Nandish M. Nagappa

Sulfonylated 5-piperazine-substituted 1,3-oxazole-4-carbonitriles were synthesized and evaluated for in vitro anticancer activity. Cytotoxicity was assessed in hepatocellular (HepG2, Huh7), breast (MCF-7, MDA-MB-231), cervical (HeLa), melanoma (M21), and neuroblastoma (Kelly, SH-SY5Y) cell lines, with HEK293 cells used as a non-malignant control. Compounds 7a, 7b, and 8aa emerged as lead structures. Notably, compound 7b showed the highest activity in Kelly neuroblastoma cells (IC₅₀ = 1.3 µM) while exhibiting low cytotoxicity toward HEK293 cells (IC₅₀ > 10 µM), indicating an improved selectivity profile relative to doxorubicin. In silico molecular docking suggested favorable interactions of the lead compounds with several cancer-associated proteins, with the highest predicted affinity observed for Aurora A kinase, along with additional predicted interactions with cyclin-dependent kinases. Predicted ADMET properties of compounds 7a, 7b, and 8aa compared favorably with doxorubicin, although the lead compounds were not readily biodegradable under OECD 301D conditions. Overall, these findings identify oxazole-4-carbonitriles as promising anticancer candidates with a putative kinase-directed mechanism of action.

Deep Eutectic Solvents (DESs), particularly Naturally Available Deep Eutectic Solvents (NADESs), are increasingly regarded as green solvents due to their low vapor pressure, non-flammability, thermal stability, strong solvent power, and low toxicity. In line with Green Chemistry principles, the use of renewable and biocompatible components such as amino acids, lipids, and naturally derived acids enables the development of more sustainable solvent systems. This study addresses the need for environmentally safer NADESs by evaluating their physico-chemical suitability and environmental impact. Fifteen NADESs were prepared using naturally derived components and assessed for environmental safety. Biodegradability was evaluated using the OECD 301D Closed Bottle Test (CBT), while toxicity toward Raphidocelis subcapitata was examined to characterize ecotoxicological behavior. The results demonstrated that the synthesized NADESs exhibit high biodegradability levels and low toxicity toward microalgae. Toxicity control indicated no significant inhibition of microbial activity during biodegradation, suggesting favorable environmental compatibility. Overall, the findings indicate that the NADESs represent more sustainable solvent alternatives with low toxicological profiles. However, the potential role of these compounds in enhancing eutrophication processes cannot be excluded and warrants further investigation.

Neuroblastoma, a leading cause of pediatric cancer mortality, requires efficient and selective therapeutics. We synthesized and characterized a series of sulfonated 5-piperazine-containing 1,3-oxazole-4-carbonitrile derivatives via sulfonylation protocols and evaluated their in vitro cytotoxicity against human hepatocellular carcinoma (HepG2, Huh7), breast (MCF7, MDA-MB-231), cervical (HeLa), melanoma (M21), and two neuroblastoma (Kelly, SHSY5Y) cell lines, alongside non-malignant HEK293 cells. Three compounds (7a, 7b, and 8aa) demonstrated efficient and selective cytotoxicity toward MYCN-amplified (Kelly) and MYCN-non-amplified (SHSY5Y) neuroblastoma cells, with 7b being the most active (IC₅₀ = 1.9 µM in Kelly cells) and showing minimal toxicity in HEK293 (IC₅₀ > 10 µM). In Kelly cells, 7b matched doxorubicin while showing lower off-target toxicity and low-micromolar activity in solid tumors. The hit compounds were shown to be not readily biodegradable under OECD 301D test. In silico docking revealed high-affinity binding to the ATP-binding site of Aurora A kinase in the Aurora A/N-MYC complex (ΔG = –10.8 to –10.9 kcal/mol). Compound 7b exhibited broad cytotoxicity across all tested cancers (IC₅₀ = 1.5–4.0 µM). ADMET profiling of 7a, 7b, and 8aa indicated favorable pharmacokinetic and toxicity parameters compared with doxorubicin. These findings identify sulfonylated oxazole-4-carbonitriles as neuroblastoma therapeutics with potential use against proliferating malignancies.

Deep Eutectic Solvents (DESs) and in essence naturally available DESs (NADESs) are considered to be green solvents due to their low vapor pressure, non-flammability, thermal stability, good solvent power and low oxicity. These properties make them attractive as safer and more environmentally acceptable solvent options. Green Chemistry promotes the use of renewable and biocompatible compounds such as amino acids, lipids and acids of natural origin to yield more sustainable DESs, which yields their application in several industrial processes. Driven by the current requisite for sustainable progress, along with overcoming dependence on fossil-based resources, the current work details important findings pertaining to the design of sustainable NADESs from the perspective of green chemistry to exhibit suitable physico-chemical properties and a low toxicological profile. Biodegradation studies using OECD 301D closed bottle test (CBT) were performed to observe the biodegradability of 15 selected NADESs. Toxicity controls were run along with the CBT run to observe the behavior of these NADESs in the environment. In this framework, the present paper investigates the development of safer NADESs. The results obtained suggest that our synthesized NADESs, have high biodegradability and low toxicity towards microalgae. Although a conventional threat to the environment would seem out of reach, it must be hypothesized that such compounds might act as enhancers of eutrophication phenomena.