Quantitative structure-activity relationship of the thymidylate synthase inhibitors of Mus musculus in the series of quinazolin-4-one and quinazolin-4-imine derivatives.

A quantitative structure-activity relationship analysis of the 2-methylquinazolin-4-one and quinazolin-4-imine derivatives, well-known antifolate thymidylate synthase (TYMS) inhibitors, has been performed in the range IC50 = 0.4÷380000.0 nmoL/L using the GUSAR 2013 program. Based on the MNA and QNA descriptors using the self-consistent regression, 6 statistically significant consensus models for predicting the IC50 numerical values have been constructed. These models demonstrate high and moderate prognostic accuracies for the training and external validation test sets, respectively. The molecular fragments of TYMS inhibitors regulating their antitumor activity are identified. The obtained data open opportunities for developing novel promising inhibitors of TYMS.

Anti-Inflammatory Activity of Novel 12-N-methylcytisine Derivatives.

BACKGROUND AND OBJECTIVES: Neurodegenerative diseases and inflammation are always linked to each other; therefore the elaboration of new chemical compounds, which interact with pharmacological targets involved into these two processes, can become one of ways of correction of these types of human CNS pathology. In the field of this problem the anti-inflammatory activity of ten 3-amino derivatives of quinolizidine alkaloid (.)-cytisine (the data about nootropic activity of these compounds are outlined by us previously) was studied by using in vivo, in vitro and in silico approaches. METHODS: The anti-inflammatory activity of novel compounds was investigated on carrageenan- induced model of inflammation in Rat paw following an established protocol. COX-1 (ovin) and COX-2 (human recombinant) inhibition activities of tested compounds assessed using a COX Fluorescent Inhibitor Screening Assay Kit. And as part of an in silico screening the leading compounds were docked into the tyrosine sites of COX-1/COX-2 enzymes (PDB code: 1DIY and 1CVU). RESULTS: It was established that ability of 3-(2-hydroxyphenyl)amino, 3-(4-hydroxyphenyl) amino and 3-(3-phenylprop-2-en-1-yl)amino derivatives of 12-N-metylcytisine to inhibit the carrageenan-induced paw oedema in rats is comparable with reference drug diclofenac. The results of in vitro COX-1/COX-2 inhibition assay showed no significant activity of tested compounds, except compounds with 2-hydroxyphenyl, 3-phenylprop-2-en-1-yl, furyl and thiophenyl fragments which slightly reduce the activity of COX-2. CONCLUSION: The tendency to occurrence of anti-inflammatory properties of synthesized derivatives of quinolizidine alkaloid (-)-cytisine can be explained on the basis of molecular docking results, which assume the possibility of interaction of more potent compounds with key amino acids of COX-1/COX-2 active sites.