Pyridazinone hybrids: Design, synthesis and evaluation as potential anticonvulsant agents

Partap, Sangh; Akhtar, Md. Jawaid; Yar, Mohammad Shahar; Hassan, Mohd. Zaheen; Siddiqui, Anees A.

doi:10.1016/j.bioorg.2018.01.001

Cited by 28 publications

(19 citation statements)

References 23 publications

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“…To be an effective anticonvulsant drug, the candidate compounds must be able to cross the BBB to exert their action. They should also possess good pharmacokinetic and oral bioavailability properties (Dehestani et al, ; Sangh Partap, Akhtar, Yar, Hassan, & Siddiqui, ). The drug‐like properties of the designed compounds were predicted using the web tool Molinspiration (http://www.molinspiration.com) based on Lipinski's “Rule of five” (Lipinski, ).…”

Section: Resultsmentioning

confidence: 99%

“…The ability of the synthesized compounds to exert better activity in the PTZ test suggests that they may act via a GABAergic activity enhancement mechanism (Bialer & White, 2010;Obniska et al, 2015;Partap et al, 2018).…”

Section: Structure-activity Relationship (Sar)mentioning

confidence: 99%

“…Despite the presence of many antiepileptic drugs (AEDs), approximately 30% of patients still suffer from uncontrolled episodes (Abd‐Allah et al, ; Abram et al, ; Siddiqui et al, ; Waszkielewicz et al, ). Moreover, AEDs have numerous undesirable side effects including neurotoxicity, which is very common and dose‐dependent (Edayadulla & Ramesh, ; Sangh Partap, Akhtar, Yar, Hassan, & Siddiqui, ; Rybka et al, ; St Louis, ). As AEDs are usually used as long‐term treatments, there is an ongoing need for more effective and safer AEDs that have fewer side effects (Edayadulla & Ramesh, ; Partap et al, ; Rybka, Obniska, Rapacz, Filipek, & Żmudzki, ).…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, AEDs have numerous undesirable side effects including neurotoxicity, which is very common and dose‐dependent (Edayadulla & Ramesh, ; Sangh Partap, Akhtar, Yar, Hassan, & Siddiqui, ; Rybka et al, ; St Louis, ). As AEDs are usually used as long‐term treatments, there is an ongoing need for more effective and safer AEDs that have fewer side effects (Edayadulla & Ramesh, ; Partap et al, ; Rybka, Obniska, Rapacz, Filipek, & Żmudzki, ). The design of new AEDs is challenging because the exact etiology of epilepsy is still unknown.…”

Section: Introductionmentioning

confidence: 99%

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

Kothayer

Ibrahim

Soltan

et al. 2018

Drug Development Research

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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 (ED50) values of 40.7 and 6 mg/kg, respectively. The six most promising derivatives, 4b, 4a, 4c, 4f, 4j, and 4i, showed very low ED50 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 GABAA 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

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Section: Resultsmentioning

confidence: 99%

Section: Structure-activity Relationship (Sar)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Kothayer

Ibrahim

Soltan

et al. 2018

Drug Development Research

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“…The GABA AT inhibition of the most potent compound is SPS-5F (IC50 9.10 μM) through anticonvulsant test. Compound SPS-5F significantly increases the whole brain GABA level, might be through the inhibition of GABA AT enzyme (Partap at al., 2018).…”

Section: Biological Activitiesmentioning

confidence: 99%

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

Int¹

2019

Preprint

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A series of heterocyclic compounds incorporating pyridazine moiety were for diverse biological activities. Pyridazines and pyridazinones derivatives showed wide spectrum of biological activities such as vasodialator, cardiotonic, anticonvulsant, antihypertensive, antimicrobial, anti-inflammatory, analgesic, anti-feedant, herbicidal, and various other biological, agrochemical and industrial chemical activities. The results illustrated that the synthesized pyridazine/pyridazine compounds have diverse and significant biological activities. Mechanistic insights into the biological properties of pyridazinone derivatives and various synthetic techniques used for their synthesis are also described.

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Amide as a Potential Pharmacophore for Drug Designing of Novel Anticonvulsant Compounds

Kamal¹,

Jawaid²,

Dar³

et al. 2021

Chemistry of Biologically Potent Natural Products and Synthetic Compounds

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Pyridazinone hybrids: Design, synthesis and evaluation as potential anticonvulsant agents

Cited by 28 publications

References 23 publications

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

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

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

Amide as a Potential Pharmacophore for Drug Designing of Novel Anticonvulsant Compounds

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