Pyrido[1,2-e]purine: Design and Synthesis of Appropriate Inhibitory Candidates against the Main Protease of COVID-19

Abstract

A series of tricyclic and polycyclic pyrido[1,2- e ]purine derivatives were designed and synthesized via a two-step, one-pot reaction of 2,4-dichloro-5-amino-6-methylpyrimidine with pyridine under reflux conditions. Various derivatives of pyrido[1,2- e ]purine were also synthesized by substituting the chlorine atom with secondary amines. After careful physiochemical and pharmacokinetic predictions, the inhibitory effects of the synthesized compounds against the main protease of SARS-CoV-2 have been evaluated by molecular docking and molecular dynamics approaches. The in silico results revealed that among all of the studied compounds, the morpholine/piperidine-substituted pyrido[1,2- e ]purine derivatives are the best candidates as effective inhibitors of SARS-CoV-2.

Synthesis of new derivatives of Alkylselanyl[1,2,4]triazolo[4,3‐a]pyrimidine asselenium‐containingheterocyclic system

“…As derivatives of [1,2,4]triazolo [4,3-a]pyrimidine incorporating selenium has not been synthesized and studied, it is anticipated that these compounds are good candidates for biological activities. Therefore, in continuation of our previous studies, selenopheno [2,3-e] [1,2,4] triazolo [1,5-c]pyrimidine derivatives [40], [1,3]selenazolo [5,4-e][1,2,4]triazolo [1,5-c]pyrimidine [41,42], and pyrido[1,2-e]purine [43], herein, we report the synthesis of organoselenides with metal-free procedure comprising of the alkylation of selenium anions.…”

Recent Developments towards the Synthesis of Pyrimidopyrimidine and Purine Derivatives

“…Very recently, Moghimi et al reported the synthesis of pyrido[1,2-e]purine derivatives (195) via a two-step, one-pot reaction of 2,4-dichloro-5-amino-6-methylpyrimidine (194) with 2-amino pyridine (168 a) under reflux conditions. [136] In this approach, 2,4-dichloro-5-amino-6-methylpyrimidine reacted with 2-amino pyridine; which acts as both a solvent and a substrate under the reflux conditions afforded 2-chloro-4methylpyrido[1,2-e]purine (195) in 44 % yield. Various derivatives of pyrido[1,2-e]purine (196) were then synthesized by substituting the chlorine atom with a variety secondary amines (Scheme 58).…”

“…Treatment of the amides with NaOH yielded the corresponding 1,3-dialkyl-7H-xanthine analogues 137) and evaluated in vitro for adenosine receptor binding affinity and in vivo for bronchospasmolytic effects. [121] The condensation reaction of 1,3-dimethyl-5,6diaminouracil (121) with para-substituted phenyl acetic acids (135) in the presence of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI) in MeOH, followed by the cyclization with NaOH provided the xanthine derivatives (136) which on nucleophilic substitution of Cl atom with various heterocyclic amines gave the desired xanthine derivatives 137 (Scheme 42).…”

The origin of experimental regioselectivity in ring-closing reaction of pyrido[1,2-e]purine systems and comparison of the aromaticity character of probable products: a mechanistic study based on DFT insights

“…30 Among the triazole derivatives, we became interested in 3-alkyl-pyrido [1,2-e] [1,2,4]triazolo [4,3-a]purines, due to their roles as potential candidates against the main protease of COVID-19. 31 Thus, a deep understanding of their structures can be useful to design novel inhibitors. Shiri and coworkers reported the synthesis of 3-alkyl-pyrido [1,2-e] [1,2,4]triazolo [4,3-a]purines (3-H, 3-Me and 3-Et) by 2-chloro-4-methylpyrido[1,2-e]purine (1) via a nucleophilic aromatic substitution (S N Ar) amination mechanism.…”

“…Shiri and coworkers reported the synthesis of 3-alkyl-pyrido [1,2-e] [1,2,4]triazolo [4,3-a]purines (3-H, 3-Me and 3-Et) by 2-chloro-4-methylpyrido[1,2-e]purine (1) via a nucleophilic aromatic substitution (S N Ar) amination mechanism. 31 The treatment of (1) with hydrazine hydrate led to 2-hydrazinyl-4-methylpyrido[1,2-e]purine (2), and after that, the reaction between (2) and three triethyl orthoesters (RC(OEt) 3 )s was promoted to give three derivatives of heterocyclic compounds (3) as two regioisomers of 3-H, 3-Me and 3-Et substituents (Scheme 1). They reported that the ring-closing in the presence of triethyl orthoesters goes through a regioselective cyclization reaction.…”