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A series of new 4-arylpiperazine derivatives of isothiazolopyridine of Mannich base type and their non-4-arylpiperazine analogues (3 and 4) were synthesized and assayed as potential analgesic agents. Pharmacological assay demonstrated that all the compounds prepared, without exception, displayed significant activity in the mouse writhing assay. The analgesic action, expressed as ED50, was found to be 2-10 times more potent than that of acetylsalicylic acid and 1.5-10 times weaker than that of morphine, these being used as standards. The toxicities (LD50) of the investigated derivatives varied and ranged from 250 to 2000 mg/kg. Additionally, the computational investigations were performed in order to find correlation between molecular structure and biological effects (toxicity, analgesic action) of discussed compounds. Useful model was found for toxicity assessment.

Thirty 1-aryl-5-dimethylamino-1-penten-3-one hydrohalides and related compounds were prepared as candidate anticonvulsants and evaluated in maximal electroshock seizure (MES), subcutaneous pentylenetetrazole threshold, and neurotoxicity screens. Following administration by the intraperitoneal route, many of the compounds were active in the MES screen, whereas only 10% of the Mannich bases afforded protection in the subcutaneous pentylenetetrazole test. Quantitation of half of the compounds prepared revealed that many had activity comparable with that of clinically useful drugs in the MES screen. The anticonvulsant properties of eight of the compounds following oral administration were reduced considerably or abolished compared with those following intraperitoneal administration. Various synthetic strategies for future development of potential anticonvulsants are outlined.

Analogs of some antineoplastic and cytotoxic Mannich bases derived from conjugated styryl ketones were prepared and evaluated for activity in the P-388 lymphocytic leukemia screen. Most of the new compounds had lower antineoplastic and murine toxicity than the parent compounds. Antimicrobial evaluation of some oximes and alcohols related to the Mannich bases revealed activity against certain Gram-positive bacteria and fungi. Primary pharmacological evaluation showed that some compounds containing a dimethylaminomethyl group displayed analgesic and antihistaminic properties. Five of the Mannich bases were evaluated as respiratory inhibitors in mitochondria derived from hepatic tumors, liver tissue from tumor-bearing animals, and normal rat liver. No statistical difference between the sensitivity of the three tissues to the compounds was obtained.