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Synthesis, in vivo and in silico evaluation of novel 2,3‐dihydroquinazolin‐4(1H)‐one derivatives as potential anticonvulsant agents
Author(s) -
Kothayer Hend,
Ibrahim Samy M.,
Soltan Moustafa K.,
Rezq Samar,
Mahmoud Shireen S.
Publication year - 2019
Publication title -
drug development research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.582
H-Index - 60
eISSN - 1098-2299
pISSN - 0272-4391
DOI - 10.1002/ddr.21506
Subject(s) - anticonvulsant , chemistry , in vivo , pentylenetetrazol , lipinski's rule of five , lipophilicity , pharmacology , benzamide , in silico , picrotoxin , docking (animal) , stereochemistry , combinatorial chemistry , epilepsy , biochemistry , antagonist , medicine , psychiatry , gene , biology , receptor , microbiology and biotechnology , nursing
In light of the pharmacophoric structural requirements for achieving anticonvulsant activity, a series of N‐(1‐methyl‐4‐oxo‐2‐un/substituted‐1,2‐dihydroquinazolin‐3[4H]‐yl)benzamide (4a‐g) and N‐(1‐methyl‐4‐oxo‐2‐un/substituted‐1,2‐dihydroquinazolin‐3[4H]‐yl)‐2‐phenylacetamide (4h‐n) derivatives were synthesized in two steps starting from the reaction of N‐methyl isatoic anhydride with the appropriate hydrazide and followed by condensation with the appropriate aldehyde. The anticonvulsant activities of the synthesized compounds were evaluated according to the anticonvulsant drug development (ADD) programme protocol. Among the synthesized compounds, 4n showed promising activity in both the maximal electroshock (MES) and pentylenetetrazole (PTZ) tests with median effective dose (ED 50 ) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b , 4a , 4c , 4f , 4j , and 4i , showed very low ED 50 values in the PTZ test (3.1, 4.96, 8.68, 9.89, 12, and 13.53 mg/kg, respectively). All the tested compounds showed no to low neurotoxicity in the rotarod test with a wide therapeutic index. Docking studies of compound 4n suggested that GABA A binding could be the mechanism of action of these derivatives. The in silico drug likeliness parameters indicated that none of the designed compounds violate Lipinski's rule of five and that they are able to cross the blood–brain barrier.Hit, Lead & Candidate Discovery