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.

Synthesis, Characterization and Molecular Docking of Novel Bioactive Thiazolyl-Thiazole Derivatives as Promising Cytotoxic Antitumor Drug.

Reactions of ethylidenethiocarbohydrazide with hydrazonoyl halides gave 1,3-thiazole or 1,3,4-thiadiazole derivatives according to the type of hydrazonoyl halides. Treatment of ethylidenethiosemicarbazide with hydrazonoyl halides and dimethylacetylene dicarboxylate (DMAD) afforded the corresponding arylazothiazoles and 1,3-thiazolidin-4-one derivatives, respectively. The structures of the synthesized products were confirmed by IR, ¹H-NMR, (13)C-NMR and mass spectral techniques. The cytotoxic activity of the selected products against the Hepatic carcinoma cell line (Hepg-2) was determined by MTT assay indicating a concentration dependent cellular growth inhibitory effect, especially for compounds 14c and 14e. The dose response curves indicated the IC50 (the concentration of test compounds required to kill 50% of cell population) were 0.54 µM and 0.50 µM, respectively. Confocal laser scanning imaging of the treated cells stained by Rhodamin 123 and Acridine orange dyes confirmed that the selected compounds inhibit the mitochondrial lactate dehydrogenase enzymes. The binding mode of the active compounds was interpreted by a molecular docking study. The obtained results revealed promising cytotoxic activity.

Design and Synthesis of Imidazopyrazolopyridines as Novel Selective COX-2 Inhibitors.

The usefulness of non-steroidal anti-inflammatory drugs (NSAIDs) is hampered by their gastrointestinal side effects. Non-selective cyclooxygenases inhibitors interfere with both COX-1 and COX-2 isozymes. Since COX-1 mediates cytoprotection of gastric mucosa, its inhibition leads to the undesirable side effects. On the other hand, COX-2 is undetectable in normal tissues and selectively induced by inflammatory stimuli. Therefore, it is strongly believed that the therapeutic benefits derive from inhibition of COX-2 only. The presence of a strong connection between reported COX-2 inhibitors and cardiac toxicity encourages medicinal chemists to explore new scaffolds. In the present study, we introduced imidazopyrazolopyridines as new potent and selective COX-2 inhibitors that lack the standard pharmacophoric binding features to hERG. Starting from our lead compound 5a, structure-based drug-design was conducted and more potent analogues were obtained with high COX-2 selectivity and almost full edema protection, in carrageenan-induced edema assay, in case of compound 5e. Increased bulkiness around imidazopyrazolopyridines by adding a substituted phenyl ring(s) afforded less active compounds.

Synthesis and Molecular Docking Study of Some New Thiazole-coumarin Molecular Hybrids as Antibacterial Agents.

BACKGROUND: The emergence of drug-resistant bacteria and multidrug-resistant diseases, both of which are associated with high mortality, has posed a serious global health issue. Thiazoles and coumarins were reported as antimicrobial agents. OBJECTIVE: This research paper aims to describe the synthesis of some novel thiazole derivatives bear-ing a coumarin residue as antibacterial agents Methods: The thiazole - coumarin hybrids were synthesized starting from the condensation of 3-acetyl coumarin (1) hydrazine carbothioamide (2) or thisemicarbazide then reacting the resulting products with different p-substituted phenacyl bromides (4a-e), hydrazonoyl chlorides (8a-e), and (11). In vitro antibacterial activity was studied in this work. In addition, molecular docking studies for the new compounds have also been carried out to investigate the binding mode of actions against the target DNA gyrase B. RESULTS: Some of the newly synthesized compounds such as compounds 10b, 7, and 6b showed pronounced activities against Gram (+ve) and Gram (-ve) bacteria compared to a reference antibacterial agent. Compounds 10b, 7, and 6b exhibited the best binding affinity against the target. CONCLUSION: We could obtain a series of precious hitherto unknown thiazole derivatives with varied antibacterial activities from cheap laboratory-available starting material following rather simple environmentally friendly techniques avoiding the use of hazardous or heavy metal-containing catalysts.

Facile synthesis and antiproliferative activity of new 3-cyanopyridines.

