Structural Exploration of Quinazolin‐4(3H)‐ones as Anticonvulsants: Rational Design, Synthesis, Pharmacological Evaluation, and Molecular Docking Studies

Abstract

Anticonvulsants effective against multiple seizures are of wide interest as antiepileptic drugs, especially if active against pharmaco-resistant seizures. Herein, we synthesized 16 different, rationally designed 2-((6,7-dimethoxy-4-oxo-2-phenylquinazolin-3(4H)-yl)amino)-N-(substituted phenyl)acetamides and screened for anticonvulsant activities through in vivo experiments. Compound 4d emerged as prototype with excellent anti-seizure action in mice against electroshock, chemically induced and pharmaco-resistant 6-Hz seizure models with no symptoms of neurotoxicity and hepatotoxicity (ED = 23.5 mg/kg, MES, mice, i.p.; ED = 32.6 mg/kg, scPTZ, mice, i.p.; ED = 45.2 mg/kg, 6-Hz, mice, i.p.; TD = 325.9 mg/kg, mice, i.p.). In addition, investigation of compound 4l in mice for its pharmacological profile proved it as safer anticonvulsant, devoid of the side effects such as motor dysfunction and hepatotoxicity of classical antiepileptic drugs (ED = 26.1 mg/kg, MES, mice, i.p.; ED = 79.4 mg/kg, scPTZ, mice, i.p.; TD = 361.2 mg/kg, mice, i.p.). We also predicted physiochemical and pharmacokinetic properties of structurally optimized quinazolin-4(3H)-ones by a computational protocol. A combination of in vivo anticonvulsant profile, ex vivo toxicity, and in silico studies suggested that the synthesized compounds may be useful as broad-spectrum anti-seizure drug candidates with favorable pharmacokinetic parameters.

Exploring Quinazolinones as Anticonvulsants by Molecular Fragmentation Approach: Structural Optimization, Synthesis and Pharmacological Evaluation Studies

“…In our previous findings, we reported 6,7‐dimethoxy‐quinazolin‐4(3 H )‐ones with substitution of phenyl ring at second position to enhance lipophilicity so as to produce potent anticonvulsants . Few of these reported analogues have shown symptoms of hepatotoxicity and neurotoxicity.…”

Synthesis, in vivo and in silico evaluation of novel 2,3‐dihydroquinazolin‐4(1H)‐one derivatives as potential anticonvulsant agents

“…The design of new AEDs is challenging because the exact etiology of epilepsy is still unknown. Moreover, many of the existing AEDs have multiple and complex mechanisms (Sahu, Siddiqui, Iqbal, Sharma, & Wakode, ; Ugale & Bari, ).…”

“…The quinazoline moiety has attracted great interest in the field of anticonvulsant drug development (ADD). As the discovery of methaqualone (an anticonvulsant drug bearing a quinazolin‐4(3H)‐one scaffold) and the presence of the common anticonvulsant activity structural features (such as an amide group and a phenyl ring) in quinazoline derivatives many studies targeted the potential of quinazoline derivatives as anticonvulsants (compounds I‐II; El‐Azab & ElTahir, ; Malik, Bahare, & Khan, ; Prashanth, Madaiah, Revanasiddappa, & Veeresh, ; Ugale & Bari, , ; Figure b).…”

“…An effective antiepileptic agent must cross the blood–brain barrier (BBB); thus, a balance between hydrophilicity and lipophilicity (Log P ) is important in the design of novel AEDs (Palaty & Abbott, ; Rybka, Obniska, Żmudzki, et al, ; Ugale & Bari, ). Thus, the log P values for most of the synthesized compounds were between 2.60 and 4.42, which are consistent with those of most AEDs.…”

Synthesis, Anticonvulsant Activity, and SAR Study of Novel 4‐Quinazolinone Derivatives

“…A literature survey concerning quinazolin‐4(3 H )‐one nucleus‐based anticonvulsants implied that alteration in its substituents has led to the generation of many CNS active agents . Several natural and synthetic quinazolin‐4(3 H )‐one compounds with a substituent at 1‐position that is not likely present in the prototype methaqualone retain neuroprotective propriety and hence anticonvulsant activity ( II and III ) .…”