Screening strategies to identify new chemical diversity for drug development to treat kinetoplastid infections

Abstract

The Drugs for Neglected Diseases initiative (DNDi) has defined and implemented an early discovery strategy over the last few years, in fitting with its virtual R&D business model. This strategy relies on a medium- to high-throughput phenotypic assay platform to expedite the screening of compound libraries accessed through its collaborations with partners from the pharmaceutical industry. We review the pragmatic approaches used to select compound libraries for screening against kinetoplastids, taking into account screening capacity. The advantages, limitations and current achievements in identifying new quality series for further development into preclinical candidates are critically discussed, together with attractive new approaches currently under investigation.

Leishmaniasis visceral en América Latina y perspectivas terapéuticas

“…Los compuestos químicos sometidos al análisis generalmente se conocen su acción farmacológica. Aunque son metodologías costosas por la infraestructura y equipamiento requerido, son una de las grandes perspectivas para el desarrollo de nuevos medicamentos (47). En el caso de Leishmaniasis se han realizado ensayos moléculas evaluando su acción contra promastigotes in vitro y amastigotes intracelulares, generando expectativas frente al desarrollo de metabolitos con acción antikinetoplasto (48).…”

PREPARAÇÃO DE Α-Acetiloxi-N-Cicloexilamidas ATRAVÉS DA REAÇÃO DE PASSERINI UTILIZANDO DIMETILCARBONATO COMO SOLVENTE AMBIENTALMENTE AMIGÁVEL

“…Tal atividade poderia ser melhorada com modificações moleculares na estrutura do composto, a fim de levar ao aumento do potencial leishmanicida. Segundo Don e Ioset, 32 compostos que apresentam resultados de IC 50 inferiores a 10 µmol L -1 (cutoff definido pelo DNDi) são bons candidatos para estudos em leshimaniose visceral. Por outro lado, os próprios autores chamam atenção para o fato de que este critério não é aplicado rigorosamente.…”

“…33 3,83-3,78 (m, 1H), 2,19 (s, 3H), 1,93-1,88 (m, 2H), 1,78-1,58 (m, 3H), 1,47-1,11 (m, 5H) 90 (m, 2H), 6,01 (s, 1H), 5,95 (d, J = 8.0 Hz, 1H), 3,80 (s, 3H), 3,77-3,84 (m, 1H), 2,16 (s, 3H), 1,88-1,95 (m, 2H), 1,60-1,72 (m, 3H), 1,12-1,42 (m, 5H) 5, 160,0, 132,2, 129,0, 114,1, 75,1, 55,3, 48,2, 33,0, 32,9, 25,4 6,168,8,73,9,33,9,33,0,32,9,25,4,24,7,20,9,17,9,13,7 (7,59), N (4,59); encontrado: C (67,11), H (7,49), N (4,38). …”

Overcoming the Challenges of Drug Discovery for Neglected Tropical Diseases: The A·WOL Experience

“…23 There is potential for this axenic assay to act as a prescreen prior to using the more technically challenging intramacrophage assays. 25 Nevertheless, the Leishmania donovani intracellular screen has been validated, and screening of 200,000 compounds has been completed, although it is, as yet, unpublished. 15,24 This number is greater than the total number of compounds that has historically been tested against visceral leishmaniasis, a disease that is fatal if left untreated, demonstrating the progress that can be made with adequate investment and collaboration.…”