BACKGROUND: Pyridines have been reported to possess various pharmacological activities. RESULTS: Sodium 3-oxo-3-(2-oxo-2H-chromen-3-yl)prop-1-en-1-olate (2) and sodium 3-oxo-3-(3-oxo-3H-benzo[f]chromen-2-yl)prop-1-en-1-olate (7) were prepared and reacted with 2-cyano-N'-(1-aryl(heteryl)ethylidene)acetohydrazides 3a-d to produce 2-oxo-1,2-dihydropyridine-3-carbonitrile derivatives 5a-d and 9a-d, respectively, in good yields. Also, 3a-d reacted with sodium (2-oxocyclopentylidene)methanolate (11a) or sodium (2-oxocyclohexylidene) methanolate (11b) to yield 2-oxo-tetrahydro-1H-cyclopenta[b]pyridine-3-carbonitriles 13a-d and 2-oxo-hexahydroquinoline-3-carbonitriles 13e-h, respectively. The mechanisms that account for the formation of the products are discussed. Additionally, the structures of all the newly synthesized products are confirmed, based on elemental analysis and spectral data. Several of the newly synthesized compounds are evaluated for their antitumor activity against HEPG2 and their structure activity relationship (SAR) was studied. CONCLUSIONS: The results revealed that the pyridine derivatives 5c and 5d (IC50 = 1.46, 7.08 µM, respectively) have promising antitumor activity against liver carcinoma cell line (HEPG2), compared to the reference drug, doxorubicin.

Green Synthesis and Molecular Docking of Thiazolyl-thiazole Derivatives as Potential Cytotoxic Agents.

METHOD: A series of novel thiazole derivatives were synthesized in a good yield via reaction of 2-(1-(4-methyl-2-phenylthiazol-5-yl)ethylidene)hydrazine carbothioamide with hydrazonoyl halides. The reaction was performed in the presence of DABCO as an organocatalyst in short reaction times, easy workup, good to excellent yields. The structure of the newly synthesized products was elucidated via elemental analysis, spectral data and alternative routes whenever possible. Ten compounds were evaluated for their anti-cancer activity against the colon carcinoma cell line (HCT-116). RESULTS & CONCLUSION: The results revealed that most of the tested compounds showed high or moderate anti-cancer activity. The molecular docking of five novel thiazolyl-thiazole derivatives was performed by the Molecular Operating Environment (MOE) program.

A facile access and evaluation of some novel thiazole and 1,3,4-thiadiazole derivatives incorporating thiazole moiety as potent anticancer agents.

BACKGROUND: Many heterocyclic compounds containing thiazole or 1,3,4-thiadiazole ring in their skeletons have been reported to possess various pharmacological activities especially anticancer activities. RESULTS: 4-Methyl-2-phenylthiazole-5-carbohydrazide (2) was used as a synthon to prepare 2-(4-methyl-2-phenylthiazole-5-carbonyl)-N-phenylhydrazinecarbothioamide (3) and 2-(2-(4-methyl-2-phenylthiazole-5-carbonyl)hydrazono)-N'-phenylpropane hydrazonoyl chlorides 5a-c. In addition, thioamide 3 was used as starting material for preparation of a new series of thiadiazole derivatives via its reaction with hydrazonoyl chlorides 5a-c in dioxane using triethylamines as catalyst. In addition, a series of thiazole derivatives was synthesized by reaction of thioamide 3 with a number of α-halo compounds, namely, 3-chloropentane-2,4-dione (8) or 2-chloro-3-oxo-N-phenyl butanamide (10) phenacyl bromide 12 ethyl chloroacetate (14) in EtOH in the presence of triethylamine. The structures assigned for all the new products were elucidated based on both elemental analyses and spectral data and the mechanisms of their formation was also discussed. Moreover, the new products was evaluated in vitro by MTT assays for their anticancer activity against cell lines of Hepatocellular carcinoma cell line (HepG-2). The best result observed for compounds 7b (IC50 = 1.61 ± 1.92 (µg/mL)) and 11 (IC50 = 1.98 ± 1.22 (µg/mL)). The structure-activity relationships have been suggested based on their anticancer results. CONCLUSIONS: A novel series of new pharmacophores containing thiazole moiety have been synthesized using a facile and convenient methods and evaluated as potent anticancer agents.