The Structure-AChE Inhibitory Activity Relationships Study in a Series of Pyridazine Analogues

Abstract

The structure-activity relationships (SAR) are investigated by means of the Electronic-Topological Method (ETM) followed by the Neural Networks application (ETM-NN) for a class of anti-cholinesterase inhibitors (AChE, 53 molecules) being pyridazine derivatives. AChE activities of the series were measured in IC(50) units, and relative to the activity levels, the series was partitioned into classes of active and inactive compounds. Based on pharmacophores and antipharmacophores calculated by the ETM-software as sub-matrices containing important spatial and electronic characteristics, a system for the activity prognostication is developed. Input data for the ETM were taken as the results of conformational and quantum-mechanics calculations. To predict the activity, we used one of the most well known neural networks, namely, the feed-forward neural networks (FFNNs) trained with the back propagation algorithm. The supervised learning was performed using a variant of FFNN known as the Associative Neural Networks (ASNN). The result of the testing revealed that the high ETM's ability of predicting both activity and inactivity of potential AChE inhibitors. Analysis of HOMOs for the compounds containing Ph1 and APh1 has shown that atoms with the highest values of the atomic orbital coefficients are mainly those atoms that enter into the pharmacophores. Thus, the set of pharmacophores and antipharmacophores found as the result of this study forms a basis for a system of the anti-cholinesterase activity prediction.

Artificial neural network‐based quantitative structure–activity relationships model and molecular docking for virtual screening of novel potent acetylcholinesterase inhibitors

“…where Y represents the pIC50 activity; B 0 : the intercept of the equation; and B n : regression coefficients of the descriptors, X n . Note: *pIC 50 Exp in μM on electric eel AChE [8][9][10] ; superscript t denotes test.…”

“…Due to these side effects, along with other factors such as short-lived inhibitors, the search for better AChEIs is ongoing and is important. A class of anti-AChEIs (AChE, 52 molecules), that is, pyridazine derivatives, was proposed by Contreras et al; [8][9][10] they demonstrated that the members of this class show increased inhibitory activity toward AChE. In this study, we implemented a computational workflow based on a series of pyridazine derivatives to probe the structural features necessary to optimize AChEIs, and to search for new AChEIs compounds.…”

"Design and in Silico Studies on Different Dengue Viral Proteins of Some Compounds Based on Acetophenone Skeleton"

“…antihypertensive [4], diuretic [5], antiplatelet [6], cardiotonic [7] anticancer [8], anti-HIV [9], anti-inflammatory [10], antimicrobial [11] anti-tuberculosis [12] etc. Dengue virus is part of the family Flaviviridae, genus Flavivirus [13,14].…”

Synthesis and In vitro Analysis of Novel Dihydroxyacetophenone Derivatives with Antimicrobial and Antitumor Activities

“…Pyridazine derivatives and its condensed systems phthalazines, are well known scaffolds in medicinal chemistry [3,4], possessing a large variety of biological activities such as antihypertensive [5], diuretic [6], antiplatelet [7], cardiotonic [8], anticancer [9], anti-HIV [10], anti-inflammatory [11], antimicrobial (antibacterial, antifungal, anti-tuberculosis) [12,13], so on. Synthesis of functionalized acetophenone derivatives is an important goal for organic synthesis, these derivatives and particulary dihydroxyacetophenone, exhibiting interesting biological properties, these including antimicrobial [14] and anticancer activities [15].…”