Bioinformatics in Leishmania Drug Design

Gupta, Shishir; Dandekar, Thomas

doi:10.1007/978-3-319-74186-4_13

Cited by 1 publication

(1 citation statement)

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“…Prospects for developing an effective leishmaniasis vaccine are not immediate and disease control is based primarily on chemotherapeutic treatment, although the arsenal of available drugs is reduced and with significant associated toxicity; vector control is problematic generating environmental risk; comorbidity with HIV is increasing; and finally, almost all endemic regions exhibit a growing incidence of therapeutic failure [ 11 , 12 , 13 , 14 ]. Consequently, the design of more effective and safer therapeutic alternatives has become an extraordinary and urgent need [ 15 , 16 , 17 ]. Meanwhile, there is a delay in the development of new drugs, mainly due to the lack of economic stimuli that this disease represents for the pharmaceutical companies.…”

Section: Introductionmentioning

confidence: 99%

Leishmanicidal Activity of Betulin Derivatives in Leishmania amazonensis; Effect on Plasma and Mitochondrial Membrane Potential, and Macrophage Nitric Oxide and Superoxide Production

et al. 2021

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Herein, we evaluated in vitro the anti-leishmanial activity of betulin derivatives in Venezuelan isolates of Leishmania amazonensis, isolated from patients with therapeutic failure. Methods: We analyzed promastigote in vitro susceptibility as well as the cytotoxicity and selectivity of the evaluated compounds. Additionally, the activity of selected compounds was determined in intracellular amastigotes. Finally, to gain hints on their potential mechanism of action, the effect of the most promising compounds on plasma and mitochondrial membrane potential, and nitric oxide and superoxide production by infected macrophages was determined. Results: From the tested 28 compounds, those numbered 18 and 22 were chosen for additional studies. Both 18 and 22 were active (GI50 ≤ 2 µM, cytotoxic CC50 > 45 µM, SI > 20) for the reference strain LTB0016 and for patient isolates. The results suggest that 18 significantly depolarized the plasma membrane potential (p < 0.05) and the mitochondrial membrane potential (p < 0.05) when compared to untreated cells. Although neither 18 nor 22 induced nitric oxide production in infected macrophages, 18 induced superoxide production in infected macrophages. Conclusion: Our results suggest that due to their efficacy and selectivity against intracellular parasites and the potential mechanisms underlying their leishmanicidal effect, the compounds 18 and 22 could be used as tools for designing new chemotherapies against leishmaniasis.

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