Green synthesis, biological evaluation, molecular docking studies and 3D-QSAR analysis of novel phenylalanine linked quinazoline-4(3H)-one-sulphonamide hybrid entities distorting the malarial reductase activity in folate pathway

Article abstract of DOI:10.1016/j.bmc.2019.06.038

A modified Grimmel's method for N-heterocyclization of phenylalanine linked sulphonamide side arm at position-2 was optimized leading to 2,3-disustituted-4-quinazolin-(3H)-ones. Further, [Bmim][BF₄]-H2O (IL) was used as green solvent as well as catalyst for the synthesis of twenty two hybrid quinazolinone motifs (4a-4v) by N-heterocyclization reaction using microwave irradiation technique. The in vitro screening of the hybrid entities against the malarial species Plasmodium falciparum yielded five potent molecules 4l, 4n, 4r, 4t & 4u owing comparable antimalarial activity to 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 as well as the selectivity of the test candidates was ascertained by toxicity study against vero cells. The perception of good oral bioavailability was also proved by study of pharmacokinetic properties.

Full text of DOI:10.1016/j.bmc.2019.06.038

Accepted Manuscript
Green synthesis, biological evaluation, molecular docking studies and 3D-
QSAR analysis of novel phenylalanine linked quinazoline-4(3H)-one-sulpho-
namide hybrid entities distorting the malarial reductase activity in folate
pathway
Tarosh S. Patel, Jaimin D. Bhatt, Ritu B. Dixit, Chaitanya J. Chudasama,
Bhavesh D. Patel, Bharat C. Dixit
PII:
S0968-0896(19)30579-6
https://doi.org/10.1016/j.bmc.2019.06.038
BMC 14975
DOI:
Reference:
Bioorganic & Medicinal Chemistry
To appear in:
Received Date:
Revised Date:
Accepted Date:
10 April 2019
19 June 2019
22 June 2019
Please cite this article as: Patel, T.S., Bhatt, J.D., Dixit, R.B., Chudasama, C.J., Patel, B.D., Dixit, B.C., Green
synthesis, biological evaluation, molecular docking studies and 3D-QSAR analysis of novel phenylalanine linked
quinazoline-4(3H)-one-sulphonamide hybrid entities distorting the malarial reductase activity in folate pathway,
Bioorganic & Medicinal Chemistry (2019), doi: https://doi.org/10.1016/j.bmc.2019.06.038
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Highlights
 Synthesis of quinazolin-4(3H)-one as predominantly E-stereoisomer from amino
acid
 Phenylalanine linked quinazolinones were synthesized using [Bmim][BF4]-H2O as
media
 In vitro Antimalarial screening of quinazolinones and their DHFR inhibitory potency
 3D-QSAR and In silico study of targets quinazolinone entities for lead optimization
 Molecular docking of potent 4(3H)-quinazolinones at the binding site of DHFR
enzyme