The ratios of E/Z isomers of sixteen synthesized 1,3-dihydro-3-(substituted phenylimino)-2H-indol-2-one were studied using experimental and theoretical methodology. Linear solvation energy relationships (LSER) rationalized solvent influence of the solvent-solute interactions on the UV-Vis absorption maxima shifts (ν) of both geometrical isomers using the Kamlet-Taft equation. Linear free energy relationships (LFER) in the form of single substituent parameter equation (SSP) was used to analyze substituent effect on pK, NMR chemical shifts and ν values. Electron charge density was obtained by the use of Quantum Theory of Atoms in Molecules, i.e. Bader's analysis. The substituent and solvent effect on intramolecular charge transfer (ICT) were interpreted with the aid of time-dependent density functional (TD-DFT) method. Additionally, the results of TD-DFT calculations quantified the efficiency of ICT from the calculated charge-transfer distance (D) and amount of transferred charge (Q). The antimicrobial activity was evaluated using broth microdilution method. 3D QSAR modeling was used to demonstrate the influence of substituents effect as well as molecule geometry on antimicrobial activity.
The derivatives of isatin have already been reported to show a variety of biological activities. However, there has been no report on solvatochromic effect of isatin derivatives so far, and that could be of interest to study and relate to their electronic structure, as a part of the characterisation of these compounds. Linear solvation energy relationships (LSER) were used to analyze solvent influence on the UV absorption maxima shifts of investigated isatin derivatives, i.e. isatin based Schiff bases, by using Kamlet-Taft model. Linear free energy relationships (LFER) were applied to the substituent-induced NMR chemical shifts (SCS) using SSP (single substituent parameter). The obtained correlations together with theoretical calculations gave insight into the influence of the molecular conformation on the transmission of substituent effects, as well as on solute/solvent interactions. The molecular electrostatic potential (MEP) surface map was plotted over the optimized geometry of the molecules in order to visualize electron density distribution and explain origin of solvent/solute interactions. [Projekat Ministarstva nauke Republike Srbije, br. 172013]
A comparative study of antitumor activity of mono-and bis-quinoline based (thio)carbohydrazones was investigated by a series of tests on two human malignant cell lines: acute monocytic leukemia (THP-1) and pancreatic adenocarcinoma cancer stem cells (AsPC-1). Thiocarbohydrazones (TCHs) revealed superior pro-apoptotic activity over carbohydrazones (CHs) on both tested cell phenotypes, also displaying multi-target profile activities. Programmed cell death triggered by TCHs was partially caspasedependent, mainly caspase-8 related. Activity against cancer stem cells (CSCs) was evaluated on 2D monolayers and 3D spheroidal models, where two out of three tested bis-TCHs successfully stimulated apoptosis accompanied by a reduction in size of treated spheres. Additionally, all bis-TCHs induced significant decrease in percentage of CD44-expressing AsPC-1 cells that indicate on their ability to induce reprogramming of CSC phenotype. Current results highly support further assessment of bisTCHs in order to specify their specific targets in cancer cells and particularly in the CSCs subpopulation.
Due to the rise of microbial strains resistant to conventional therapies, there is an urgent need for finding the new antimicrobial chemotypes. Heterocyclic compounds such as thiocarbohydrazones (TCHs) are able to interact with many metalloenzymes essential for microbes, while sulfur atom increases lipophilicity which is generally positively correlated with potency. In this paper, we report antibacterial and antifungal activity of twenty-two TCHs toward eight bacterial and three fungal strains. Furthermore, three alignment independent 3D QSAR models based on descriptors derived from molecular interaction fields (MIFs) are developed in order to rationalize structure-activity relationships for activities of TCHs toward S. aureus, P. aeruginosa and C. albicans. Several structural fragments important for biological activity are recognized in each model, and structural modifications which could lead to increased potency are suggested. Designed structures will be synthesized accordingly and tested toward the same microbial strains in order to obtain more potent derivatives.
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