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<p>A small set of heterocyclic-tethered aryl carbohydrazones and semicarbazones was prepared and screened for their in vivo anticonvulsant properties. The chemical structure of synthesized compounds was confirmed by vibrational and nuclear magnetic resonance spectral data. Among the compounds tested in the maximal electroshock (MES) model, compound <b>13d</b> displayed moderate activity (25% protection at 0.5 h and 4 h) and compound <b>15c</b> exhibited good anticonvulsant activity (50% protection at 0.5 h and 25% at 4 h) at 100 and 300 mg/kg respectively. Both the MES active compounds <b>13d</b> and <b>15c</b> were non-neurotoxic at their minimal anticonvulsant dose (100 mg/kg) up to 4 h. However, a dose-dependent neurotoxicity was observed with both the lead compounds and the effect was significantly high with the hydrazone lead <b>13d</b>. These results suggest that the incorporation of the heteroaryl moiety to the distal aryl ring (site C) of the hydrazone or semicarbazone template, in general, decreased the anticonvulsant activity. However, further studies on diverse heteroaryl incorporated (at site C) semicarbazone and hydrazone analogs are warranted to optimize the four-featured pharmacophore model proposed previously. Docking results disclosed that the MES active compounds occupied the drug binding site of human neuronal voltage-gated sodium channel isoform hNa<sub>v</sub>1.2 and offered optimal binding interactions. Computational drug-likeness and ADMET studies predicted that the lead compounds exhibit good pharmacokinetic profile and minimal off-target toxicity.</p>

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Synthesis and Anticonvulsant Evaluation of Some Heterocyclic Tethered Aryl Carbohydrazone and Semicarbazone Analogs

  • 期刊论文

  • 发表日期：

    2025年5月1日

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  • Samarth Dwivedi,
  • Harish J,
  • Omprakash Goshain,
  • Sandeep Kumar,
  • Senthil Raja Ayyannan

摘要

A small set of heterocyclic-tethered aryl carbohydrazones and semicarbazones was prepared and screened for their in vivo anticonvulsant properties. The chemical structure of synthesized compounds was confirmed by vibrational and nuclear magnetic resonance spectral data. Among the compounds tested in the maximal electroshock (MES) model, compound 13d displayed moderate activity (25% protection at 0.5 h and 4 h) and compound 15c exhibited good anticonvulsant activity (50% protection at 0.5 h and 25% at 4 h) at 100 and 300 mg/kg respectively. Both the MES active compounds 13d and 15c were non-neurotoxic at their minimal anticonvulsant dose (100 mg/kg) up to 4 h. However, a dose-dependent neurotoxicity was observed with both the lead compounds and the effect was significantly high with the hydrazone lead 13d. These results suggest that the incorporation of the heteroaryl moiety to the distal aryl ring (site C) of the hydrazone or semicarbazone template, in general, decreased the anticonvulsant activity. However, further studies on diverse heteroaryl incorporated (at site C) semicarbazone and hydrazone analogs are warranted to optimize the four-featured pharmacophore model proposed previously. Docking results disclosed that the MES active compounds occupied the drug binding site of human neuronal voltage-gated sodium channel isoform hNav1.2 and offered optimal binding interactions. Computational drug-likeness and ADMET studies predicted that the lead compounds exhibit good pharmacokinetic profile and minimal off-target toxicity.