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.
Optimization of a modified Grimmel's method for N-heterocyclization of a leucinelinked sulfonamide side-arm at position 2 leading to 2,3-disustituted-4-quinazolin-(3H)-ones was accomplished. Further, 22 hybrid quinazolinone motifs (4a-v) were synthesized by N-heterocyclization reaction under microwave irradiation using the ionic liquid [Bmim] [BF 4 ]-H 2 O as green solvent as well as the catalyst. The in vitro screening of the hybrid entities against the malarial species Plasmodium falciparum yielded five potent molecules 4l, 4n, 4o, 4t, and 4u owning antimalarial activity comparable to those of the reference drugs. In continuation, an in silico study was carried out to obtain a pharmacophoric model and quantitative structure-activity relationship. We also built a 3D-QSAR model to procure more information that could be applied to design new molecules with more potent Pf-DHFR inhibitory activity.The designed pharmacophore was recognized to be more potent for the selected molecules, exhibiting five pharmacophoric features. The active scaffolds were further evaluated for enzyme inhibition efficacy against alleged receptor Pf-DHFR computationally and in vitro, proving their candidature as lead dihydrofolate reductase inhibitors, and the selectivity of the test candidates was ascertained by toxicity study against Vero cells. Good oral bioavailability was also proved by studying pharmacokinetic properties.
A series of diarylpyrazole clubbed dihydropyrimidine derivatives (J1-J30) was synthesized under microwave-assisted heating conditions by employing Biginelli reaction methodology and utilizing triethylammonium acetate both as a catalyst and as reaction medium, leading towards a greener reaction pathway. The synthesized entities were screened for their antimalarial efficacy against a Plasmodium falciparum strain in vitro. The active entities (J9, J15, J21, J25, and J27) obtained out of the in vitro screening were further evaluated for their enzyme inhibitory potency against the Pf-DHFR enzyme in vitro as well as in silico using Glide. Furthermore, the active scaffolds were tested for their cytotoxicity against Vero cells, proving their nontoxic behavior and selectivity. The ADME parameters were also evaluated and predicted in silico, indicating good oral bioavailability of the compounds.
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