Design, synthesis, and evaluation of dihydropyrimidinone (DHPM) based muscarinic receptor antagonist

Abstract

Organophosphorus compounds (OPCs) are highly toxic being used in pest control. Some of the OPCs are lethal chemical warfare agents and their toxicity is due to inhibition of acetylcholine esterase (AChE), the enzyme that hydrolyses neurotransmitter acetylcholine (ACh). Due to over accumulation of ACh at muscarinic acetylcholine receptors (mAChRs) several cholinergic functions increase uncontrollably like salivation, lacrimation, urination, defecation, gastrointestinal upset, and emesis. Atropine is used to treat OPC poisoning because it is a mAChR antagonist. But atropine has several unwanted side effects including dryness of mucous membrane, hot and dry skin, tachycardia, and restlessness. Our goal was to find out molecules having antimuscarinic activity which may be developed as potential alternatives for atropine in future. In this work pharmacophore-based screening, structure identification, synthesis and ex vivo evaluation of a new class of muscarinic receptor antagonist are described. The antagonists are based on dihydropyrimidinone scaffold with a tertiary or quaternary amine side group. A series of molecules were evaluated for preliminary pharmacological activity on rat ileum out of which three molecules found active.

The Evaluation of DHPMs as Biotoxic Agents on Pathogen Bacterial Membranes

“…Reported data show other possible targets for these molecules, such as centrin [12], calcium channels [13] and topoisomerase I [14]. Pharmacological properties are reported to include anticancer [15] anti-inflammatory [16], antihypertensive [17], antibacterial [18], antifungal [19], antiviral [20], antiparasitic [21], antithyroid [22], antimuscarinic [23], antidiabetic [24] and hypolipidemic [25] activities. DHPMs play an antagonistic/inhibitory role against acetylcholinesterase [26], urease [27], calcium channel modulation [28,29] and GABA agonism [30].…”

Hantzsch Reaction: A Greener and Sustainable Approach to 1,4‐Dihydropyridines Using Non‐commercial β‐Ketoesters

“…As a part of our foregoing work and much endeavor over the years to develop an efficient synthetic procedures for multi‐component reactions under greener conditions , there was a requirement to construct a huge library of diversified 1,4‐dihydropyridine analogs with dropping time, outstanding yields, and exceptional biological activities. Initially, we examine the different common ammonium salts (nitrogen source) for the synthesis of 1,4‐dihydropyridine derivatives using non‐commercial β‐ketoesters that are generated by the reaction between tert ‐butylacetoacetate and corresponding alcohol via trans ‐esterification .…”

Amodiaquine as COVID-19 Mpro Inhibitor: A Theoretical Study

“…These crystal structures can be used in structure based design of new inhibitors for COVID-19 viral M pro . Earlier we have demonstrated a pharmacophore based method to design dihydropyrimidione (DHPM) based molecules showing mAChR antagonist activity [6]. The molecules were designed based on three template molecules screened from NCI2000 database by pharmacophore modeling.…”