Novel 4-quinoline-thiosemicarbazone derivatives: Synthesis, antiproliferative activity, in vitro and in silico biomacromolecule interaction studies and topoisomerase inhibition.

Twelve 2-(quinolin-4-ylmethylene) hydrazinecarbothioamide derivatives were synthetized and their biological properties were investigated, among which, the ability to interact with DNA and BSA through UV-Vis absorption, fluorescence, Circular Dichroism, molecular docking and relative viscosity, antiproliferative activity against MCF-7 and T-47D mammary tumor cells and RAW-264.7 macrophages and inhibitory capacity of the enzyme topoisomerase IIα. In the binding study with DNA and BSA, all the compounds displayed affinity for interaction with both biomolecules, especially JF-92 (p-ethyl-substituted), with binding constant of 1.62 × 106 and 1.43 × 105, respectively, and DNA binding mode by intercalation. The IC50 values were obtained between 0.81 and 1.48 µM and topoisomerase inhibition results in 10 µM. Thus, we conclude that the reduction of the acridine to quinoline ring did not disrupt the antitumor action and that substitution patterns are important for biomolecule interaction affinity as they demonstrate the potential of these compounds for anticancer therapy.

Synthesis, in vitro and in vivo biological evaluation, COX-1/2 inhibition and molecular docking study of indole-N-acylhydrazone derivatives.

The objective of this work was to obtain and evaluate anti-inflammatory in vitro, in vivo and in silico potential of novel indole-N-acylhydrazone derivatives. In total, 10 new compounds (3a-j) were synthesized in satisfactory yields, through a condensation reaction in a single synthesis step. In the lymphoproliferation assay, using mice splenocytes, 3a and 3b showed inhibition of lymphocyte proliferation of 62.7% (±3.5) and 50.7% (±2), respectively, while dexamethasone presented an inhibition of 74.6% (±2.4). Moreover, compound 3b induced higher Th2 cytokines production in mice splenocytes cultures. The results for COX inhibition assays showed that compound 3b is a selective COX-2 inhibitor, but with less potency when compared to celecoxib, and compound 3a not presented selectivity towards COX-2. The molecular docking results suggest compounds 3a and 3b interact with the active site of COX-2 in similar conformations, but not with the active site of COX-1, and this may be the main reason to the COX-2 selectivity of compound 3b. In vivo carrageenan-induced paw edema assays were adopted for the confirmation of the anti-inflammatory activity. Compound 3b showed better results in suppressing edema at all tested concentrations and was able to induce an edema inhibition of 100% after 5 h of carrageenan injection at the 30 mg kg-1 dosage, corroborating with the COX inhibition and lymphoproliferation results. I addition to our experimental results, in silico analysis suggest that compounds 3a and 3b present a well-balanced profile between pharmacodynamics and pharmacokinetics. Thus, our preliminary results revealed the potentiality of a new COX-2 selective derivative in the modulation of the inflammatory process.

Effectiveness and safety evaluation in the dyslipidemia treatment with statins

Statins are used to reduce morbidity and mortality in patients with a high risk of cardiovascular disease. However, the use of statins does not ensure effectiveness and pharmacotherapeutic safety. In this context, the present study aimed to evaluate the effectiveness and safety of the therapy with statins in patients with dyslipidemia and high cardiovascular risk. To evaluate these parameters, this study selected 113 dyslipidemic patients with regular statins use of at least seven months. It was an observational cross-sectional study, based on data analysis collected from biochemical tests of patients with dyslipidemia in the public health system in the state of Pernambuco, Brazil. Isolated hypercholesterolemia was the most prevalent dyslipidemia type and the most used statin was atorvastatin (84%), followed by simvastatin (16%). The study observed no effectiveness in 58.4% of the patients; 28% had no safety in the treatment, and 48.3% were using doses above the standard dosage. Comparing effectiveness and safety between the same drugs, at standard dosage with higher dosages, there was not any statistical difference in biochemical test results. Therapeutic goals for LDL-C ≤ 70 mg/dL were found in 28% of cases. However, the use of doses above the standard dosage intended to reach very low LDL-C levels should be reevaluated, since there was no statistical difference in reducing the lipid profile, suggesting that the same results can be obtained with a lower standardized dose. This study provides data relevant to the discussion of statins use and to the necessity of strengthening pharmacotherapeutic monitoring in dyslipidemia treatment.