Ayoub Boualli

A novel series of aromatic ester‐1.4‐disubstituted‐1,2,3‐triazole hybrids containing himachalene was efficiently synthesized by a regioselective copper‐catalyzed azide‐alkyne cycloaddition between an azidomethyl‐himachalene derivative and various propargylated esters. These compounds were characterized by NMR and HRMS analyses. The Hemisynthesized products were studied for their in vitro cytotoxicity against four cancer cell lines (HT‐1080, A‐549, MCF‐7, and MDA‐MB‐231). Most of the tested compounds showed moderate to significant activities with IC ₅₀ values ranging from 8.06 to 47 µM on all cancer cell lines. Notably, compound 6d, with a 4‐methoxy substituent, was the most potent against HT‐1080 and MCF‐7 cells. The mechanism of action study revealed that compound 6d induced apoptosis through caspase‐3/7 activation and cell cycle arrest at G0/G1. These results were confirmed by in silico molecular docking investigations, which demonstrated that compound 6d had a strong binding affinity toward caspase‐3/7 (‐8.6 kcal/mol), much higher than the co‐crystallized ligand. Key hydrogen bonds with ARG207 and SER205, π‐cation interaction with ARG207, π – π stacking with HIS121 and TYR204, and hydrophobic interactions with MET61 and PHE128 were all present in its well‐balanced interaction profile. These interactions give the ligand a molecular basis for its increased biological activity and aid in its stable position inside the active site.

Leishmaniasis and toxoplasmosis are neglected parasitic diseases that remain major global health concerns due to limited therapeutic options, drug toxicity, and emerging resistance. In this context, the development of new antiparasitic agents based on natural product scaffolds is highly relevant. Totarol, a naturally occurring abietane-type diterpene isolated from Tetraclinis articulata, was used as a starting scaffold for hemisynthetic modification. A series of totarol-derived functionalized ketones, including α-bromoketone (4) and chalcone derivatives (5a–g), was synthesized and fully characterized by NMR, IR, and HRMS analyses. The compounds were evaluated for their in vitro antiparasitic activity against Leishmania major and Toxoplasma gondii. Compound 4 showed the highest activity, with half-maximal inhibitory concentration (IC₅₀) values of 3.2–5.3 µM against Leishmania major and 6.1 µM against T. gondii. However, compound 4 showed none strong host–cell selectivity, with selectivity indices of 0.79–1.5. Docking against L. major pteridine reductase 1 (PTR1) gave a Glide XP score of −5.3 kcal/mol, and the modeled complex persisted during a 100 ns molecular dynamics simulation. These computational results generate a hypothesis for antileishmanial activity without demonstrating PTR1 inhibition or explaining T. gondii activity. The active structures require substantial optimization of selectivity before consideration as antiparasitic candidates.

The current study reports the design and synthesis of novel totarol‐based 1,3‐thiazole derivatives DBT 2 ‐ 9 and evaluates their anticancer potential. The synthesis involved the reaction of totarol derivatives with thiosemicarbazone derivatives under optimized conditions. Structural characterization of the synthesized compounds was accomplished using high‐resolution mass spectrometry (HRMS), infrared spectroscopy (IR), and nuclear magnetic resonance (NMR) spectroscopy, confirming their chemical identities and purity. The antitumor activity of these compounds was evaluated using the in vitro MTT and apoptosis assays. The compounds demonstrated selective anti‐proliferative effects against MCF‐7 breast cancer cells, and compound DBT 9 had an IC ₅₀ value comparable to those of reference anticancer drugs. By activating caspases 4 and 8, which mediate the stress‐mediated and extrinsic apoptosis pathways, respectively, compound DBT 9 caused MCF‐7 cell death. Furthermore, density functional theory (DFT) was carried out to study the electronic properties and the chemical reactivity of the synthesized compounds. Furthermore, molecular docking studies revealed that DBT 9 displayed the highest binding affinity toward multiple cancer‐associated target proteins, including EGFR, VEGFR‐2, and FGFR1. These findings indicate that DBT 9 showed the best cytotoxic activity through the induction of apoptosis via caspase 4 and 8 pathways, indicating its potential as a promising bioactive compound.