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History of antifungals
Published in Mahmoud A. Ghannoum, John R. Perfect, Antifungal Therapy, 2019
Emily L. Larkin, Ali Abdul Lattif Ali, Kim Swindell
The advent of echinocandins (Figure 1.1), was heralded by the development and approval of caspofungin acetate (Cancidas; Merck & Co., Inc.) for the treatment of candidiasis in 2002 [66]. The echinocandins are a group of large, semisynthetic, cyclic lipopeptides discovered in the 1970s. Large molecular weight may explain their poor absorption through the digestive tract. Therefore, all three commercially available echinocandin compounds—caspofungin acetate, micafungin, and anidulafungin—are used only intravenously [74,75]. Echinocandins inhibit synthesis of 1,3-ß-D-glucan, an essential component of the fungal cell wall [76]. The synthesis of caspofungin acetate based on pneumocandin B0 requires chemical modification at two sites of the peptide core, reduction of a primary amide to an amine, and condensation of the hemiaminal moiety with ethylenediamine [76].
Caspofungin
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
Russell E. Lewis, Nicholas D. Beyda, Dimitrios P. Kontoyiannis
The development of compounds capable of inhibiting glucan synthesis of the fungal cell wall has been a milestone achievement in antifungal chemotherapy. Three classes of compounds—aculeracins, papulacandins, and echinocandins—were discovered as fermentation metabolites during screening programs for new antibiotics (Hector, 1993). To date, only semisynthetic derivatives of echinocandins have been developed for clinical use. Caspofungin (L-743872; MK-0991) was the first glucan synthesis inhibitor of the echinocandin class approved for use in humans. It is a synthetically modified fermentation product pneumocandin B0 of Glarea lozoyensis consisting of a cyclic hexapeptide with modified N-linked acyl lipid side-chain (Figure 146.1). The chemical structure of caspofungin is (1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine] pneumocandin B0 diacetate.
Echinocandins – structure, mechanism of action and use in antifungal therapy
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Mateusz Szymański, Sandra Chmielewska, Urszula Czyżewska, Marta Malinowska, Adam Tylicki
In 1974, in Switzerland the first antifungal drug of the echinocandin class – echinocandin B was discovered, which showed good antifungal properties but at the same time strong haemolytic effects. To counteract this, cilofungin, a semi-synthetic analogue of echinocandin B with a 4-octyloxybenzoate side chain, was synthesised. This compound significantly reduced haemolytic activity while retaining antifungal properties11. However, cilofungin was withdrawn from Phase II clinical trials due to the poor water solubility and toxicity of its co-solvent12. An important step in echinocandin research was the discovery of pneumocandin A0 and pneumocandin B0, of which pneumocandin B0 was used to synthesise a new antifungal agent13 (Table 2).