Discovery of Novel Isonipecotic Acid-Based Heteroaryl Amino Acid Derivatives as Potential Anticonvulsant Agents: Design, Synthesis, In-Silico ADME Study, and Molecular Docking Studies

Mohammad M Ahmad; Naseem Akhtar; Shamshir Khan; Mohd Rashid; Md Tanwir Athar; Zabih Ullah; Mohamad Taleuzzaman

doi:10.4103/jpbs.jpbs_478_23

Discovery of Novel Isonipecotic Acid-Based Heteroaryl Amino Acid Derivatives as Potential Anticonvulsant Agents: Design, Synthesis, In-Silico ADME Study, and Molecular Docking Studies

J Pharm Bioallied Sci. 2023 Oct-Dec;15(4):205-211. doi: 10.4103/jpbs.jpbs_478_23. Epub 2023 Dec 11.

Authors

Mohammad M Ahmad¹, Naseem Akhtar¹, Shamshir Khan², Mohd Rashid², Md Tanwir Athar², Zabih Ullah³, Mohamad Taleuzzaman⁴

Affiliations

¹ Department of Pharmaceutics, College of Dentistry and Pharmacy, Buraydah Private Colleges, Buraydah, Al-Qassim, Saudi Arabia.
² Department of Pharmacognosy and Pharmaceutical Chemistry, College of Dentistry and Pharmacy, Buraydah Private Colleges, Buraydah, Al-Qassim, Saudi Arabia.
³ Department of Clinical Pharmacy, College of Dentistry and Pharmacy, Buraydah Private Colleges, Buraydah, Al-Qassim, Saudi Arabia.
⁴ Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Maulana Azad University, Jodhpur, Rajasthan, India.

Abstract

Background: Epilepsy is a neurological disorder characterized by anomalous brain activity, convulsions, and odd behavior. Several substituted-(naphthalen-2-yl)-3-(1H-indol-3-yl) allyl)-1,4-dihydropyridine-4-carboxylic acid derivatives (5a-j) were intended to be produced in the current research effort to reduce convulsions and seizures.

Materials and methods: The newly developed compounds were produced by the prescribed process. Numerous methods (infrared spectroscopy (IR), nuclear magnetic resonance (NMR), mass, elemental analysis, etc.) were used to characterize these substances. Several models were used to test each of these molecules for anticonvulsant activity. By using the rotarod and ethanol potentiation techniques, neurotoxicity was also evaluated. The study meticulously examined each parameter and showed absorption, distribution, metabolism, and excretion (ADME) predictions for each of the 10 congeners that were produced. In addition, studies on molecular docking employed the gamma amino butyric acid (GABA)-A target protein.

Results: Anticonvulsant screening results identified compounds 5f, 5h, 5d, and 5b as the most efficacious of the series. All synthesized equivalents largely passed the neurotoxicity test. The results of molecular docking revealed significant interactions at the active site of GABA-A with LEU B: 99, TYR A: 62, Ala A: 174, and THR B: 202, and the outcomes were good and in agreement with in vivo findings.

Conclusions: The study's findings showed that some substances had promising anticonvulsant properties that were comparable to those of the standard drug. The highly active novel anticonvulsant analogs may therefore represent a possible lead, and additional studies may result in a potential new drug candidate.

Keywords: Anticonvulsant activity; GABA-A indole; in-silico; molecular docking; pyridine.