M. Shamsher Alam

Design, Synthesis and Evaluation of Anticonvulsant Activity of Pyridinyl-Pyrrolidones: A Pharmacophore Hybrid Approach

Various 1‐[6‐(4‐substituted phenyl)‐3‐cyano‐4‐(substituted phenyl)‐pyridin‐2‐yl]‐5‐oxopyrrolidine‐3‐carboxylic acids (3a–t) were designed and synthesized by clubbing pyrrolidinones and pyridines, the two active anticonvulsant pharmacophores. All the synthesized compounds fulfilled the requirements of suggested pharmacophoric model for anticonvulsant activity. Their in vivo anticonvulsant evaluation was performed by maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ) tests. The minimal motor impairment was assessed by rotorod test and the estimation of various liver enzymes was performed to check the magnitude of liver toxicity posed by the synthesized compounds. Compounds 3d and 3k displayed comparable anticonvulsant activity to the standard drugs with ED50 values of 13.4 and 18.6 mg/kg in electroshock screen, repectively. The compounds 3d and 3k were also found to have encouraging anticonvulsant activity (ED50 = 86.1 and 271.6 mg/kg, respectively) in scPTZ screen. Interestingly, they did not show any sign of motor impairment at the maximum dose administered and were not toxic to the liver.

Synthesis and anticonvulsant properties of 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea derivatives

Abstract Various 1-(amino-N-arylmethanethio)-3-(1-substituted benzyl-2, 3-dioxoindolin-5-yl) urea (5a–p) were designed keeping in view the structural requirements suggested in the pharmacophore model for anticonvulsant activity. Their in vivo anticonvulsant screenings were performed by two most adopted seizure models, maximal electroshock seizure (MES) and subcutaneous pentylenetetrazole (scPTZ). Compound 5f was found active in MES screening while compounds 5h, 5i, 5k and 5l showed significant anticonvulsant activity in both the screenings and were devoid of any neurotoxicity. Compound 5h and 5i showed marked protection at 300mg/kg against MES and scPTZ screening. Compound 5i also showed protection against MES screening at the dose of 100mg/kg. In 6Hz screening these two compounds showed significant protection and emerged as lead compounds for future investigations.

Anticonvulsant and Toxicity Evaluation of Newer 4H‐Benzo[1,4]oxazin‐3‐ones: The Effect of Two Hydrogen Bonding Domains

A series of (Z)‐2‐(substituted aryl)‐N‐(3‐oxo‐4‐(substituted carbamothioyl)‐3,4‐dihydro‐2H‐benzo[b][1,4]oxazin‐7‐yl) hydrazine carboxamides (6a–r) was synthesized using 2‐amino‐5‐nitrophenol as a starting material. All the synthesized compounds possessed two hydrogen‐bonding domains and their effect on the activity was studied thereof. The anticonvulsant activity was assessed by the maximal electroshock test (MES), subcutaneous pentylenetetrazole test (scPTZ) and intraperitoneal thiosemicarbazide test (ipTSC). Compounds (6b, 6h, 6i, and 6p) were found to be the most potent of the series as they showed 83–100% protection in the MES test. They also displayed considerable activity in the chemically induced seizure tests. Most of the tested compounds were devoid of the neurotoxic and hepatotoxic effects.

Synthesis of 8-substituted-4-(2/4-substituted phenyl)-2H-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2-thiones and their anticonvulsant, anti-nociceptive, and toxicity evaluation in mice.

A number of new 8-substituted-4-(2/4-substituted phenyl)-2H-[1,3,5]triazino[2,1-b][1,3]benzothiazole-2-thiones (4a–t) were synthesized and evaluated for their anticonvulsant, anti-nociceptive, hepatotoxic, and neurotoxic properties. The titled compounds (4a–t) were obtained by cyclization of N-{[6-substituted-1,3-benzothiazol-2-yl)amino]carbonothioyl}-2/4-substituted benzamides (3a–t) by refluxing in n-butanol. All the newly synthesized compounds were screened for their anticonvulsant activity in a mouse seizure model and were compared with the standard drug phenytoin. Compounds 4a, 4c, 4f, and 4l showed complete protection after time periods of 0.5 h and 4 h. Some of the selected compounds were evaluated for their neurotoxic and hepatotoxic effects, and none of these showed any sign of neurotoxicity or hepatotoxicity. Compounds 4a–t were also evaluated for their anti-nociceptive activity by a thermal stimulus technique using diclofenac as standard. Compounds 4o, 4q, and 4t displayed highly potent analgesic activity with p < 0.01.

Synthesis of new piperidyl indanone derivatives as anticonvulsant agents

A series of 5,6-dimethoxy-2-{1-[arylamino/alkylamino(thioxo)methyl]-4-piperidyl-methyl}-1-indanones (4a–l) were designed and synthesized by the reaction of 5,6-dimethoxy-2-(piperidin-4-yl-methyl)-indan-1-one with aryl/alkyl isothiocyanates. The anticonvulsant activity was evaluated in animal models by maximal electroshock seizure and subcutaneous pentylenetetrazole tests. The neurotoxic effects were assessed by rotorod and ethanol potentiation tests. Gamma amino butyric acid (GABA) estimation of the selected compounds was performed in rat brain utilizing UV absorbance data. Compounds 4d, 4g, and 4j displayed encouraging anticonvulsant profile against both seizure models with remarkably lower neurotoxicity. These compounds were found to increase the GABA level in rat brain significantly.

An Insight into the New Anticonvulsant Agents

The use of current antiepileptic drugs has been questioned due to the nonselectivity of the drugs and the undesirable side effects posed by them. This led to an intensive investigation in this area worldwide during the past 10 years. There have been some significant outcomes and the findings are promising as far as drug efficacy and safety is concerned. This review covers the new anticonvulsant agents that have shown encouraging activities and less neurotoxicity. A detailed pharmacology and pathophysiology of different types of epilepsy is described here with the structural classification of most active agents. The new structural classes of compounds may prove as lead molecules and good candidates for the future investigations.