Microwave Assisted Synthesis of Pyrimidines in Ionic Liquid and Their Potency as Non‐Classical Malarial Antifolates

Abstract

Synthesis of pyrazole-linked triazolo-pyrimidine hybrids was achieved by employing Biginelli-type reaction methodology in an ionic liquid (triethylammonium acetate) under microwave irradiation. This method proved to be highly efficient and the ionic liquid employed was found recyclable for up to five consecutive cycles. The synthesized molecules were further screened for their antimalarial efficacy screening out the active scaffolds J15, J18, J21, J24, J27, and J30. The active molecules were evaluated in an enzyme inhibition study against the active Plasmodium falciparum dihydrofolate reductase (Pf-DHFR), computationally as well as in vitro, demonstrating their potency as DHFR inhibitors. The active entities were also investigated for their oral bioavailability by predicting ADME properties in silico, indicating good bioavailability.

The Beneficial Sinergy of MW Irradiation and Ionic Liquids in Catalysis of Organic Reactions

“…The versatility of the MW assisted and IL-catalyzed Biginelli reaction prompted the extension of the method to the synthesis of other pharmaceutically relevant heterocyclic compounds. Thus, potentially non-classical malarial antifolates made of pyrazole-linked triazolo-pyrimidine hybrids were prepared by Biginelli-type reaction, using the inexpensive triethylammonium acetate as IL catalyst and MW heating [162]. A library of 30 compounds was prepared, simply changing substituents in the heteroaromatic aldehyde and in the β-dicarbonyl compound (Scheme 69).…”

Novel heterocyclic hybrids of pyrazole targeting dihydrofolate reductase: design, biological evaluation and in silico studies

“…Furthermore, several reports exhibited that pyrazoles I-IV and pyrazolo [3,4- (Figure 1) had high bactericidal and fungicidal activity against the reference strains [20][21][22][23][24] . Additionally, the pyrazole-containing cores (VI-VII) were found to be active as antimicrobial and antimalarial through inhibition of DHFR [25][26][27] (Figure 2). Regarding to their broad spectrum of biological activities, pyrazole ring has been considered as a favourable unit for addition in the field of drug discovery and therefore in the pharmaceutical industry 10 .…”

Diarylpyrazole Ligated Dihydropyrimidine Hybrids as Potent Non‐Classical Antifolates and Their Efficacy Against Plasmodium falciparum

“…The increase in the resistance against the present drug molecules has alarmed the emergence of urgency and continuous need for the discovery of new therapeutics. To answer the resistance developed in the parasitic strain as well as to combat the diseased condition, a major initiative claimed is to target the crucial enzymes involved in the biochemical pathways of the parasite and besiege them .…”

“…It was revealed from the literature study that the hybrid molecules containing pyrazole core ligated with pyrimidine nucleus rendered potent and varied biological activities . The carbamoyl side chain has shown enhancement in the pharmacological output of pyrimidine as parent motif and further it was noted that replacement of benzene by pyridine ring augmented fungicidal, antibacterial, and anticancer activities .…”

“…In continuation of our previous work and considering the pharmacological importance of 1,3‐diarylpyrazole, DHPMs, and pyridines, we have attempted the synthesis of desired hybrid molecules equipped with three pharmacophoric nucleus in single molecular framework. With an aim to eliminate the use of toxic organic solvents, expensive catalysts, and harsh reaction conditions, we have modified, optimized, and developed Biginelli reaction condition utilizing TEAA as catalyst and reaction medium as well yielding the hybrid entities in green, clean, and inexpensive manner.…”