Quinolines as Chemotherapeutic Agents for Leishmaniasis

Abstract

The development of leishmanicidal quinolines and their in vitro (promastigote and amastigote) and, where applicable, in vivo activities are reviewed. This survey provides a direct comparison of bioactivity across different species(e.g. L. donovani, L. amazonensis, L. chagasi, L infantum), and in different animal models (e.g. L. donovani Balb/c mice and L. donovani infected hamsters). The progress of selected quinolines through pre-clinical development and phase I/II trials, and the lead quinoline drugs sitamaquinine and Imiquimod, are discussed in conjunction with delivery systems and combination therapies.

Expression profiling of Sudanese visceral leishmaniasis patients pre‐ and post‐treatment with sodium stibogluconate

“…The observation that the quinoline alkaloid camptothecin was a potential upstream regulator was also of interest, especially given the progress of the orally active 8‐aminoquinoline sitamaquine (formerly WR‐6026) through preclinical and phase I/II clinical trials against VL in India, Brazil and Kenya (reviewed Ref. ), as well as a similar resurgence of interest in testing known and novel quinoline derivatives . Of interest also in relation to response to drug therapy was the observation of enrichment for a gene set associated with response to arsenic, supporting recent research suggesting that arsenic contamination in drinking water in areas endemic for VL may have led to increased resistance to antimonial compounds like SSB …”

Structure-activity relationships and mechanistic studies of novel mitochondria-targeted, leishmanicidal derivatives of the 4-aminostyrylquinoline scaffold

“…Quinolines offer a high potential to develop effective and affordable oral treatments for leishmaniasis. 9 Among them, some 2-substituted derivatives have shown a high in vitro activity, low toxicity and a higher metabolic stability than their non-substituted counterparts. 10 The presence of a conjugated double bond on the side chain seems beneficial for activity, and in this context a class of styrylquinolines has shown activity at micromolar concentrations against L. major amastigotes infecting human monocyte-derived macrophages.…”

Biochemical analysis of leishmanial and human GDP-Mannose Pyrophosphorylases and selection of inhibitors as new leads

“…A high throughput screening performed on L. major GDP-MP allowed the identification of a quinoline derivative, presenting an IC 50 value on the enzyme at the submicromolar range and on intramacrophage parasites at about 20 µM 8 . Various quinoline derivatives have been identified exhibiting antileishmanial activity 9 . Our laboratory has previously revealed the 2-substituted quinoline series as antileishmanial lead 10, 11 .…”