Novel 2,3-disubstituted quinazoline-4(3H)-one molecules derived from amino acid linked sulphonamide as a potent malarial antifolates for DHFR inhibition

Patel, Tarosh S.; Vanparia, Satish F.; Patel, Urmila H.; Dixit, Ritu B.; Chudasama, Chaitanya J.; Patel, Bhavesh D.; Dixit, Bharat C.

doi:10.1016/j.ejmech.2017.02.012

Cited by 52 publications

(21 citation statements)

References 40 publications

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“…Moreover, the reagents and catalysts utilized for the procurement of single isomer E (Scheme ) as an end product were hazardous, as well as the reaction protocol was tedious. Thus, to rectify the drawback of stereoisomerism and develop efficient synthetic pathway for synthesis of 2,3‐disubstituted‐4(3 H )‐quinazolinone‐sulfonamide in a single isomeric form we decided to employ green reaction protocol including ILs for the crucial ring closure step leading to 3‐aminoquinazolinone 3 from ester 2 and further imine synthesis 4 (Scheme ). The synthesis of our targeted molecules was undertaken using ILs as solvent as well as a catalyst to perform ring closure and imine formation step in situ under conventional as well as microwave heating conditions (Scheme ).…”

Section: Resultsmentioning

confidence: 99%

“…With impressive biological results of our previous work and with an interest in the synthesis of leucine linked sulfonamide clubbed quinazolinone with an active site at position‐3 with medicinal significance and potent lead molecule, we aimed towards utilization of greener and cleaner methodology for synthesis of benzylideneamino derivatives containing sulfonamide linked quinazolin‐4(3 H )‐one moiety using ionic liquid (IL) leading to predominantly single stereoisomer with E ‐configuration in situ. Further, to evaluate the pharmacological potency of the synthesized compounds, in vitro efficacy was investigated and further for comprehensive know‐how of the mechanism of action the 3D‐QSAR models were constructed by a series of quinazolinone based DHFR inhibitors revealing the relationship between the structure and biological activity of the inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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Design and synthesis of leucine‐linked quinazoline‐4(3H)‐one‐sulphonamide molecules distorting malarial reductase activity in the folate pathway

Patel

Bhatt

Dixit³

et al. 2019

Archiv der Pharmazie

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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.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Design and synthesis of leucine‐linked quinazoline‐4(3H)‐one‐sulphonamide molecules distorting malarial reductase activity in the folate pathway

Patel

Bhatt

Dixit³

et al. 2019

Archiv der Pharmazie

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“…Sulfonamides, being antibacterial, having the prominent mechanism of action including attachment of sulfonamides with the dihydropteroate synthetase (DHPS) enzyme and alteration of bacterial pathways of folic acid synthesis in few eukaryotic cells, but in human beings, this mechanism is not followed [3,4]. The sulfonamides have been recognized due to various reported biological activities such as anticancer [5][6][7][8][9], anti-Alzheimer [10,11], anti-tubercular [12,13], antimicrobial [14][15][16][17], anti-inflammatory [18], carbonic anhydrase inhibitors [19][20][21][22], antidiabetic [11], anticonvulsant [23], and antimalarial [24][25][26].…”

Section: Introductionmentioning

confidence: 99%

Biological Evaluation, Qsar and Molecular Modeling Studies of 2,4-Dichlorobenzoic Acid Derivatives as Antimicrobial Agents

Thakral

Singh

2019

Asian J Pharm Clin Res

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Objective: The aim of this study was to evaluate 2,4-dichlorobenzoic acid derivatives as antimicrobial agents through in vitro, QSAR and molecular docking studies. Methods: The compounds were subjected to in vitro antimicrobial screening by test tube dilution method and the structural characteristics governing the antimicrobial potential were studied using QSAR methodology. These compounds were also screened for docking simulation to find out binding confirmation of reported compounds with PDB 1aj0 and 5fsa using AutoDock tools and discovery studio. Results: The antimicrobial evaluation data indicated that compounds 13 and 18 were found to be the most effective against all the bacterial strains and Aspergillus niger while compounds 1 and 14 exhibited more antifungal potential against Candida albicans. QSAR studies confirmed the role of molar refractivity and Balaban index (J) as controlling parameters for antimicrobial potential. Molecular modeling study revealed that compounds interact with the active site of PDB by hydrophobic, hydrogen bonding, and Van der Wall interactions. Conclusion: These test compounds were identified as potent candidates for the control of microbial strains tested, and structural relationship with activity may provide valuable information for further design and synthesis of compounds with antimicrobial potential.

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“…Folate pathway-related inhibition and resistance mechanisms have been actively studied in bacteria (32)(33)(34)(35). The previously mentioned metabolic processes involving THF operate more slowly with monoglutamylated folyl coenzymes than with polyglutamylated cofactors because folate-dependent enzymes exhibit low affinity for the monoglutamylated cofactors (36).…”

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confidence: 99%

The uridylyltransferase GlnD and tRNA modification GTPase MnmE allosterically control Escherichia coli folylpoly-γ-glutamate synthase FolC

Rodionova

Goodacre

et al. 2018

Journal of Biological Chemistry

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Folate derivatives are important cofactors for enzymes in several metabolic processes. Folate-related inhibition and resistance mechanisms in bacteria are potential targets for antimicrobial therapies and therefore a significant focus of current research. Here, we report that the activity of poly-γ-glutamyl tetrahydrofolate/dihydrofolate synthase (FolC) is regulated by glutamate/glutamine-sensing uridylyltransferase (GlnD), THF-dependent tRNA modification enzyme (MnmE), and UDP-glucose dehydrogenase (Ugd) as shown by direct protein-protein interactions. Using kinetics analyses, we observed that GlnD, Ugd, and MnmE activate FolC many-fold by decreasing the of FolC for its substrate l-glutamate. Moreover, FolC inhibited the GTPase activity of MnmE at low GTP concentrations. The growth phenotypes associated with these proteins are discussed. These results, obtained using direct enzyme assays, reveal unanticipated networks of allosteric regulatory interactions in the folate pathway in and indicate regulation of polyglutamylated tetrahydrofolate biosynthesis by the availability of nitrogen sources, signaled by the glutamine-sensing GlnD protein.

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Novel 2,3-disubstituted quinazoline-4(3H)-one molecules derived from amino acid linked sulphonamide as a potent malarial antifolates for DHFR inhibition

Cited by 52 publications

References 40 publications

Design and synthesis of leucine‐linked quinazoline‐4(3H)‐one‐sulphonamide molecules distorting malarial reductase activity in the folate pathway

Design and synthesis of leucine‐linked quinazoline‐4(3H)‐one‐sulphonamide molecules distorting malarial reductase activity in the folate pathway

Biological Evaluation, Qsar and Molecular Modeling Studies of 2,4-Dichlorobenzoic Acid Derivatives as Antimicrobial Agents

The uridylyltransferase GlnD and tRNA modification GTPase MnmE allosterically control Escherichia coli folylpoly-γ-glutamate synthase FolC

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