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1.
Bioorg Med Chem ; 92: 117417, 2023 09 07.
Article in English | MEDLINE | ID: mdl-37531922

ABSTRACT

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. In this study, the antiproliferative activity on six different solid tumor cell lines was evaluated with a series of lipophilic thioether modified salirasib analogues, including those with or without a 1,2,3-triazole linker. A combination of bioassay, cheminformatics, docking, and in silico ADME-Tox was also performed. SAR analysis that analogues with three or more isoprene units or a long aliphatic chain exhibited the most potent activity. Furthermore, three compounds display superior antiproliferative activity than salirasib and similar potency compared to control anticancer drugs across all tested solid tumor cell lines. In addition, the behavior of the collection on migration and invasion, a key process in tumor metastasis, was also studied. Three analogues with specific antimigratory activity were identified with differential structural features being interesting starting points on the development of new antimetastatic agents. The antiproliferative and antimigratory effects observed suggest that modifying the thiol aliphatic/prenyl substituents can modulate the activity.


Subject(s)
Antineoplastic Agents , Antineoplastic Agents/pharmacology , Salicylates/pharmacology , Farnesol/pharmacology , Cell Line, Tumor , Cell Proliferation
2.
Eur J Med Chem ; 254: 115378, 2023 Jun 05.
Article in English | MEDLINE | ID: mdl-37084599

ABSTRACT

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 22,26-azasterol (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 µM), T brucei (E1, IC50 0.12 µM) and T. cruzi (B1- IC50 0.33 µM), 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.


Subject(s)
Chagas Disease , Parasites , Trypanosoma cruzi , Trypanosomiasis, African , Animals , Sterols/pharmacology , Sterols/chemistry , Trypanosomiasis, African/drug therapy , Antiparasitic Agents/chemistry , Chagas Disease/drug therapy , Mammals
3.
Bioorg Med Chem ; 44: 116304, 2021 08 15.
Article in English | MEDLINE | ID: mdl-34289431

ABSTRACT

A series of C15-C20 isoprenyl derivatives bearing terminal alkenyl and alkynyl groups were synthesized as possible substrates of the methyl-branched lipid ω-hydroxylase CYP124A1 from Mycobacterium tuberculosis. The interactions of each compound with the enzyme active site were characterized using UV-vis spectroscopy. We found that C10 and C15 analogs bind with similar affinity to the corresponding parent C10 and C15 substrates geraniol and farnesol, respectively. Three analogs (C10-ω-ene, C10-ω-yne, C15-ω-yne) interact with the proximal side of the heme iron by coordinating to the oxygen atom of the ferric heme, as judged by the appearance of typical Type-IA binding spectra. On the other hand, the C15-ω-ene analog interacts with the ferric heme by displacing the bound water that generates a typical Type I binding spectrum. We were unable to detect P450-mediated oxidation of these probes following extended incubations with CYP124A1 in our reconstituted assay system, whereas a control reaction containing farnesol was converted to ω-hydroxy farnesol under the same conditions. To understand the lack of detectable oxidation, we explored the possibility that the analogs were acting as mechanism-based inhibitors, but we were unable to detect time-dependent loss of enzymatic activity. In order to gain insight into the lack of detectable turnover or time-dependent inhibition, we examined the interaction of each compound with the CYP124A1 active site using molecular docking simulations. The docking studies revealed a binding mode where the terminal unsaturated functional groups were sequestered within the methyl-binding pocket, rather than positioned close to the heme iron for oxidation. These results aid in the design of specific inhibitors of Mtb-CYP124A1, an interesting enzyme that is implicated in the oxidation of methyl-branched lipids, including cholesterol, within a deadly human pathogen.


Subject(s)
Cytochrome P-450 CYP4A/metabolism , Molecular Probes/metabolism , Mycobacterium tuberculosis/enzymology , Terpenes/metabolism , Cytochrome P-450 CYP4A/chemistry , Molecular Probes/chemistry , Molecular Structure , Terpenes/chemistry
4.
J Agric Food Chem ; 65(47): 10325-10331, 2017 Nov 29.
Article in English | MEDLINE | ID: mdl-29099589

ABSTRACT

A series of benzyl-substituted thiobenzoazoles were synthesized by an environmentally friendly approach, to search for new antifungal agrochemicals. Compounds were prepared starting from 2-mercaptobenzoazoles, using KOH, benzyl halides, and water, resulting in a simple and ecological method. New antifungals were tested against a group of phytopathogenic fungi. Two compounds showed an interesting activity against Botrytis cinerea, Fusarium oxysporum, and Aspergillus spp.: 2-((4-(trifluoromethyl)benzyl)thio)benzo[d]thiazole, 3ac, and 2-((4-methylbenzyl)thio)benzo[d]thiazole, 3al. Thus, 3ac and 3al can be considered as broad spectrum antifungal agents. Furthermore, two new compounds, 2-((4-iodobenzyl)thio)benzo[d]thiazole, 3aj, and 2-(benzylthio)benzo[d]oxazole, 3ba, showed better inhibitory effect against Botrytis cinerea and Fusarium oxysporum when compared to the commercial fungicide Captan. Thus, 3aj and 3ba can be considered reduced-spectrum antifungals.


Subject(s)
Fungicides, Industrial/chemical synthesis , Fungicides, Industrial/pharmacology , Aspergillus/drug effects , Azoles/chemistry , Benzyl Compounds/chemistry , Botrytis/drug effects , Fungicides, Industrial/chemistry , Fusarium/drug effects , Green Chemistry Technology , Microbial Sensitivity Tests , Molecular Structure
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