Microwave-Assisted One Pot Three-Component Synthesis of Novel Bioactive Thiazolyl-Pyridazinediones as Potential Antimicrobial Agents against Antibiotic-Resistant Bacteria.

Pyridazine and thiazole derivatives have various biological activities such as antimicrobial, analgesic, anticancer, anticonvulsant, antitubercular and other anticipated biological properties. Chitosan can be used as heterogeneous phase transfer basic biocatalyst in heterocyclic syntheses. Novel 1-thiazolyl-pyridazinedione derivatives were prepared via multicomponent synthesis under microwave irradiation as ecofriendly energy source and using the eco-friendly naturally occurring chitosan basic catalyst with high/efficient yields and short reaction time. All the prepared compounds were fully characterized by spectroscopic methods, and their in vitro biological activities were investigated. The obtained results were compared with those of standard antibacterial/antifungal agents. DFT calculations and molecular docking studies were used to investigate the electronic properties and molecular interactions with specific microbial receptors.

Clean Grinding Technique: A Facile Synthesis and In Silico Antiviral Activity of Hydrazones, Pyrazoles, and Pyrazines Bearing Thiazole Moiety against SARS-CoV-2 Main Protease (Mpro).

A novel series of some hydrazones bearing thiazole moiety were generated via solvent-drop grinding of thiazole carbohydrazide 2 with various carbonyl compounds. Also, dehydrative-cyclocondensation of 2 with active methylene compounds or anhydrides gave the respective pyarzole or pyrazine derivatives. The structures of the newly synthesized compounds were established based on spectroscopic evidences and their alternative syntheses. Additionally, the anti-viral activity of all the products was tested against SARS-CoV-2 main protease (Mpro) using molecular docking combined with molecular dynamics simulation (MDS). The average binding affinities of the compounds 3a, 3b, and 3c (-8.1 ± 0.33 kcal/mol, -8.0 ± 0.35 kcal/mol, and -8.2 ± 0.21 kcal/mol, respectively) are better than that of the positive control Nelfinavir (-6.9 ± 0.51 kcal/mol). This shows the possibility of these three compounds to effectively bind to SARS-CoV-2 Mpro and hence, contradict the virus lifecycle.

Utility of anthranilic acid and diethylacetylenedicarboxylate for the synthesis of nitrogenous organo/organometallic compounds as urease inhibitors.

Fumarate diester 3 was synthesized upon reacting anthranilic acid with diethylacetylenedicarboxylate. Compound 3 was reacted with different nucleophiles in mild reaction conditions. Selected reaction routes that afforded products 6, 9, 10, 11, and 12 were explained. The estimated mechanism for the reaction of 3 with ethylenediamine to afford 9 was proved by X-ray single-crystal and retro-synthetic reaction. Acetyl anthranilic acid was utilized with zinc and copper to afford the organometallic compounds 14a and 14b, respectively. Three single crystals were afforded for 3, 9 and the organocopper complex 14b. Target compounds were screened for their inhibitory potential against urease enzyme. Most compounds were more potent than thiourea as standard inhibitor, considering that oxopiperazine 9 exhibited double the activity: IC50 = 8.16 ± 0.65 µM (thiourea IC50 = 20.04 ± 0.33 µM). Docking studies were in agreement with the in vitro enzyme assay.

Synthesis and Biological Evaluation of Some Novel Thiazole-Based Heterocycles as Potential Anticancer and Antimicrobial Agents.

A novel series of thiazole-based heterocycles was synthesized using 1,3-dipolar cycloaddition reactions in the presence of chitosan-grafted-poly(vinylpyridine) as an eco-friendly biopolymeric basic catalyst. The molecular structure of the synthesized compounds was illustrated by spectroscopic and elemental analysis. Various in vitro biological assays were performed to explore the potential antitumor, antimicrobial and hepatoprotective activities of the newly synthesized compounds. The cytotoxic activities were assessed against human hepatocellular carcinoma (HepG-2), colorectal carcinoma (HCT-116) and breast cancer (MCF-7) cell lines and results revealed that all compounds displayed antitumor activities with the chlorine-containing derivatives, 11c and 6g, being the most potent. The majority of the tested thiazole derivatives exhibited satisfactory antibacterial activity towards the used gram positive and gram-negative bacterial species. Moreover, many derivatives showed weak hepatoprotective activity against CCl4-induced hepatotoxicity.

Eco-Friendly Synthesis, Characterization and Biological Evaluation of Some Novel Pyrazolines Containing Thiazole Moiety as Potential Anticancer and Antimicrobial Agents.

