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Article

Design, Synthesis and In Vitro Investigation of Novel Basic Celastrol Carboxamides as Bio-Inspired Leishmanicidal Agents Endowed with Inhibitory Activity against Leishmania Hsp90

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Istituto di Scienze e Tecnologie Chimiche “Giulio Natta”—Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131 Milano, Italy
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Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milano, Italy
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Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via Mangiagalli 31, 20133 Milano, Italy
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Centro Interuniversitario di Ricerca sulla Malaria-Italian Malaria Network (CIRM-IMN), Università degli Studi di Milano, 20133 Milano, Italy
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Dipartimento di Scienze Biomediche, Chirurgiche e Odontoiatriche, Università degli Studi di Milano, Via Pascal 36, 20133 Milano, Italy
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Dipartimento di Scienze Farmacologiche e Biomolecolari, Università degli Studi di Milano Via Pascal, 36, 20133 Milano, Italy
*
Authors to whom correspondence should be addressed.
Biomolecules 2021, 11(1), 56; https://doi.org/10.3390/biom11010056
Received: 26 November 2020 / Revised: 28 December 2020 / Accepted: 31 December 2020 / Published: 5 January 2021
The natural triterpene celastrol (CE) is here used as lead compound for the design and synthesis of a panel of eleven CE carboxamides that were tested in vitro for their growth inhibitory activity against Leishmania infantum and L.tropica parasites. Among them, in vitro screening identified four basic CE carboxamides endowed with nanomolar leishmanicidal activity, against both the promastigotes and the intramacrophage Leishmania amastigotes forms. These compounds also showed low toxicity toward two human (HMEC-1 and THP-1) and one murine (BMDM) cell lines. Interestingly, the most selective CE analogue (compound 3) was also endowed with the ability to inhibit the ATPase activity of the Leishmania protein chaperone Hsp90 as demonstrated by the in vitro assay conducted on a purified, full-length recombinant protein. Preliminary investigations by comparing it with the naturally occurring Hsp90 active site inhibitor Geldanamycin (GA) in two different in vitro experiments were performed. These promising results set the basis for a future biochemical investigation of the mode of interaction of celastrol and CE-inspired compounds with Leishmania Hsp90. View Full-Text
Keywords: celastrol; natural compounds; Leishmania Hsp90; Hsp90 inhibition; leishmanicidal compounds; protozoa celastrol; natural compounds; Leishmania Hsp90; Hsp90 inhibition; leishmanicidal compounds; protozoa
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MDPI and ACS Style

Bassanini, I.; Parapini, S.; Ferrandi, E.E.; Gabriele, E.; Basilico, N.; Taramelli, D.; Sparatore, A. Design, Synthesis and In Vitro Investigation of Novel Basic Celastrol Carboxamides as Bio-Inspired Leishmanicidal Agents Endowed with Inhibitory Activity against Leishmania Hsp90. Biomolecules 2021, 11, 56. https://doi.org/10.3390/biom11010056

AMA Style

Bassanini I, Parapini S, Ferrandi EE, Gabriele E, Basilico N, Taramelli D, Sparatore A. Design, Synthesis and In Vitro Investigation of Novel Basic Celastrol Carboxamides as Bio-Inspired Leishmanicidal Agents Endowed with Inhibitory Activity against Leishmania Hsp90. Biomolecules. 2021; 11(1):56. https://doi.org/10.3390/biom11010056

Chicago/Turabian Style

Bassanini, Ivan, Silvia Parapini, Erica E. Ferrandi, Elena Gabriele, Nicoletta Basilico, Donatella Taramelli, and Anna Sparatore. 2021. "Design, Synthesis and In Vitro Investigation of Novel Basic Celastrol Carboxamides as Bio-Inspired Leishmanicidal Agents Endowed with Inhibitory Activity against Leishmania Hsp90" Biomolecules 11, no. 1: 56. https://doi.org/10.3390/biom11010056

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