Isatin derivatives potentially act on various biological targets. In this article, a series of novel isatin-hydrazones were synthesized in excellent yields. Their cytotoxicity was tested against human breast adenocarcinoma (MCF7) and human ovary adenocarcinoma (A2780) cell lines using MTT assay. Compounds 4j (IC50 = 1.51 ± 0.09 µM) and 4k (IC50 = 3.56 ± 0.31) showed excellent activity against MCF7, whereas compound 4e showed considerable cytotoxicity against both tested cell lines, MCF7 (IC50 = 5.46 ± 0.71 µM) and A2780 (IC50 = 18.96± 2.52 µM), respectively. Structure-activity relationships (SARs) revealed that, halogen substituents at 2,6-position of the C-ring of isatin-hydrazones are the most potent derivatives. In-silico absorption, distribution, metabolism and excretion (ADME) results demonstrated recommended drug likeness properties. Compounds 4j (IC50 = 0.245 µM) and 4k (IC50 = 0.300 µM) exhibited good inhibitory activity against the cell cycle regulator CDK2 protein kinase compared to imatinib (IC50 = 0.131 µM). A molecular docking study of 4j and 4k confirmed both compounds as type II ATP competitive inhibitors that made interactions with ATP binding pocket residues, as well as lacking interactions with active state DFG motif residues.

In the brain, propionic acid (PA) can cross cell membranes and accumulate within cells, leading to intracellular acidification, which may alter neurotransmitter release (NT), communication between neurons, and behavior. Such elevation in levels of PA constitutes a neurodevelopmental metabolic disorder called propionic acidemia, which could clinically manifest as autism. The purpose of this study was to investigate the protective effects of different fractions of bee pollen (BP) on PA‐induced autism in rats, and to evaluate their effects on the expression of liver and renal biomarkers. Groups of rats received treatments of different fractions of BP at a dose of 250 mg/kg of body weight/day for a period of 1 month. Normal control group I and group II were orally administered with phosphate‐buffered saline and propionic acid, respectively, for 3 days. BP contains various health‐promoting phenolic components. Different fractions of BP administered pre‐ and post‐treatment with PA showed significant reduction in the levels of liver and renal biomarkers (p < .05). Also, a significant enhancement in the levels of glutathione S‐transferase (GST), catalase CAT), and ascorbic acid (VIT C) was observed. Supplementation with BP significantly reduced biochemical changes in the liver, kidneys, and brain of rats with PA‐induced toxicity. It exhibited protective effects against oxidative damage and reactive oxygen species produced by PA‐induced adverse reactions in rats. Taken together, our study shows that BP possesses protective effects in PA‐induced liver and kidney damage.

Recently, we have reported a series of isatin hydrazone, two of them, namely, 3-((2,6-dichlorobenzylidene)hydrazono)indolin-2-one (1) and 3-((2-chloro-6-fluorobenzylidene)hydrazono)indolin-2-one (2) having potent cytotoxicity, showing cyclin-dependent kinases (CDK2) inhibitory activity and bearing recommended drug likeness properties. Since both compounds (1 and 2) showed inhibitory activity against CDK2, we assumed it would also have multiple receptor tyrosine kinases (RTKs) inhibitory activity. Considering those points, here, above-mentioned two isatin hydrazone 1 and 2 were synthesized using previously reported method for further investigation of their potency on RTKs (EGFR, VEGFR-2 and FLT-3) inhibitory activity. As expected, Compound 1 exhibited excellent inhibitory activity against epidermal growth factor receptor (EGFR, IC50 = 0.269 µM), vascular epidermal growth factor receptor 2 (VEGFR-2, IC50 = 0.232 µM) and FMS-like tyrosine kinase-3 (FLT-3, IC50 = 1.535 µM) tyrosine kinases. On the other hand, Compound 2 also exhibited excellent inhibitory activity against EGFR (IC50 = 0.369 µM), VEGFR-2 (IC50 = 0.266 µM) and FLT-3 (IC50 = 0.546 µM) tyrosine kinases. A molecular docking study with EGFR, VEGFR-2 and FLT-3 kinase suggested that both compounds act as type I ATP competitive inhibitors against EGFR and VEGFR-2, and type II ATP non-competitive inhibitors against FLT-3.

Developing anticancer therapeutics with no/few side effects is a challenge for medicinal chemists. The absence of antibacterial activity of an anticancer drug removes its detrimental effect toward intestinal flora and therefore leads to reduced side effects. Here, a series of novel N-benzylisatin-aryl-hydrazones was designed, synthesized and evaluated for their antimicrobial and antiproliferative activities with SAR and ADME studies, aiming to develop anticancer drugs with no antimicrobial, yet high antiproliferative activities. The results were then compared with the effects of first-line treatments for lung cancer drug Gefitinib. Novel N-benzylisatin-aryl-hydrazones were synthesized from isatin and benzyl bromide in three steps with good to moderate yields. Antimicrobial activity was tested with six Gram-positive/negative bacterial strains, antifungal activity with a fungal strain and antiproliferative activity against ‘A549’ and ‘HeLa cell lines’, respectively. As expected, synthesized hydrazones reveled no effects on any of the strains of bacteria and fungi up to 100-µg/disc concentration. However, four compounds showed two-to-four fold antiproliferative activity over Gefitinib. For instance, IC50 of a compound (6c) shows concentration of 4.35 µM, whereas gefitinib shows 15.23 µM against ‘A549.’ ADME predicted studies reveled that our synthesized hydrazones exhibited higher ADME values than the Gefitinib. Therefore, our synthesized hydrazones can be an excellent scaffold for the development of anticancer therapeutics after considering further investigations.

Cancer cells frequently develop drug resistance, which leads to chemotherapeutic treatment failure. Additionally, chemotherapies are hindered by their high toxicity. Therefore, the development of new chemotherapeutic drugs with improved clinical outcomes and low toxicity is a major priority. Several indole derivatives exhibit distinctive anti-cancer mechanisms which have been associated with various molecular targets. In this study, target compounds 4a–q were obtained through the reaction of substituted benzyl chloride with hydrazine hydrate, which produces benzyl hydrazine. Subsequently, the appropriate substituted benzyl hydrazine was allowed to react with 1H-indole-2-carboxylic acid or 5-methoxy-1H-indole-2-carboxylic acid using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide as a coupling agent. All compounds exhibited cytotoxicity in three cell lines, namely, MCF-7, A549, and HCT. Compound 4e exhibited the highest cytotoxicity, with an average IC50 of 2 µM. Moreover, a flow cytometry study revealed a significantly increased prevalence of Annexin-V and 7-AAD positive cell populations. Several derivatives of 4a–q showed moderate to high cytotoxicity against the tested cell lines, with compound 4e having the highest cytotoxicity, indicating that it may possess potential apoptosis-inducing capabilities.