Prediction of caspase-3 inhibitory activity of 1,3-dioxo-4-methyl-2,3-dihydro-1h-pyrrolo[3,4-c] quinolines: QSAR study

Abstract

Neurodegenerative disorders are consequences of progressive and irreversible loss of neurons due to unwanted apoptosis which involves caspases, a group of cysteine proteases that cleave other proteins and inactivate them. Among several different groups of caspase enzymes, caspases-3 plays a key role in apoptosis and are a therapeutic target for their inhibition. In pursuit of better caspase-3 inhibitors, a quantitative structure-activity relationship (QSAR) analysis was performed on a series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c] quinolines as caspase-3 inhibitors using WIN CAChe 6.1 and Medicinal Chemistry Regression Machine. The best QSAR model was selected and validated by internal and external validation method. The values of statistical data are r ¼ 0.955, F ¼ 72.95, SEE ¼ 0.397, q 2 ¼ 0.885, S PRESS ¼ 0.44. The present study reveals that when the conformational minimum energy is increased, and lowest unoccupied molecular orbital energy and highest occupied molecular orbital energy are decreased the biological activity can be increased. On the basis of a selected QSAR model, we designed a new series of 1,3-dioxo-4-methyl-2,3-dihydro-1H-pyrrolo[3,4-c]quinolines compounds, calculated their caspases inhibitory activity and found that the designed compounds were more potent than the existing compounds.

Overcoming Back Electron Transfer in the Electron Donor–Acceptor Complex-Mediated Visible Light-Driven Generation of α-Aminoalkyl Radicals from Secondary Anilines

“…Generation of secondary α-aminoalkyl radicals and reacting them with alkenes would potentially give access to N -H–THQ (Scheme A), a useful core structure that can be used for the synthesis of a range of biologically active compounds including cytotoxins, γ-sectretase inhibitors, and caspase inhibitors (Scheme D). − N -H–THQs are typically accessible via Povarov-type reactions between imines and electron-rich alkenes . However, synthesis of N -H–THQs bearing electron-withdrawing groups is limited to reverse polarity cycloadditions catalyzed by iridium complexes or via deprotection of the N -Bn–THQ derivative (Scheme B). − …”

Comparison of the performance of different “local reactive descriptors” in 3D-QSAR analysis of enantioselective molecules

“…However, one LRD may indicate the interaction mechanism from the other. HOMO/LUMO frontier orbital coefficients (partial atomic charges derived from electron densities on atoms), Fukui index, and other electronic properties have been used alone or in combination with conventional descriptors [21][22][23][24]. According to frontier orbital theory, nucleophilic/electrophilic and hydrogen bond interactions can be explained according to energy maps in HOMO/ LUMO orbitals [6].…”

An efficient piecewise linear model for predicting activity of caspase-3 inhibitors

“…Caspase-3 is a key executioner member of the caspase family which propagates death signals from intrinsic and extrinsic stimuli to downstream targets. Inappropriate control of caspases (especially caspase-3) as apoptosis machinery has been implicated in many diseases, including neurodegenerative disorders, cancer, and autoimmune diseases [7,8]. In this study, we tried to develop and choose a robust model to predict caspase-3 inhibition activity as a scientific method to facilitate the discovery of anti-neurodegenerative agents.…”