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

Abstract

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.

Drug repurposing to face Covid-19: Celastrol, a potential leading drug capable of inhibiting SARS-CoV-2 replication and induced inflammation

“…To surpass celastrol toxicity, solubility, and pharmacokinetic issues, several pharmaceutical approaches have been proposed, such as nanoencapsulation, liposomes, and sugar-silica nanoparticles [111][112][113] . Celastrol has been considered a lead drug for several human illnesses, but its toxicity to humans remains to be determined 64,73,114 .…”

In Vitro Antiparasitic Activities of Monovalent Ionophore Compounds for Human and Canine Leishmaniases

“…To estimate the 50% inhibitory concentration (IC 50 ) of compounds on both cells and Leishmania promastigotes, the MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) assay was used with minor modifications [ 19 , 20 ]. Briefly, monensin and nigericin were dissolved in ethanol (10 mg/mL), and salinomycin and amphotericin B in DMSO (10 mg/mL).…”

Structural Characterization of Human Heat Shock Protein 90 N-Terminal Domain and Its Variants K112R and K112A in Complex with a Potent 1,2,3-Triazole-Based Inhibitor

“…Abolishing chaperone activity leads to protein degradation and subsequent cell death. Since various oncoproteins and proteins linked to tumor progression and invasiveness are included among human Hsp90 clients, this chaperone is a validated drug target for the development of anticancer therapies [ 7 , 8 , 9 , 10 ]. On the other hand, Hsp90 plays a key role in the survival and proliferation of a wide variety of human protozoan parasites, making it a promising target for the treatment of various neglected diseases [ 9 , 11 , 12 , 13 ].…”

“…Since various oncoproteins and proteins linked to tumor progression and invasiveness are included among human Hsp90 clients, this chaperone is a validated drug target for the development of anticancer therapies [ 7 , 8 , 9 , 10 ]. On the other hand, Hsp90 plays a key role in the survival and proliferation of a wide variety of human protozoan parasites, making it a promising target for the treatment of various neglected diseases [ 9 , 11 , 12 , 13 ]. Indeed, the environmental differences encountered by the parasites moving from the insect vector to the mammalian host (including variations in temperature, pH, and ionic strength) stimulate the production of this protein [ 14 ].…”