mpro), papain-like protease (PLpro), RNA-dependent RNA polymerase (RdRp), and receptor-binding domain (RBD) of the spike protein. Compound 7 demonstrated promising binding affinities with the target enzymes Mpro, PLpro, RdRp, and RBD with docking scores of -11.4, -9.4, -8.2, and -6.8 kcal/mol, respectively. In addition, compound 7 exhibited MM-GBSA//100 ns MD docking score of -35.9 kcal/mol against Mpro. Structural and energetic analyses revealed the stability of the 7-Mpro complex over 100 ns MD simulations. In addition, compound 7 obeyed Lipinski's rule of five, as it has acceptable absorption, distribution, and oral bioavailability inside the body. Therefore, compound 7 is considered as a promising starting point for designing potential therapeutic agents against Covid-19. Supplementary Information: The online version contains supplementary material available at 10.1007/s11224-022-01985-1.

Towards Covid-19 TMPRSS2 enzyme inhibitors and antimicrobial agents: Synthesis, antimicrobial potency, molecular docking, and drug-likeness prediction of thiadiazole-triazole hybrids.

1,3,4-Thiadiazole analogues 3 and 4 were synthesised via the reaction of 1-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)ethan-1one 2 with vanillin or thiophene-2-carboxaldhyde, respectively through chalcone reaction. Compounds 3 and 4 were submitted to react with thiosemicarbazide affording 5-(4­hydroxy-3-methoxyphenyl)-3-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide (5) give 3-(5-methyl-1-(5-(methylthio)-1,3,4-thiadiazol-2-yl)-1H-1,2,3-triazol-4-yl)-5-(thiophen-2-yl)-4,5 dihydro-1H-pyrazole-1-carbothioamide (6), respectively. The letters were reacted with N-(4-chlorophenyl)-2-oxopropanehydrazonoyl chloride to give compounds 7 and 8. The chemical compositions of the novel compounds were affirmed by spectral and microanalytical data. Meanwhile, all the newly synthesized compounds have been screened for their ability to prevent the proliferation of different pathogens named Escherichia coli, Pseudomonas aeruginosa, Bacillus subtilis, Staphylococcus aureus, and Candida albicans in vitro. Additionally, the potency of the newly synthesized compounds to be anti-COVID-19 candidates was studied through a molecular docking study. The newly prepared molecules 2-8 were studied in silico against transmembrane serine protease 2 (TMPRSS2) to identify their potential therapeutic activity against Coronavirus. Moreover, the drug-likeness of the compounds was tested theoretically by ADMET studies. Compound 8 exhibited a better binding affinity (-9.1 kcal/mol) against the target enzyme TMPRSS2. Additionally, it respects Lipinski's rule of five and has acceptable ADMET properties, indicating that compound 8 could be interesting for the treatment of Covid-19.

Synthesis of new Spiropyrazole derivatives under microwaves irradiation and docking study for inhibition the microbes and COVID-19.

Synthesis of a new series of spiropyrazole derivatives using microwaves irradiation with high yield in minutes was achieved through a cycloaddition reaction of nitrile imines and arylidenes of 5-bromo-indan-1-one. The structure of the new spiropyrazoles was assured based on their available spectral analyses and the comparison of the extracted data with the literature reports. Molecular docking simulations of all new synthesized spiropyrazole derivatives into leucyl-tRNA synthetase editing domain of Candida albicans (Pdb: 2WFC) indicated that about seven spiropyrazole derivatives can fit deeply in the active site via the formation of stable complexes. In addition, the docking study was utilized to tested the ability of these spiropyrazoles to inhibit COVID-19 through the interaction with COVID-19 main protease (Pdb: 6LU7). The results were surprising which revealed high docking score ranging from -7.764 to -5.9464 kcal/mol. Moreover, the nitrogen atom of pyrazole, Br atom and the C=O group of indanone are essential parts in the binding mode of almost the active derivatives. The results of the docking study are a glimmer of hope to complete the study on these compounds and examine them in the laboratory to ensure their effectiveness as antimicrobials and antiviral, especially Covid-19. Moreover, pharmacokinetics and physicochemical properties were studied.

Novel Thiadiazole-Based Molecules as Promising Inhibitors of Black Fungi and Pathogenic Bacteria: In Vitro Antimicrobial Evaluation and Molecular Docking Studies.

Novel 1,3,4-thiadiazole derivatives were synthesized through the reaction of methyl 2-(4-hydroxy-3-methoxybenzylidene) hydrazine-1-carbodithioate and the appropriate hydrazonoyl halides in the presence of a few drops of diisopropylethylamine. The chemical structure of the newly fabricated compounds was inferred from their microanalytical and spectral data. With the increase in microbial diseases, fungi remain a devastating threat to human health because of the resistance of microorganisms to antifungal drugs. COVID-19-associated pulmonary aspergillosis (CAPA) and COVID-19-associated mucormycosis (CAM) have higher mortality rates in many populations. The present study aimed to find new antifungal agents using the disc diffusion method, and minimal inhibitory concentration (MIC) values were estimated by the microdilution assay. An in vitro experiment of six synthesized chemical compounds exhibited antifungal activity against Rhizopus oryzae; compounds with an imidazole moiety, such as the compound 7, were documented to have energetic antibacterial, antifungal properties. As a result of these findings, this research suggests that the synthesized compounds could be an excellent choice for controlling black fungus diseases. Furthermore, a molecular docking study was achieved on the synthesized compounds, of which compounds 2, 6, and 7 showed the best interactions with the selected protein targets.