Facile one-pot synthesis and in silico study of new heterocyclic scaffolds with 4-pyridyl moiety: Mechanistic insights and X-ray crystallographic elucidation.

4-Acetylpyridine 1 and malononitrile 2 were allowed to react in a 3MCRs with dimedone 3a or cyclohexa-1,3-dione 3b under reflux to afford 4-methyl-4-(pyridin-4-yl)-5,6,7,8-tetrahydro-4H-chromene derivatives 4a,b respectively. The mechanism of the reaction has been studied and the structures elucidated by analytical, spectral as well as X-ray crystallographic data. Heterocyclic compounds find widespread application in pharmaceutical and agrochemical products. Docking analyses were performed on the synthesized compounds to assess their binding modes with various amino acids of the target protein tubulin (PDB Code - 1SA0). The results indicated promising binding scores for compounds 4a and 4b, suggesting a strong affinity for the tubulin binding site. Finally, ADMET for the synthesized compounds 4a, 4b, 5, 8a and 8b were carried out. The drug likeness and pharmacokinetic properties of the prepared compounds were also evaluated. Notably, all of the novel compounds adhered to Lipinski's rule (Ro5) without any violations.

Green Biocatalyst for Ultrasound-Assisted Thiazole Derivatives: Synthesis, Antibacterial Evaluation, and Docking Analysis.

The catalytic activity of chitosan (Cs) and grafted Cs led to the preparation of terephthalohydrazide Cs Schiff's base hydrogel (TCsSB), which was then investigated as an eco-friendly biocatalyst for synthesizing novel thiazole derivatives. TCsSB exhibited greater surface area and higher thermal stability compared to Cs, making it a promising eco-friendly biocatalyst. We synthesized two novel series of thiazoles via the reaction of 2-(2-oxo-1,2-diphenylethylidene) hydrazine-1-carbothioamide with various hydrazonoyl chlorides and 2-bromo-1-arylethan-1-ones, employing ultrasonic irradiation and using TCsSB as a catalyst. A comparative study between Cs and TCsSB revealed higher yields than TCsSB. The methodology offered advantages such as mild reaction conditions, quick reaction times, and high yields. TCsSB could be reused multiple times without a significant loss of potency. The chemical structures of the newly synthesized compounds were verified through IR, 1H NMR, 13C NMR, and MS analyses. Six synthesized compounds were assessed for their in vitro antibacterial effectiveness by establishing the minimum inhibitory concentration against four distinct bacterial strains. The docking analyses revealed favorable binding scores against several amino acids within the selected protein (PDB Code-1MBT) for these compounds, with compound 4c exhibiting particularly noteworthy binding properties. Additionally, the in silico ADME parameter estimation for all compounds indicated favorable pharmacological properties for these compounds.

Synthesis of Bis-thiazoles Tethered 1,4-Dihydropyridine and Pyridine Linkers via Simple Oxidation and their Molecular Docking as VEGFR -TK Inhibitors.

AIM: In this study, a neoteric and expedient oxidation method is applied for a variety of Hantzsch 1,4-dihydropyridine derivatives such as 1,4-dihydro- 2,6-dimethyl-3,5-diacetylpyridine, 3,5-bis-hydrazono--2,6-dimethyl-1,4-dihydropyridine, and 3,5-bis-thiazoly-2,6-dimethyl-1,4-dihydro pyridine. METHOD: This simple oxidation is based upon the in situ generation of nitrous acid from an aqueous sodium nitrite and acetic acid mixture and could be used to downgrade costs, sustain resources, and minimize chemical wastes. Also, a molecular modeling strategy was used to study the mechanism of action for various derivatives of bis-hydrazinylidene- thiazole as the protein Vascular Endothelial Growth Factor Receptor Tyrosine Kinase (VEGFR TK) inhibitor through evaluating their binding scores and modes compared with Sorafenib as a reference standard. RESULT: The results revealed that the interaction of hydrazinylidene and thiazole as an anticancer Tyrosine Kinase inhibitor has been improved. CONCLUSION: Additionally, the compounds exhibiting the highest activity were assessed for their potential anticancer effects against HepG-2, MCF-7, and WI-38 cells, and the outcomes demonstrated encouraging activity against cancer.

Chitosan-sulfonic acid-catalyzed green synthesis of naphthalene-based azines as potential anticancer agents.

Aim: This study focuses on advancing green chemistry in anticancer drug discovery, particularly through the synthesis of azine derivatives with a naphthalene core using CS-SO3H as a catalyst. Methods: Novel benzaldazine and ketazine derivatives were synthesized using (E)-(naphthalen-1-ylmethylene)hydrazine and various carbonyl compounds. The methods employed included thermal and grinding techniques, utilizing CS-SO3H as an eco-friendly and cost-effective catalyst. Results: The approach resulted in high yields, short reaction times and demonstrated catalyst reusability. Cytotoxicity tests highlighted compounds 3b, 11 and 13 as potent against the HEPG2-1. Conclusion: This study successfully aligns with the objectives of eco-conscious drug development in organic chemistry. Molecular docking and in silico studies further indicate the potential of these ligands as antitumor medicines, with favorable oral bioavailability properties.

Mechanochemical Synthesis and Molecular Docking Studies of New Azines Bearing Indole as Anticancer Agents.

