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New Biological Targets for the Treatment of Leishmaniasis
Published in Venkatesan Jayaprakash, Daniele Castagnolo, Yusuf Özkay, Medicinal Chemistry of Neglected and Tropical Diseases, 2019
Fabrizio Carta, Andrea Angeli, Christian D.-T. Nielsen, Claudiu T. Supuran, Agostino Cilibrizzi
Various reports have recently hypothesized relevance for the trace element selenium to be effective in leishmaniasis treatment. The increased concentration of this chalcogen in plasma has been indeed recognized as a new defensive strategy against Leishmania infection (Araujo et al. 2008, Culha et al. 2008). In this regard, the sulphonamide moieties and a di-selenide linker were jointly incorporated into derivatives 12a–d (Figure 11) by Baquedano and collaborators (Baquedano et al. 2014). These agents exhibited potent antiparasitic activity in vitro against L. infantum, with a selectivity index (i.e., quantity of compound that is active against the pathogen but is not toxic towards the host cell) higher than that of miltefosine and edelfosine (i.e., reference drugs used as controls in the tests).
Miltefosine
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Andrew Stewardson, Douglas Johnson
Imbert et al. (2014) evaluated the combination of miltefosine and voriconazole for in vitro synergy against 33 filamentous fungi, including Aspergillus spp., Scedosporium apiospermum, and Fusarium solani. Using a complete inhibition endpoint, all interactions but one were indifferent (Imbert et al., 2014). There is in vitro synergy between miltefosine and sterol biosynthesis inhibitors, such as voriconazole and ketoconazole, against T. cruzi (Lira et al., 2001; Santa-Rita et al., 2005). Combination therapy with edelfosine (another alkylphospholipid) and ketoconazole disrupts the plasma membrane, reservosomes, and mitochondria of T. cruzi epimastigotes to a greater degree than either drug alone (Santa-Rita et al., 2005).
The preclinical discovery and development of oral miltefosine for the treatment of visceral leishmaniasis: a case history
Published in Expert Opinion on Drug Discovery, 2020
Juliana Q. Reimão, Débora P. Pita Pedro, Adriano C. Coelho
In the 1960s, the glycerol-linked ester bond at position C1 of LPC was replaced by an ether linkage and another ether-linked methyl group was added at the C2 position. The resulting ALP, edelfosine (Figure 1(b)), showed a potent immune modulator effect and potent antitumor activity (reviewed by [16]). However, its clinical application has been limited due mainly to its metabolic instability and low selectivity for tumor cells, high hemolytic potential, and gastrointestinal toxicity (reviewed by [17]). Although the clinical use of edelfosine has been limited, these findings prompted a series of chemical and biological experiments aiming to improve the next generation compounds. New analogs were developed, such as ilmofosine (Figure 1(c)); however, this compound did not improve the metabolic stability or reduce the toxicity to the gastrointestinal tract, with no clinical activity in patients [17].