Design and synthesis of leucine-linked quinazoline-4(3H)-one-sulphonamide molecules distorting malarial reductase activity in the folate pathway
Corresponding Author
Tarosh S. Patel
Chemistry Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Correspondence Tarosh S. Patel and Bharat C. Dixit, Chemistry Department, V. P. & R. P. T. P. Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar-388 120, Gujarat, India.
Email: [email protected] and [email protected]
Search for more papers by this authorJaimin D. Bhatt
Industrial Chemistry Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Search for more papers by this authorRitu B. Dixit
Pharmaceutical Chemistry Department, Ashok & Rita Patel Institute of Integrated Studies and Research in Biotechnology and Allied Sciences, New Vallabh Vidyanagar, Gujarat, India
Search for more papers by this authorChaitanya J. Chudasama
Department of Biochemistry, Shree Alpesh N. Patel P. G. Institute, Affiliated to Sardar Patel University, Anand, Gujarat, India
Search for more papers by this authorBhavesh D. Patel
Microbiology Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Search for more papers by this authorCorresponding Author
Bharat C. Dixit
Chemistry Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Correspondence Tarosh S. Patel and Bharat C. Dixit, Chemistry Department, V. P. & R. P. T. P. Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar-388 120, Gujarat, India.
Email: [email protected] and [email protected]
Search for more papers by this authorCorresponding Author
Tarosh S. Patel
Chemistry Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Correspondence Tarosh S. Patel and Bharat C. Dixit, Chemistry Department, V. P. & R. P. T. P. Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar-388 120, Gujarat, India.
Email: [email protected] and [email protected]
Search for more papers by this authorJaimin D. Bhatt
Industrial Chemistry Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Search for more papers by this authorRitu B. Dixit
Pharmaceutical Chemistry Department, Ashok & Rita Patel Institute of Integrated Studies and Research in Biotechnology and Allied Sciences, New Vallabh Vidyanagar, Gujarat, India
Search for more papers by this authorChaitanya J. Chudasama
Department of Biochemistry, Shree Alpesh N. Patel P. G. Institute, Affiliated to Sardar Patel University, Anand, Gujarat, India
Search for more papers by this authorBhavesh D. Patel
Microbiology Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Search for more papers by this authorCorresponding Author
Bharat C. Dixit
Chemistry Department, V. P. & R. P. T. P Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar, Gujarat, India
Correspondence Tarosh S. Patel and Bharat C. Dixit, Chemistry Department, V. P. & R. P. T. P. Science College, Affiliated to Sardar Patel University, Vallabh Vidyanagar-388 120, Gujarat, India.
Email: [email protected] and [email protected]
Search for more papers by this authorAbstract
Optimization of a modified Grimmel's method for N-heterocyclization of a leucine-linked 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][BF4]-H2O 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.
CONFLICT OF INTERESTS
The authors declare that there is no conflict of interests.
Supporting Information
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