The development of new approaches for the synthesis of new bioactive heterocyclic derivatives is of the utmost importance for pharmaceutical industry. In this regard, the present study reports the green synthesis of new benzaldazine and ketazine derivatives via the condensation of various carbonyl compounds (aldehydes and ketones with the 3-(1-hydrazineylideneethyl)-1H-indole using the grinding method with one drop of acetic acid). Various spectroscopic techniques were used to identify the structures of the synthesized derivatives. Furthermore, the anticancer activities of the reported azine derivatives were evaluated against colon, hepatocellular, and breast carcinoma cell lines using the MTT technique with doxorubicin as a reference medication. The findings suggested that the synthesized derivatives exhibited potential anti-tumor activities toward different cell lines. For example, 3c, 3d, 3h, 9, and 13 exhibited interesting activity with an IC50 value of 4.27-8.15 µM towards the HCT-116 cell line as compared to doxorubicin (IC50 = 5.23 ± 0.29 µM). In addition, 3c, 3d, 3h, 9, 11, and 13 showed excellent cytotoxic activities (IC50 = 4.09-9.05 µM) towards the HePG-2 cell line compared to doxorubicin (IC50 = 4.50 ± 0.20 µM), and 3d, 3h, 9, and 13 demonstrated high potency (IC50 = 6.19-8.39 µM) towards the breast cell line (MCF-7) as compared to the reference drug (IC50 = 4.17 ± 0.20 µM). The molecular interactions between derivatives 3a-h, 7, 9, 11, 13, and the CDK-5 enzyme (PDB ID: 3IG7) were studied further using molecular docking indicating a high level of support for the experimental results. Furthermore, the drug-likeness analysis of the reported derivatives indicated that derivative 9 (binding affinity = -8.34 kcal/mol) would have a better pharmacokinetics, drug-likeness, and oral bioavailability as compared to doxorubicin (-7.04 kcal/mol). These results along with the structure-activity relationship (SAR) of the reported derivatives will pave the way for the design of additional azines bearing indole with potential anticancer activities.

Synthesis and in vitro study of pyrimidine-phthalimide hybrids as VEGFR2 inhibitors with antiproliferative activity.

Aim: Thalidomide, a once notorious sedative, is now clinically used as an antitumor agent. We aimed to use it as a lead compound for designing pyrimidine-phthalimide hybrids. Materials & methods: Nucleophilic substitution reaction of thalidomide analog 4 with primary and/or secondary aliphatic amines afforded pyrimidine-phthalimide hybrids 5a-g, 6 and 7a-d. Results & conclusion: Compound 7c showed high antiproliferative activity against four cell lines: HepG-2 (IC50: 7.86 ± 0.5 µM), MCF-7 (IC50: 2.77 ± 0.1 µM), HCT-116 (IC50: 5.73 ± 0.4 µM) and PC-3 (IC50: 8.32 ± 0.5 µM), with selective cytotoxicity for WI-38 (IC50: 43.2 ± 2.56 µM). 7c arrested MCF-7 cells at S phase of the cell cycle and increased the total apoptotic cells by 50-fold. 7c inhibited VEGFR2 in vitro (IC50: 0.130 ± 0.02 µM). 7c was capable of binding at the VEGFR2 binding site, forming hydrogen bond interactions with Asp1046 and Glu885 in a similar way to sorafenib.

Design, synthesis and antitumor activity of novel pyran-functionalized uracil derivatives: docking studies.

Aim: Synthesis of novel pyran-based uracils that may have potent antitumor activity against hepatocellular carcinoma HepG2 and ovarian cancer SKOV3 cell lines. Materials & methods: Novel pyran-based uracils were synthesized and their anticancer activity was assessed using methyl thiazolyl tetrazolium and wound-healing assays to detect their cytotoxicity and their antiproliferative and antimigratory activities. Results: Compounds 3, 5, 6, 7, 8, 9, 10, 11 and 13 significantly inhibited cell proliferation of the HepG2 cell line. Compounds 7, 8, 9 and 13 significantly inhibited the proliferation of SKOV3 cells, which was also proven through docking studies with topoisomerase I. Conclusion: The molecular docking analysis revealed that 7 and 9 are two major compounds found to possess higher degrees of interaction with DNA gyrase.

Synthesis and Molecular Docking of Some Novel 3-Thiazolyl-Coumarins as Inhibitors of VEGFR-2 Kinase.

One crucial strategy for the treatment of breast cancer involves focusing on the Vascular Endothelial Growth Factor Receptor (VEGFR-2) signaling system. Consequently, the development of new (VEGFR-2) inhibitors is of the utmost importance. In this study, novel 3-thiazolhydrazinylcoumarins were designed and synthesized via the reaction of phenylazoacetylcoumarin with various hydrazonoyl halides and α-bromoketones. By using elemental and spectral analysis data (IR, 1H-NMR, 13C-NMR, and Mass), the ascribed structures for all newly synthesized compounds were clarified, and the mechanisms underlying their formation were delineated. The molecular docking studies of the resulting 6-(phenyldiazenyl)-2H-chromen-2-one (3, 6a-e, 10a-c and 12a-c) derivatives were assessed against VEGFR-2 and demonstrated comparable activities to that of Sorafenib (approved medicine) with compounds 6d and 6b showing the highest binding scores (-9.900 and -9.819 kcal/mol, respectively). The cytotoxicity of the most active thiazole derivatives 6d, 6b, 6c, 10c and 10a were investigated for their human breast cancer (MCF-7) cell line and normal cell line LLC-Mk2 using MTT assay and Sorafenib as the reference drug. The results revealed that compounds 6d and 6b exhibited greater anticancer activities (IC50 = 10.5 ± 0.71 and 11.2 ± 0.80 µM, respectively) than the Sorafenib reference drug (IC50 = 5.10 ± 0.49 µM). Therefore, the present study demonstrated that thiazolyl coumarins are potential (VEGFR-2) inhibitors and pave the way for the synthesis of additional libraries based on the reported scaffold, which could eventually lead to the development of efficient treatment for breast cancer.