SYNTHESIS, COMPUTER AIDED SCREENING AND PHARMACOLOGICAL EVALUATION OF 2/3-SUBSTITUTED-6(4-METHYLPHENYL)-4,5-DIHYDROPYRIDAZIN3(2H)-ONES, AND PYRIDAZINE SUBSTITUTED TRIAZINE

Asif Husain; Sukhbir Lal Khokra; Sonakshi Seth; Shama S Garg; Pawan Kaushik; Aftab Ahmad; Shah Alam Khan

doi:10.14499/indonesianjpharm26iss4pp200

SYNTHESIS, COMPUTER AIDED SCREENING AND PHARMACOLOGICAL EVALUATION OF 2/3-SUBSTITUTED-6(4-METHYLPHENYL)-4,5-DIHYDROPYRIDAZIN3(2H)-ONES, AND PYRIDAZINE SUBSTITUTED TRIAZINE

Asif Husain, Sukhbir Lal Khokra, Sonakshi Seth, Shama S Garg, Pawan Kaushik, Aftab Ahmad, Shah Alam Khan

Abstract

The present research work involved synthesis of some novel pyridazine derivatives and evaluation of their analgesic and anti-inflammatory activities in experimental animals to obtain safer non-steroidal anti-inflammatory drugs (NSAIDs). Friedal craft acylation reaction of succinic anhydride with toluene in the presence of anhydrous aluminum chloride gave 4-(4-methylphenyl)-4-oxo-butanoic acid (1). The aryl propionic acid 1 on reaction with phenyl hydrazine and hydrazine hydrate yielded the pyridazinone derivative 2 and 3, respectively. Reaction of the compound 3 with phosphorus oxychloride (POCl₃) produced the corresponding chloropyridazine derivative 4. A 4-hydroxymethyl derivative of dihydropyridazinone (5) was synthesized by condensing 3 with methanol and formaldehyde (HCHO). The compound 5 on further treatment with guanidine hydrochloride in ethanol gave the pyridazino-triazine (6). The synthesized compounds were investigated for their analgesic activity in mice and anti-inflammatory activity in Wistar albino rats. The molecular, pharmacokinetic and toxicity properties of the synthesized compounds were calculated by Molinspiration and Osiris property explorer software. The results of in-vivo anti-inflammatory studies revealed that the compound. 4 showed maximum inhibition in paw edema volume followed by compound no. 3 while the compound no. 4 exhibited excellent peripheral analgesic activity (74%) followed by the compound no. 5. Compound no. 4 and 5 also showed good central analgesic effect increased the reaction time to 90 minutes. All the title compounds except compound 5 are predicted to be safe by Osiris online software and are likely to have good oral bioavailability as they obey Lipinski’s rule of five for drug likeness.

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DOI: http://dx.doi.org/10.14499/indonesianjpharm26iss4pp200