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.

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.

A novel and efficient route towards the synthesis of pyrido [2,3d:6,5-d']dipyrimidines 4 a-g as unexpected products through the reaction of 6-aminouracil (1) and arylidenemalononitrile or ethyl arylidenecyanoacetate in acetic acid were investigated. On the other hand, reaction of 6-aminouracil and ethyl 4nitrobenzylidenecyanoacetate in ethanol in presence of piperidine (few drops) afforded pyrido[2,3-d]pyrimidine-6-carbonitrile 5. In addition, pyrido[2,3-d]pyrimidines 6 a-g were obtained through the reaction of 5 with different aliphatic amines in ethanol in presence of triethylamine (few drops). All reactions proceeded in good to excellent yields and the resulting compounds were characterized by different spectroscopic techniques. The antiproliferative activity of these compounds was evaluated towards HEPG-2, MCF-7 and HCT-116 cell lines. The compound 6 a displayed the highest activity against the tested cell lines, followed by compound 6 d, 6 g and 6 b, with strong affinity to bind with the active and allosteric sites of topoisomerase II, as authenticated from the molecular docking analyses.

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.

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.

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.