Some new derivatives of 1,2,4-triazolo[2,3-a]benzimidazoles were synthesized through the reaction of 1,2-diaminobenzimidazole with carbon disulfide. The resulting 1,2,4-triazolo[2,3-a]benzimidazole-2-thione intermediate was reacted with one equivalent of acyl halides to give the corresponding 2-acylthio derivatives 3a and 3b. The latters were alkylated or acylated to afford the 1-alkyl (acyl)-2-acylthio-1,2,4-triazolo[2,3-a]-benzimidazole derivatives 4a-j and 5a-j in good yields. The structures of the new compounds were verified on the basis of their spectral and elemental analyses. Twelve of the target compounds were tested for their possible antifungal activities. Most of the test compounds showed results against Candida albicans and Fusarium oxysporum comparable to that of fluconazole as a reference drug. Compounds 4e, 5g, and 5h are the most active ones against most of the used fungi strains. Six of the final compounds 3a, 3b, 4g, 4j, 5g, and 5j were tested for their possible anti-inflammatory effect; most of these compounds showed potent and significant results in comparison with indomethacin as a reference drug. Moreover, the ulcerogenicity of the most active compound 5j was determined in mice and it showed superior GIT safety profile than indomethacin as a reference drug.

Objective: Pharmacokinetic interactions of co-administered herbal isolates with pharmaceuticals and the mechanisms of interactions are remaining to be elucidated. Herein, we evaluated the in vitro effect of Air Jamu Pak Tani (AJPT), a mixture of plant isolates, on the phase I aminopyrine metabolism, and the molecular mechanism involved in spontaneous hypertensive rat (SHR) livers.

Methods: Hepatocytes were isolated by collagenase perfusion technique. Aminopyrine n-demethylase activity was determined using the colorimetric method of Nash.

Results: Compared to control AJPT, dose independently, increased significantly the aminopyrine n-demethylase activity by 29.6% (P<0.05). Molecular mechanism elucidation, using protein stimulants (or inhibitors), showed that effect of AJPT was significantly abrogated by the pre-incubation of hepatocytes with 3-isobutyl-methylxanthine and okadaic acid. Trifluoperazine and genistein did not change the effect of AJPT, while no significant observation verified in the presence of guanylyl-5’-imidodiphosphate and furafylline. In conclusion, administration of AJPT induced dephosphorylation of cytochrome P450 in young male SHR hepatocytes. The effect of AJPT was mediated through different molecular mechanisms, most probably; across inhibition of tyrosine kinases, calmodulin and cAMP/PKA pathways and also due to activation of protein phosphatase. Therefore, caution should be considered when AJPT are used with n-demethylase substrates ‘drugs’ as it may reduce their bioavailability.