Design and development of novel N‐(4‐aminobenzoyl)‐l‐glutamic acid conjugated 1,3,5‐triazine derivatives as Pf‐DHFR inhibitor: An in‐silico and in‐vitro study

Abstract

In the present work, a library of 120 compounds was prepared using various aliphatic and aromatic amines. Finally, 10 compounds were selected through in silico screening carrying 4‐aminobenzoyl‐l‐glutamic acid and 1,3,5‐triazine moiety. The docking results of compounds 4d16 and 4d38 revealed higher binding interaction with amino acids Asp54 (−537.96 kcal/mol) and Asp54, Phe116 (−618.22 kcal/mol) against wild (1J3I) and quadruple mutant (1J3K) type of Pf‐DHFR inhibitors and were comparable to standard WR99210. These compounds were developed by facile and microwave‐assisted synthesis via nucleophilic substitution reaction and characterized by different spectroscopic methods. In vitro antimalarial assay results also suggested that these two compounds were having higher antimalarial activity against chloroquine‐sensitive (3D7) and chloroquine‐resistant (Dd2) strain out of the ten synthesized compounds with IC50 13.25 μM and 14.72 μM, respectively. These hybrid scaffolds might be useful in the lead discovery of a new class of Pf‐DHFR inhibitors.

Synthesis of Novel Triazine-Based Chalcones and 8,9-dihydro-7H-pyrimido[4,5-b][1,4]diazepines as Potential Leads in the Search of Anticancer, Antibacterial and Antifungal Agents

“…3.1.2. General Procedure for the Synthesis of Disubstituted Triazines (8)(9)(10)(11) The synthesis of derivatives 8 [74], 9 [71] and 11 [73] was reported in previous studies. Disubstituted triazine 10 was obtained as follows: 4-hydroxy-3-methoxybenzaldehyde (13 mmol)was added slowly to a solution of monosubstituted triazine 6 (13 mmol) in acetone (35 mL) at room temperature.…”

“…Initially, using a three-step synthetic sequence, the trisubstituted triazine precursors 12-15 were synthesized by aromatic nucleophilic substitution reactions (Ar N S) from 2,4,6trichloro-1,3,5-triazine 4 [50,[68][69][70][71][72][73][74][75] (Table 1). Looking for structural diversity, substituents of aliphatic and aromatic nature and functional groups capable of forming hydrogen bonding were incorporated.…”

Recent biological applications of heterocyclic hybrids containing s-triazine scaffold

“…Likewise, a new series of 120 compounds of N -(4-aminobenzoyl)- l -glutamic acid pendant s -triazine (80) was successfully synthesized via microwave-assisted synthesis techniques in good yield. 97 Before in vitro analysis, these compounds were evaluated through in silico modeling and only 10 compounds out of 120 were selected for further screening. Through SAR analysis, it was observed that this series possessed two main hits, one with piperidine and one with piperazine moiety.…”