The one-pot synthesis of a series of pyrazoline derivatives containing the bioactive thiazole ring has been performed through a 1,3-dipolar cycloaddition reaction of N-thiocarbamoylpyrazoline and different hydrazonoyl halides or α-haloketones in the presence of DABCO (1,4-diazabicyclo[2.2.2] octane) as an eco-friendly catalyst using the solvent-drop grinding method. The structure of the synthesized compounds was elucidated using elemental and spectroscopic analyses (IR, NMR, and Mass). The activity of these compounds against human hepatocellular carcinoma cell line (HepG2) was tested and the results showed that the pyrazoline 11f, which has a fluorine substituent, is the most active. The antimicrobial activities of the newly synthesized compounds were determined against two fungi and four bacterial strains, and the results indicated that some of the newly synthesized pyrazolines are more potent than the standard drugs against test organisms.

Synthesis, Antitumor Evaluation and Molecular Docking of New Morpholine Based Heterocycles.

A series of new morpholinylchalcones was prepared and then used as building blocks for constructing a series of 7-morpholino-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-ones via their reaction with 6-aminothiouracil. The latter thiones reacted with the appropriate hydrazonoyl chloride to give the corresponding pyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidin-5(1H)-ones. The assigned structures for all the newly synthesized compounds were confirmed on the basis of elemental analyses and spectral data and the mechanisms of their formation were also discussed. Most of the synthesized compounds were tested for in vitro activity against human lung cancer (A-549) and human hepatocellular carcinoma (HepG-2) cell lines compared with the employed standard antitumor drug (cisplatin) and the results revealed that compounds 8, 4e and 7b have promising activities against the A-549 cell line (IC50 values of 2.78 ± 0.86 µg/mL, 5.37 ± 0.95 µg/mL and 5.70 ± 0.91 µg/mL, respectively) while compound 7b has promising activity against the HepG-2 cell lines (IC50 = 3.54 ± 1.11 µg/mL). Moreover, computational studies using MOE 2014.09 software supported the biological activity results.

Synthesis and Characterization of Some New Bis-Pyrazolyl-Thiazoles Incorporating the Thiophene Moiety as Potent Anti-Tumor Agents.

A new series of 1,4-bis(1-(5-(aryldiazenyl)thiazol-2-yl)-5-(thiophen-2-yl)-4,5-dihydro-1H-pyrazol-3-yl)benzenes 3a-i were synthesized via reaction of 5,5'-(1,4-phenylene)bis(3-(thiophen-2-yl)-4,5-dihydro-1H-pyrazole-1-carbothioamide) (1) with hydrazonoyl halides 2a-i. In addition, reaction of 1 with ethyl chloroacetate afforded bis-thiazolone derivative 8 as the end product. Reaction of compound 8 with methyl glyoxalate gave bis-thiazolone derivative 10. The structures of the newly synthesized compounds were established on the basis of spectroscopic evidences and their alternative syntheses. All the synthesized compounds were evaluated for their anti-tumor activities against hepatocellular carcinoma (HepG2) cell lines, and the results revealed promising activities of compounds 3g, 5e, 3e, 10, 5f, 3i, and 3f with IC50 equal 1.37 ± 0.15, 1.41 ± 0.17, 1.62 ± 0.20, 1.86 ± 0.20, 1.93 ± 0.08, 2.03 ± 0.25, and 2.09 ± 0.19 µM, respectively.

Molecular modeling study bioactive natural product of khellin analogues as a novel potential pharmacophore of EGFR inhibitors.

Khelline is naturally occurring furochromone exhibited significant Epidermal Growth Factor Receptor (EGFR) inhibitory activity. The newly synthesized compounds 2-5 displayed the most potent EGFR inhibitory activity on MCF-7 and HeLa. In vitro study against 59 different human tumour cell lines derived from nine cancer type in NCI (USA), which was presented and documented. Molecular docking simulation was performed to position compounds 1-5 into the EGFR active site to determine the probable binding mode.

Dry Grinding Synthesis and Docking Study of Cyclopentanone-Sulfur Containing Compounds with Anti-Proliferative Activity for HepG-2 and A-549 Cancer Cell Lines.

BACKGROUND: The dry grinding method is a green technique for efficient organic synthesis with numerous advantages, such as mild reaction conditions, environmental acceptability, simple segregation, and refinement, as well as elevated selectivity and efficiency. OBJECTIVE: The aim of the present work is to design and synthesize cyclopentylidene-hydrazino)- thiazole derivatives using dry grinding conditions to investigate their antitumor activity against two cell lines, namely, HepG-2 and A-549. METHODS: In this context, we synthesized a series of thiazole incorporated cyclopentane through hydrazone- group and 2-cyclopentylidenehydrazine-1-carbimidic-2-ethoxy-N-aryl-2-oxoacetohydrazonic thioanhydride under dry grinding within minutes and excellent to good yield. RESULTS: All spectral data confirmed the proposed structures. In addition to antitumor activity investigations against the two kinds of cancer cells, molecular docking studies were conducted using Macrophage Migration Inhibitory Factor (Pdb: 4k9g) and Lysozyme C (Pdb: 2f4a), the overexpressed proteins in the human liver cancer cell (HepG-2) and lung cancer cell lines (A-549), respectively. CONCLUSION: Two derivatives, 9b, and 9d, showed the highest antitumor activity against the two cell lines HepG-2 and A-549. Also, docking results revealed a high energy score ranging from -7.1590 to -5.9364 Kcal/mol with Macrophage Migration Inhibitory Factor (Pdb: 4k9g), more than that the energy score = -4.118 Kcal/mol of co-crystallized ligand. Moreover, the tested derivatives showed energy score varies from -6.0802 to -4.5503 Kcal/mol against Lysozyme C (Pdb: 2f4a).

