Febrifugine derivative antimalarial activity: quantum mechanical predictors / Descritores da atividade antimalarial de derivados de febrifugina obtidos via mecânica qüântica

Plasmodium falciparum resistant strain development has encouraged the search for new antimalarial drugs. Febrifugine is a natural substance with high activity against P. falciparum presenting strong emetic property and liver toxicity, which prevent it from being used as a clinical drug. The search for analogues that could have a better clinical performance is a current topic. We aim to investigate the theoretical electronic structure by means of febrifugine derivative family semi-empirical molecular orbital calculations, seeking the electronic indexes that could help the design of new efficient derivatives. The theoretical results show there is a clustering in well-defined ranges of several electronic indexes of the most selective molecules. The model proposed for achieving high selectivity was tested with success.

O desenvolvimento de linhagens resistentes de Plasmodium falciparum tem encorajado a busca por novas drogas antimalariais. A febrifugina é uma substância natural com alta atividade contra o P. falciparum que apresenta propriedade emética e toxicidade para o fígado tal que não permitem o seu uso clínico. A busca por análogos que possam ter uma performance clínica melhor é um tema de pesquisa atual. Nosso objetivo é investigar a estrutura eletrônica teórica de uma família de derivados da febrifugina empregando cálculos semi-empíricos de orbitais moleculares, procurando por índices eletrônicos que possam ajudar a modelar novos derivados mais eficientes. Os resultados teóricos mostram que para as moléculas mais seletivas existe um agrupamento dos valores de determinados índices em intervalos bem definidos. O modelo proposto para se obter alta seletividade foi testado com sucesso.

Design, Sythesis and Pharmacological Studies of Benzothiazolin-2-one Analogues as a Novel Anxiolytic and Antipanic - like Agents

A series of derivatives of ketanserin, a prototype 5-HT[2A] antagonist, were synthesized and evaluated for their binding profiles. Compound 6 was the most active of all tested compounds, as it displayed 5-HT[1A], 5-HT[2A],,and D[2], binding affinities at nanogram levels. It was found to exhibit anxiolytic and antipanic-like effects in mice, in doses of 0.25 mg and 0.125 mg/kg body weight, orally and intraperitoneally, respectively. These activities were obtained without significant sedative, myo-relaxant side effects, or catalepsy. Compound 6 is currently undergoing further pharmacological and toxicological investigations