Synthesis of Some Mono-Mannich Bases and Corresponding Azine Derivatives and Evaluation of their Anticonvulsant Activity

Abstract

Mono-Mannich bases, 3-amino-1-aryl-1-propanone hydrochlorides (Ig1-Ig4), and their corresponding azine derivatives, N,N'-bis(3- amino-1-aryl-propylidene) hydrazine dihydrochlorides (D1-D4), were synthesized and their anticonvulsant activities were evaluated. Alterations in biological activity depending on modifications in chemical structure were also followed. The aryl part was phenyl in Ig1, D1, Ig2, D2, Ig3, D3, or p-hydroxyphenyl in Ig4, and D4. The amine part was dimethylamine in Ig1, D1, Ig4, and D4, piperidine in Ig2, D2 or morpholine in Ig3, D3. Compounds D2, D3, and D4 are new. The anticonvulsant activity was determined by maximal electroshock (MES) and subcutaneous metrazole (pentetrazol; scMet) tests. The rotorod toxicity test was used for determining neurological deficits. While the compounds were not effective in scMet, they were found to exert protective effect in MES. The results of MES are as follows: Compound [dose level (mg/kg), time (h)]: Ig1 [30 (0.5 h), 100 (0.5 h)]; Ig2 [30 (0.5 h, 4 h)]; Ig3 [30 (0.5 h), 100 (0.5 h), 300 (0.5 h, 4 h)]; Ig4 [300 (0.5 h, 4 h), 100 (4 h)]; D1 [30 (0.5 h)]; D3 [100 (0.5 h,4 h), 300 (0.5 h), 30 (4 h)]]; D4 [300 (0.5 h, 4 h)]. D2 did not show any anticonvulsant activity in both tests. Ig1, Ig2, D1, D2, and D3 exhibited neurotoxicity. Compounds Ig2, D1, and D2 were neurotoxic at 100 mg/kg dose level at 0.5 h. Ig1 was neurotoxic at 300 mg at 0.5 h, D3 was neurotoxic at 300 mg at 4 h. Conversion of mono-Mannich bases to their corresponding azine derivatives generally decreased the anticonvulsant activity. Ig3, Ig4 and D4 seem to be promising candidates to develop new anticonvulsant compounds for grand mal epilepsy for further synthesis and in vivo studies, since they were effective in MES screening and no neurotoxicity was observed with them.

Synthesis, hematological, biochemical, and neurotoxicity screening of some Mannich base hydrochlorides

“…Indeed, it is known that the rotarod test is useful for evaluating pharmacological actions of psychotropic agents such as myorelaxant effect and anticonvulsant effect in the central or peripheral nervous system,[53] and that Mannich bases undergo deamination to give α, β-unsaturated ketones which are able to cross the blood-brain barrier to exert anticonvulsant activity. [18] Mannich bases are also known to possess centrally acting myorelaxant effect. [54]…”

“…Mannich bases are an important class of compounds in medicinal chemistry with a wide range of biological properties including antimicrobial,[3456] anticancer,[78910] anti-inflammatory,[11121314] analgesic,[15] and anticonvulsant[161718] activities. Some of these compounds are also known for their applications as anti-verus of human imminidéficience (VIH) and antituberculosis,[192021222324] antimalaria,[25262728] antifungal,[2930] antiflaviviridae,[31] and spermicidal[32] agents.…”

Evaluation of the Cytotoxicity of Some Mono-Mannich Bases and Their Corresponding Azine Derivatives against Androgen-independent Prostate Cancer Cells

“…A solution of hydrazine hydrate (1.75g, 0.035 mol) in ethanol (15 ml) was added to a solution of 3-amino-1-aryl-1-propanone hydrochloride (Ig1−Ig4) (0.07 mol) in ethanolic acetic acid (3 % w/v, 70 ml) and the mixture was stirred at room temperature for 24 h. After removal of the solvent, the residue was washed with chloroform three times (3 × 20 ml), dried and crystallized from ethanol to give corresponding azine derivatives [23].…”

Evaluation of net antioxidant activity of mono- and bis-Mannich base hydrochlorides and 3-keto-1,5-bisphosphonates from their ProAntidex parameter

“…Mannich bases are an important class of compounds in pharmaceutical chemistry with a wide range of biological properties including antimicrobial [1], anticancer [2], anti-inflammatory [3], analgesic [4], anticonvulsant [5] and anti-HIV [6] activities.…”