Structure-Activity Relationship Prediction-Based Synthesis and Cytotoxicity Evaluation against the HEp-2 Laryngeal Carcinoma Cell of Isoflavone-Cytisine Mannich Bases.

QSAR analysis of previously synthesized and nature-inspired virtual isoflavone-cytisine hybrids against the HEp-2 laryngeal carcinoma cell lines was performed using the OCHEM web platform. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds such as 8-cytisinylmethyl derivatives of 5,7- and 6,7-dihydroxyisoflavones. The synthetic procedure for selective aminomethylation of 5,7-dihydroxyisoflavones with cytisine was developed. In vitro testing identified compound 7 f with cisplatin-level cytotoxicity against HEp-2 cell lines and compound 10 which was twice active than cisplatin after 72 h of incubation.

Pharmacoeconomic and epidemiological bases of optimal rotavirus vaccine supply for Ukrainian population.

OBJECTIVE: Introduction: Several studies has shown that rotaviruses play a leading role in the structure of acute intestinal infections (AII) of viral etiology in children. In the National vaccination calendar of Ukraine, vaccination against rotavirus infection (RVI) is classified as recommended, with the expected goal of reducing the number of severe RVI cases among under five-year-old children. Nevertheless, despite the positive epidemiological and clinical effects of vaccination against RVI, it remains unclear how appropriate the introduction of rotavirus vaccines is in terms of potential costs and benefits, as well as determining the optimal level of subsidy required to cover part of the costs of voluntary vaccination of the population. The aim: Study of optimal subsidy level of rotavirus vaccine in Ukraine using epidemiological and pharmacoeconomic modeling. PATIENTS AND METHODS: Materials and methods: The retrospective epidemiological data of the monthly RVI incidence in Ukraine as well as the population number from 2010 to 2016 formed the information basis for determining the transmission parameter of the viral agent. The scenario of RVI epidemic process as an acute intestinal infection from the point of view of mathematical epidemiology is best described by developed mathematical model. Cost-benefit of rotavirus vaccination was studied with the use of developed pharmacoeconomic criteria. RESULTS: Results and conclusions: Prediction of possible implications of RVI vaccination and finding optimal level of vaccine supply involves a comprehensive study of the epidemic process peculiarities of this infection with development of an adequate epidemiological model. We have proposed a model of RVI epidemiological process in Ukraine, determining its main parameters with the use of available retrospective data of anual number of RVI cases for the period from 2010 to 2016. The developed model was used as an analytical tool for analyzing influence of different levels of vaccine supply on vaccination cost-benefit. The results of research showed that the use of epidemiological modeling in pharmacoeconomic analysis of rotavirus vaccination made it possible to determine analytically optimal level of vaccination subsidy level.

1,3-Oxazole derivatives as potential anticancer agents: Computer modeling and experimental study.

Microtubules play a significant role in cell growth and functioning. Therefore inhibition of the microtubule assemblies has emerged as one of the most promising cancer treatment strategies. Predictive QSAR models were built on a series of selective inhibitors of the tubulin were performed by using Associative Neural Networks (ANN). To overcome the problem of data overfitting due to the descriptor selection, a 5-fold cross-validation with variable selection in each step of the analysis was used. All developed QSAR models showed excellent statistics on the training (total accuracy: 0.96-0.97) and test sets (total accuracy: 0.95-97). The models were further validated by 11 synthesized 1,3-oxazole derivatives and all of them showed inhibitory effect on the Hep-2 cancer cell line. The most promising compound showed inhibitory activity IC50=60.2µM. In order to hypothesize their mechanism of action the top three compounds were docked in the colchicine binding site of tubulin and showed reasonable docking scores as well as favorable interactions with the protein.