Activity and mode of action of acridine compounds against Leishmania donovani

Abstract

In the present work, we have assayed both the in vitro and in vivo action of two acridine compounds against Leishmania donovani. As part of this effort, we have studied the possible action mechanism of these compounds at the ultrastructural and biochemical levels and in relation to the synthesis of macromolecules. The two acridinones inhibit the in vitro growth of the promastigote forms of L. donovani at the highest concentration assayed (100 micrograms/ml). The in vivo results indicate that both compounds reduce the number of amastigotes per gram of spleen, and decrease parasitism, by more than 40%. With respect to the action mechanism, both compounds inhibit the incorporation of [3H]thymidine, inducing alterations at the ultrastructural level in the DNA and mitochondria. Alterations are also caused in the enzymes of the Krebs cycle.

Identification of Potent Chemotypes Targeting Leishmania major Using a High-Throughput, Low-Stringency, Computationally Enhanced, Small Molecule Screen

“…None of the leishmanicidal compounds were structurally similar to the clinically used anti-leishmanial compounds sodium stibogluconate and amphotericin B (Tanimoto score ≤0.3), supporting our objective of expanding the pool of potential leishmanicidal chemotypes (Table S1). Importantly, however, compounds with previously documented in vivo or in vitro leishmanicidal activity were also identified using the HILCES system, including pentamidine isothionate, clotrimazole, aminacrine, aphidicolin, and acivicin, thus further validating our assay system (Table 1 and Table S1) [1],[42],[58],[63],[64].…”

Metal compounds for the treatment of parasitic diseases

“…Metal compounds have been shown to have anti-parasitic properties in models of parasitic disease [23][24][25][26][27][28][29][30][31], and the antimonial drugs are still first line treatment for leishmaniasis [2]. However the molecular mechanism of these metal compounds is undefined.…”

“…Though there is evidence to suggest that these complexes target organelles such as the nucleus and kinetoplast [27][28][29][30][31], the molecular target of these compounds has not been defined. Previously we have investigated the anti-tumor activity of gold(III) (compounds 1-3 in Fig.…”

“…Several metal complexes have been reported to have anti-parasitic activity such as gold(I) phosphine and chloroquine complexes [23][24][25], platinum(II) and (IV) complexes [26][27][28][29] and organometallic complexes of iridium, rhodium, palladium and osmium [29][30][31] against a variety of trypanosomatids. Though there is evidence to suggest that these complexes target organelles such as the nucleus and kinetoplast [27][28][29][30][31], the molecular target of these compounds has not been defined.…”

Aspects of the Cytological Activity of Edelfosine, Miltefosine, and Ilmofosine in Leishmania Donovani

“…The usual symptoms of the disease are fluctuating fever, weight loss, and a general feeling of illness, together with hepatosplenomegaly. If untreated, the disease is fatal in 91% of the cases (Mesa-Valle et al, 1996).…”