CG base pair recognition within DNA triple helices by modified N-methylpyrrolo-dC nucleosides.

3-Aminophenyl-modified analogues of the bicyclic nucleoside N-methyl-3H-pyrrolo[2,3-d]pyrimidin-2(7H)-one were synthesised and incorporated directly into triplex-forming oligonucleotides in order to utilise their extended hydrogen bonding motif for recognition of the CG base pair. All analogues demonstrated strong binding affinity and very good selectivity for CG from pH 6.2 to 7.0; a marked improvement on previous modifications.

5-(Thiophen-2-yl)-1,3,4-thiadiazole derivatives: synthesis, molecular docking and in vitro cytotoxicity evaluation as potential anticancer agents.

BACKGROUND: Nowadays, cancer is an important public health problem in all countries. Limitations of current chemotherapy for neoplastic diseases such as severe adverse reactions and tumor resistance to the chemotherapeutic drugs have been led to a temptation for focusing on the discovery and development of new compounds with potential anticancer activity. The importance of thiophene and thiadiazole rings as scaffolds present in a wide range of therapeutic agents has been well reported and has driven the synthesis of a large number of novel antitumor agents. METHODS: A series of new 1,3,4-thiadiazoles were synthesized by heterocyclization of N-(4-nitrophenyl)thiophene-2-carbohydrazonoyl chloride with a variety of hydrazine-carbodithioate derivatives. The mechanisms of these reactions were discussed and the structure of the new products was elucidated via spectral data and elemental analysis. All the new synthesized compounds were investigated for in vitro activities against human hepatocellular carcinoma (HepG-2) and human lung cancer (A-549) cell lines compared with cisplatin standard anticancer drug. Moreover, molecular docking using MOE 2014.09 software was also carried out for the high potent compound 20b with the binding site of dihydrofolate reductase (DHFR, PDB ID (3NU0)). RESULTS: The results showed that compound 20b has promising activities against HepG-2 and A-549 cell lines (IC50 value of 4.37±0.7 and 8.03±0.5 µM, respectively) and the results of molecular docking supported the biological activity with total binding energy equals -1.6 E (Kcal/mol). CONCLUSION: Overall, we synthesized a new series of 1,3,4-thiadiazoles as potential antitumor agents against HepG-2 and A-549 cell lines.

Microwave-assisted one pot three-component synthesis of some novel pyrazole scaffolds as potent anticancer agents.

BACKGROUND: Pyrazoles, thiazoles and 1,3,4-thiadiazoles have been reported to possess various pharmacological activities. RESULTS: An efficient and a novel approach for the synthesis of some novel pyrazole based-azoles are described via multi-component reaction under controlled microwave heating conditions. The structures of the synthesized compounds were assigned on the basis of elemental analysis, IR, 1H NMR and mass spectral data. All the synthesized compounds were tested for in vitro activities against two antitumor cell lines, human lung cancer and human hepatocellular carcinoma compared with the employed standard antitumor drug (cisplatin). CONCLUSIONS: All the newly synthesized compounds were evaluated for their anticancer activity against human lung cancer and human hepatocellular carcinoma cell lines using MTT assay. The results obtained exploring the high potency of six of the tested compounds compared with cisplatin. Graphical abstract Microwave-assisted one pot three-component synthesis of some novel pyrazole scaffolds as potent anticancer agents.

Antimicrobial, antitumor and 5α-reductase inhibitor activities of some hydrazonoyl substituted pyrimidinones.

A series of 2-[N-aryl-2-oxo-2-(4-chlorophenyl)ethanehydrazonoyl]-6-methyl-4(3H)-pyrimidinones 5 were prepared by coupling the diazonium salt of aniline derivatives with 2-(4-chlorobenzoylmethylene)-6-methyl-4(3H)-pyrimidinone 4 in sodium hydroxide solution. The structures of these newly synthesized compounds were confirmed by IR, NMR, mass spectrometry and elemental analyses and the tautomeric structure of these compounds was discussed. All the newly synthesized compounds were screened for their antibacterial and antifungal activities, some of which exhibited moderate activity. Also, the above compounds were evaluated for their antitumor activity against a panel of 60 human tumor cell lines by the National Cancer Institute (NCI), USA. Compounds 5b, 5d and 5i showed good cytotoxic activities against the tested cell lines. In addition, the newly synthesized compounds were screened for their 5α-reductase inhibitor activity and all the tested compounds showed activities in descending order as follows 5b, 5c, 5g, 5j, 5d, 5h, 5f, 5e and 5i.