Evaluation of the Antiparasitic and Antifungal Activities of Synthetic Piperlongumine-Type Cinnamide Derivatives: Booster Effect by Halogen Substituents.

A series of synthetic N-acylpyrrolidone and -piperidone derivatives of the natural alkaloid piperlongumine were prepared and tested for their activities against Leishmania major and Toxoplasma gondii parasites. Replacement of one of the aryl meta-methoxy groups by halogens such as chlorine, bromine and iodine led to distinctly increased antiparasitic activities. For instance, the new bromo- and iodo-substituted compounds 3 b/c and 4 b/c showed strong activity against L. major promastigotes (IC50 =4.5-5.8 µM). Their activities against L. major amastigotes were moderate. In addition, the new compounds 3 b, 3 c, and 4 a-c exhibited high activity against T. gondii parasites (IC50 =2.0-3.5 µM) with considerable selectivities when taking their effects on non-malignant Vero cells into account. Notable antitrypanosomal activity against Trypanosoma brucei was also found for 4 b. Antifungal activity against Madurella mycetomatis was observed for compound 4 c at higher doses. Quantitative structure-activity relationship (QSAR) studies were carried out, and docking calculations of test compounds bound to tubulin revealed binding differences between the 2-pyrrolidone and 2-piperidone derivatives. Microtubules-destabilizing effects were observed for 4 b in T. b. brucei cells.

Evaluation of a new series of pyrazole derivatives as a potent epidermal growth factor receptor inhibitory activity: QSAR modeling using quantum-chemical descriptors.

Pyrazole derivatives correspond to a family of heterocycle molecules with important pharmacological and physiological applications. At present, we perform a density functional theory (DFT) calculations and a quantitative structure-activity relationship (QSAR) evaluation on a series of 1-(4,5-dihydro-1H-pyrazol-1-yl) ethan-1-one and 4,5-dihydro-1H-pyrazole-1-carbothioamide derivatives as an epidermal growth factor receptor (EGFR) inhibitory activity. We thus propose a virtual screening protocol based on a machine-learning study. This theoretical model relates the studied compounds' biological activity to their calculated physicochemical descriptors. Moreover, the linear regression function is used to validate the model via the evaluation of Q2ext and Q2cv parameters for external and internal validations, respectively. Our QSAR model shows a good correlation between observed activities IC50 and predicted ones. Our model allows us to mitigate time-consuming problems and waste chemical and biological products in the preclinical phases.

p-Trifluoromethyl- and p-pentafluorothio-substituted curcuminoids of the 2,6-di[(E)-benzylidene)]cycloalkanone type: Syntheses and activities against Leishmania major and Toxoplasma gondii parasites.

A series of the title curcuminoids with structural variance in the heteroatom of the cycloalkanone and the p-substituents of the phenyl rings were tested for their activities against Leishmania major and Toxoplasma gondii parasites. The majority of them showed high activities against both parasite forms with EC50 values in the sub-micromolar concentration range. Bis(p-pentafluorothio)-substituted 3,5-di[(E)-benzylidene]piperidin-4-one 1b was not just noticeable antiparasitic, but also exhibited a considerable selectivity for L. major promastigotes over normal Vero cells. While derivatives differing only in the p-phenyl substituents being CF3 or SF5 showed similar antiparasitic activities, the cyclic ketone hub was more decisive both for the anti-parasitic activities and the selectivities for the parasites vs. normal cells. QSAR calculations confirmed the observed structure-activity relations and suggested structural variations for a further improvement of the antiparasitic activity. Docking studies based on DFT calculations revealed L. major pteridine reductase 1 as a likely molecular target protein of the title compounds.