Synthesis, in silico screening, and biological evaluation of novel pyridine congeners as anti‐epileptic agents targeting AMPA (α‐amino‐3‐hydroxy‐5‐methylisoxazole) receptors

Author:

Tyagi Shivani1,Mishra Rakhi1ORCID,Mazumder Avijit1,Mazumder Rupa1,Singh Gurvinder2,Pandey Pratibha13

Affiliation:

1. Noida Institute of Engineering and Technology (Pharmacy Institute) Greater Noida Uttar Pradesh India

2. School of Pharmaceutical Science Lovely Professional University Phagwara Punjab India

3. Noida Institute of Engineering and Technology, Biotechnology Department Greater Noida Uttar Pradesh India

Abstract

AbstractThe research involves the synthesis of a series of new pyridine analogs 5(i‐x) and their evaluation for anti‐epileptic potential using in silico and in vivo models. Synthesis of the compounds was accomplished by using the Vilsmeier‐Haack reaction principle. AutoDock 4.2 was used for their in silico screening against AMPA (‐amino‐3‐hydroxy‐5‐methylisoxazole) receptor (PDB ID:3m3f). For in vivo testing, the maximal electroshock seizure (MES) model was used. The physicochemical, pharmacokinetic, drug‐like, and drug‐score features of all synthesized compounds were assessed using the online Swiss ADME and Protein Plus software. The in silico results showed that all the synthesized compounds 5(i‐x) had 1–3 interactions and affinities ranging from −6.5 to −8.0 kJ/mol with the targeted receptor compared to the binding affinities of the standard drug phenytoin and the original ligand of the target (P99), which were −7.6 and −6.8 kJ/mol, respectively. In vivo study results showed that the compound 5‐Carbamoyl‐2‐formyl‐1‐[2‐(4‐nitrophenyl)‐2‐oxo‐ethyl]‐pyridinium gave 60% protection against epileptic seizures compared to 59% protection afforded by regular phenytoin. All of them met Lipinski's rule of five and had drug‐likeness and drug score values of 0.55 and 0.8, respectively, making them chemically and functionally like phenytoin. According to the findings of the studies, the synthesized derivatives have the potential to be employed as a stepping stone in the development of novel anti‐epileptic drugs.

Publisher

Wiley

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