Brazilian flora extracts as source of novel antileishmanial and antifungal compounds

Natural products have long been providing important drug leads for infectious diseases. Leishmaniasis is a protozoan parasitic disease found mainly in developing countries, and it has toxic therapies with few alternatives. Fungal infections have been the main cause of death in immunocompromised patients and new drugs are urgently needed. In this work, a total of 16 plant species belonging to 11 families, selected on an ethnopharmacological basis, were analyzed in vitro against Leishmania (L.) chagasi, Leishmania (L.) amazonensis, Candida krusei, and C. parapsilosis. Of these plant species, seven showed antifungal activity against C. krusei, five showed antileishmanial activity against L. chagasi and four against L. amazonensis, among them species of genus Plectranthus. Our findings confirm the traditional therapeutic use of these plants in the treatment of infectious and inflammatory disorders and also offer insights into the isolation of active and novel drug prototypes, especially those used against neglected diseases as Leishmaniasis.Instituto Adolfo Lutz Serviço de Parasitologia Laboratório de Toxinologia AplicadaUniversidade Federal de São Paulo (UNIFESP) Departamento de Ciências Exatas e da TerraInstituto Plantarum de Estudos da FloraUNIFESP, Depto. de Ciências Exatas e da TerraSciEL

Approximating Hessian matrices using Bayesian inference: a new approach for quasi-Newton methods in stochastic optimization

Using quasi-Newton methods in stochastic optimization is not a trivial task given the difficulty of extracting curvature information from the noisy gradients. Moreover, pre-conditioning noisy gradient observations tend to amplify the noise. We propose a Bayesian approach to obtain a Hessian matrix approximation for stochastic optimization that minimizes the secant equations residue while retaining the extreme eigenvalues between a specified range. Thus, the proposed approach assists stochastic gradient descent to converge to local minima without augmenting gradient noise. We propose maximizing the log posterior using the Newton-CG method. Numerical results on a stochastic quadratic function and an ℓ2-regularized logistic regression problem are presented. In all the cases tested, our approach improves the convergence of stochastic gradient descent, compensating for the overhead of solving the log posterior maximization. In particular, pre-conditioning the stochastic gradient with the inverse of our Hessian approximation becomes more advantageous the larger the condition number of the problem is

Amphibian secretions for drug discovery studies: A search for new antiparasitic and antifungal compounds

The antiparasitic and antifungal activities of nine amphibian skin secretions were studied in different in vitro models. Seven secretions presented a considerable antiprotozoan activity and one showed promising results against Candida sp. These results can be the basis for the development of new drugs, especially for neglected parasitic diseases. © 2007 Bentham Science Publishers Ltd

Synthesis and Antileishmanial Activities of Novel 3-Substituted Quinolines

The antileishmanial efficacy of four novel quinoline derivatives was determined in vitro against Leishmania chagasi, using extracellular and intracellular parasite models. When tested against L. chagasi-infected macrophages, compound 3b demonstrated 8.3-fold greater activity than did the standard pentavalent antimony. No significant activity was found for compounds 3a, 4a, and 4b. The antilesihmanial effect of compound 3b was independent of host cell activation, as demonstrated by nitric oxide production. Ultrastructural studies of promastigotes treated with compound 3b showed mainly enlarged mitochondria, with matrix swelling and reduction in the number of cristae. Synthetic analogues based on the quinoline ring structure, already an established template for antiparasitic drugs, could provide further useful compounds

Antimonials employed in the treatment of leishmaniaisis: the state of the art

Antimony preparations are the drugs of choice for the treatment of leishmaniasis over 90 years, a disease that currently affects 12 million people worldwide. Its introduction was based on 19th century concepts of therapeutic effects of metal salts as arsenicals and other metals, most of them abandoned due to toxic effects or better drugs. In the last three decades, there was a great improvement in the knowledge of cell biology and immunology of those infections, but chemotherapy has not been improved in the same strength. The structure and mechanism of action of the two pentavalent antimonial drugs of choice, meglumine antimoniate and sodium stibogluconate, are not well known and the contamination of those pharmaceutical by toxic contaminants have been verified.550555Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq