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.

Benzimidazole is crucial in drug design, with derivatives showing anticancer activity via DNA interaction and enzyme inhibition; SAR studies aim to improve efficacy, selectivity, and reduce toxicity.

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.

A novel catalytic approach for the synthesis of symmetric and asymmetric azines has been developed. The environmentally benign protocol was achieved via condensation of 1-[(2-thienyl)ethylidene]hydrazine (1) with different aromatic aldehydes 2a–h and acetyl heterocyclic compounds (4, 6, 8, 10, and 12) in the presence of cellulose sulfuric acid (CSA) as the green catalyst. These procedures offer an interesting method for the large-scale industrial manufacture of azines due to their high percentage yield, mild reaction conditions, broad substrate range, and utilization of an economical and environmentally acceptable catalyst. Additionally, the molecular docking of the products to the monoamine oxidase (MAO-A) target protein was achieved to highlight the possible binding interaction with the amino acid residues Arg51, Glu43, Gly22, Gly49, Gly443, Ala272, Ile335, and Tyr407 at the point of binding. The binding interaction energy was discovered to be (− 6.48 kcal/mol) for the protein MAO-A (PDB ID: 2Z5X). The most effective azine derivatives 7 and 13 revealed some major conserved interactions between the MAO-A protein’s binding site amino acid residues and the PDB co-crystal ligand 2Z5X. Moreover, azine derivatives 3a and 3f showed the lowest binding activity with the target MAO-A.

Terephthalohydrazide chitosan hydrogel (TCs) was prepared and investigated as an ecofriendly biopolymeric catalyst for synthesis of some novel thiazole and thiadiazole derivatives. Thus, TCs was used as a promising ecofriendly basic biocatalyst for preparation of three new series of thiazoles and two thiadiazoles derivatives via reacting 2-(2-oxo-1,2-diphenylethylidene) hydrazine-1-carbothio-amide with various hydrazonoyl chlorides and α-haloketones under mild ultrasonic irradiation. Also, their yield% was estimated using chitosan and TCs in a comparative study. The procedure being employed has the advantages of mild reaction conditions, quick reaction durations, and high reaction yields. It also benefits from the catalyst’s capacity to be reused several times without significantly losing potency. The chemical structures of the newly prepared compounds were confirmed by IR, MS, and ¹H-NMR. Docking analyses of the synthesized compounds’ binding modes revealed promising binding scores against the various amino acids of the selected protein (PDB Code—1JIJ). SwissADME’s online tool is then used to analyze the physiochemical and pharmacokinetic characteristics of the most significant substances. The majority of novel compounds showed zero violation from Lipinski’s rule (Ro5).

Green synthesis using L-proline as an organocatalyst is crucial due to its reusability, mild conditions, clean reactions, easy workup, high purity, short reaction times, and high yields. However, existing methods often involve harsh conditions and longer reaction times. In this study, 2-cyano-N’-(2-cyanoacetyl)acetohydrazide (3) was prepared and condensed with various benzaldehyde derivatives to yield 2-cyano-N’-(2-cyano-3-phenylacryloyl)-3-phenylacrylohydrazide derivatives (5a–e, 7a,b) using a grinding technique with moist L-proline. Additionally, three 2-cyano-N’-(2-cyano-3-heterylbut-2-enoyl)-3-heterylbut-2-enehydrazides (9, 11, 13) were synthesized by condensing compound 3 with respective (heteraryl)ketones (8, 10, 12) following the same method. The synthesized compounds were characterized using IR, NMR, and MS spectroscopy. L-proline’s reusability was confirmed for up to four cycles without significant yield loss, showcasing the protocol’s efficiency and sustainability. The new compounds were screened for anticancer activities against the HCT-116 colon carcinoma cell line using the MTT assay. Molecular docking studies revealed the binding conformations of the most potent compounds to the target protein (PDB ID 6MTU), correlating well with in vitro results. In silico ADMET analysis indicated favorable pharmacokinetic properties, highlighting these novel compounds as promising targeted anti-colon cancer agents.