Botulinum neurotoxin type A (BoNT/A) is an exceptionally potent neurotoxin of great therapeutic value; however, it is also considered a weapon of mass destruction, as it is one of the most poisonous biological substances known to man. The etiology behind BoNT/A is its action as a zinc-dependent protease, which can cause extended paralysis through the cleavage of SNARE proteins. Thiosemicarbazones, known zinc chelators, provide a privileged scaffold that can be leveraged for the development of BoNT/A LC inhibitors. Through a combination of biochemical and kinetic assays, it was demonstrated that the thiosemicarbazone ZMC1, an antitumor agent, is an effective competitive inhibitor of the BoNT/A LC. Based on these results, a series of thiosemicarbazones were designed/synthesized using structure-based analysis and examined in enzyme activity and cell-based assays. From this screen, two analogues presented noteworthy cellular activity. The most potent inhibitors were then tested in a BoNT/A mouse lethality assay, providing statistically significant prolonged survival.

2024-10-17·Future Medicinal Chemistry

Semicarbazone, thiosemicarbazone tailed isoxazoline-pyrazole: synthesis, DFT, biological and computational assessment

Article

作者: Ait Itto, My Youssef ; Hachim, Mouhi Eddine ; Khatabi, Khalil El ; Ajana, Mohammed Aziz ; Oubella, Ali ; Laamari, Yassine ; Morjani, Hamid ; Auhmani, Aziz ; Bimoussa, Abdoullah ; AlAjmi, Mohamed F

Aim: A series of semicarbazone and thiosemicarbazone-tailed hybrids comprising pyrazole and acetylisoxazoline were prepared from (R)-carvone and characterized by technique spectroscopies Nuclear Magnetic Resonance (NMR), IR and High-Resolution Mass Spectrometry. Density Functional Theory (DFT) determined the structural parameters. Their cytotoxic activity was evaluated in vitro against four human cancer cell lines.Methods & results: All the studied semi and thiosemicarbazone demonstrate a promising potential as anticancer agents. The mechanism of action of these compounds involves apoptosis in HT-1080 cells, supported by an increase in the level of caspase-3/7 activity, which also arrests the cell cycle in the G0/G1 phase. Molecular docking studies were performed to establish the potential of the most active compounds 4a and 5a. ADMET analysis showed appropriate pharmacokinetic properties, allowing structure prediction for anticancer activity.

2024-08-01·Journal of Taibah University Medical Sciences

QSAR, molecular docking, and pharmacokinetic analysis of thiosemicarbazone-indole compounds targeting prostate cancer cells

Article

作者: Umar, Abdullahi Bello ; Babalola, Ibrahim Tijjani ; Uzairu, Adamu ; Ibrahim, Muhammad Tukur ; Kubo, Abdulrahman Ibrahim

ObjectivesBy 2030, prostate cancer is estimated to account for 1.7 million new cases and 499,000 deaths. The objectives of this research were to create a model revealing the activity of thiosemicarbazone-indole compounds as anticancer agents against the PC3 cell line; perform docking analysis between the compounds and the target enzyme; and predict the pharmacokinetics and drug-likeness of the compounds under investigation.MethodsThe quantitative structureactivity relationship (QSAR) method was used to build the model; molecular docking between the compounds and the target enzyme was performed; and the drug-likeness and pharmacokinetics of the inhibiting compounds was examined.ResultsThe genetic function algorithm-multilinear regression approach was used for building the QSAR model. Build model 1 had the best performance, with R² (coefficient of determination) = 0.972517, R_adj (adjusted R-squared) = 0.964665, (CRp²) = 0.780922, and LOF (leave-one-out cross-validation) = 0.076524, demonstrated strongly indicated by the molecular descriptors. SHBd, SsCH3, JGI2, and RDF60P were highly dependent on proliferative activity. Compounds ID 7 and 22 had the potential to act as androgen receptor inhibitors, as suggested by molecular docking studies between the drugs and their target enzymes. Compounds ID 7 and 22 exhibited binding scores of -8.5 kcal/mol and -8.8 kcal/mol, respectively. The approved maximum medication molecules for oral bioavailability included the molecules with IDs 7 and 22.ConclusionThis research provides valuable insights into the relationships among molecular descriptors, potential inhibitors, and pharmacokinetic properties in the treatment of PC3. These findings may contribute to the understanding and potential development of new therapeutic options for prostate cancer patients.

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