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

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.

Novel hybrid diarylpyrazole clubbed dihydropyrimidine motifs were synthesized under microwave irradiation using TEAA as reaction medium, and screened for their antimalarial efficacy, revealing five active scaffolds: J9, J15, J21, J25, and J27. Enzyme inhibitory studies against Pf‐DHFR proved their potency as dihydrofolate reductase inhibitors. The obtained ADME parameters predicted oral bioavailability of these active molecules.

Autoren:   Jaimin D. Bhatt, Chaitanya J. Chudasama, Kanuprasad D. Patel
Journal:   Archiv der Pharmazie
Jahrgang:   2017
Seiten:   n/a
DOI:   10.1002/ardp.201700088
Erscheinungsdatum:   10.08.2017
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