Repositioning Salirasib as a new antimalarial agent

Porta, Exequiel O. J.; Verdaguer, Ignasi Bofill; Perez, Consuelo; Banchio, Claudia; Azevedo, Mauro Ferreira de; Katzin, Alejandro M.; Labadié, Guillermo R.

doi:10.1039/c9md00298g

Cited by 18 publications

(9 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, special concern should be devoted to the development of new antimicrobial agents, possessing completely different chemical structures, and working with different modes of actions. The Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) reaction offers a versatile synthetic access to the 1,2,3-triazole heterocycle derivatives, which are associated with a wide spectrum of pharmacological activities, including antimycobacterial [18][19][20][21], antitubercular [22][23][24][25], anticancer [26][27][28][29], antiviral [30][31][32][33][34], antidiabetic [35][36][37][38], antifungal [39][40][41][42], anti-HIV [43][44][45][46], anti-inflammatory [47][48][49][50], antimalarial [51][52][53][54], anti-oxidant [55][56][57][58], anti-proliferative [59][60][61][62] properties. The 1...…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antimicrobial Activities of 1,2,3-Triazole Glycoside Clickamers

et al. 2020

View full text Add to dashboard Cite

Bacterial resistance remains a significant threat and a leading cause of death worldwide, despite massive attempts to control infections. In an effort to develop biologically active antibacterial and antifungal agents, six novel aryl-substituted-1,2,3-triazoles linked to carbohydrate units were synthesized through the Cu(I)-catalyzed azide-alkyne cycloaddition CuAAC of substituted-arylazides with a selection of alkyne-functionalized sugars. The chemical structures of the new derivatives were verified using different spectroscopic techniques. The novel clicked 1,2,3-triazoles were evaluated for in vitro antibacterial activity against Gram-positive Staphylococcus aureus and Gram-negative Pseudomonas aeruginosa, and the obtained results were compared with the activity of the reference antibiotic “Ampicillin”. Likewise, in vitro antifungal activity of the new 1,2,3-triazoles was investigated against Candida albicans and Aspergillus niger using “Nystatin” as a reference drug. The results of the biological evaluation pointed out that Staphylococcus aureus was more susceptible to all of the tested compounds than other examined microbes. In addition, some tested compounds exhibited promising antifungal activity.

show abstract

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Antimicrobial Activities of 1,2,3-Triazole Glycoside Clickamers

et al. 2020

View full text Add to dashboard Cite

show abstract

“…In this case, an average yield of 83% (Compounds C1 to D5, Table 1) was obtained. Our group has previously reported that geranylazide exists in solution as a mixture of inseparable regioisomers [24,25], which after the cycloaddition stage allows to generate the E and Z isomers in a 3:2 ratio [26,27]. Although in some cases it is possible to separate the E and Z triazoles obtained from this azide mixture, in this case, due to the polarity of both diasteroisomers, all attempts to obtain pure isomers by chromatographic separation were unsuccessful.…”

Section: Synthesismentioning

confidence: 99%

Systematic study of triazolyl sterols for the development of new drugs against parasitic Neglected Tropical Diseases.

Porta¹,

Ballari²,

Wilkinson

et al. 2022

Preprint

View full text Add to dashboard Cite

A series of thirty 1,2,3-triazolylsterols, inspired by azasterols with proven antiparasitic activity, were prepared by a stereocontrolled synthesis. Ten of these compounds constitute chimeras/hybrids of AZA and 1,2,3-triazolyl azasterols. The entire library was assayed against the kinetoplastid parasites Leishmania donovani, Trypanosoma cruzi, and Trypanosoma brucei, the causatives agents for visceral leishmaniasis, Chagas disease, and sleeping sickness, respectively. Most of the compounds were active at submicromolar/nanomolar concentrations with high selectivity index, when compared to their cytotoxicity against mammalian cells. Analysis of in silico physicochemical properties were conducted to rationalize the activities against the neglected tropical disease pathogens. The analogs with selective activity against L. donovani (E4, IC50 0.78 uM), T brucei (E1, IC50 0.12 uM) and T. cruzi (B1- IC50 0.33 uM), and the analogs with broad-spectrum antiparasitic activities against the three kinetoplastid parasites (B1 and B3), may be promising leads for further development as selective or broad-spectrum antiparasitic drugs.

show abstract

“…We have previously reported the synthesis and antimalarial activity of salirasib analogues as a means of drug repurposing. [23] This compound collection consists of thiosalicylic acid (TSA) derivatives. The library has two variables based on the absence (compounds 1 -13, Fig.…”

Section: Introductionmentioning

confidence: 99%

Lipophilic modification of Salirasib modulate the antiproliferative and antimigratory activity.

Ballari¹,

Porta²,

Zalazar

et al. 2023

Preprint

View full text Add to dashboard Cite

Salirasib, or farnesylthiosalicylic acid (FTS), is a salicylic acid derivative with demonstrated antineoplastic activity. While designed as a competitor of the substrate S-farnesyl cysteine on Ras, it is a potent competitive inhibitor of isoprenylcysteine carboxymethyl transferase. Although different salirasib derivatives have been reported, the isoprenyl tail has not been modified. In this study, we used a series of synthetic salirasib analogues with lipophilic thioether modifications, including those with or without a 1,2,3-triazole linker, and tested their antiproliferative activity against six different solid tumor cell lines. We carried out a combination of bioassay, cheminformatics, and in silico ADME-Tox to identify new potent analogues. SAR analysis revealed structural and physicochemical features that enhance antiproliferative activity. Analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, we identified three compounds with superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behaviour of the collection on migration and invasion, the key processes in tumor metastasis, were also studied. Three analogs with specific antimigratory activity were identified with differential structural features. The combination of the antiproliferative and antimigratory results prompts to propose that the modification on the thiol aliphatic/prenyl substituents can modulate the activity. Our findings provide valuable insight on the lipophilic salirasib analogues with enhanced antiproliferative activity against solid tumor cell lines. Also, we have been able to identify analogues with specific antimigratory activity that could be the starting points on the development of new antimetastatic agents.

show abstract

Repositioning Salirasib as a new antimalarial agent

Abstract: Repurposing strategies present an enormous advantage for drug discovery, especially in malaria, where resources are scarce.

Cited by 18 publications

References 33 publications

Design, Synthesis, and Antimicrobial Activities of 1,2,3-Triazole Glycoside Clickamers

Design, Synthesis, and Antimicrobial Activities of 1,2,3-Triazole Glycoside Clickamers

Systematic study of triazolyl sterols for the development of new drugs against parasitic Neglected Tropical Diseases.

Lipophilic modification of Salirasib modulate the antiproliferative and antimigratory activity.

Contact Info

Product

Resources

About