Thiazole compounds with activity against Cryptococcus gattii and Cryptococcus neoformans in vitro

Sá, Nívea Pereira de; Lino, Cleudiomar Inácio; Fonseca, Nayara Cristina; Borelli, Beatriz Martins; Ramos, Jonas Pereira; Souza-Fagundes, Elaine M.; Rosa, Carlos A.; Santos, Danielle Anjos dos; Oliveira, Renata Barbosa de; Johann, Susana

doi:10.1016/j.ejmech.2015.07.032

Cited by 32 publications

(29 citation statements)

References 38 publications

(35 reference statements)

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“…Thus, there is a possibility that the high concentration of superoxide protects against the action of hydrogen peroxide. This would explain the result found by our group, where there is an antagonistic interaction between these thiazoles and amphotericin B against various isolates of C. neoformans and C. gattii (Table 4) (26). Some studies have demonstrated that amphotericin B, in addition to the action on the membrane ergosterol, also acts by promoting an increase in intracellular H 2 O 2 and lipid peroxidation, which helps the fungicide action of this drug and prevents the emergence of resistant organisms (33,34).…”

Section: Discussionsupporting

confidence: 62%

“…In an earlier study, we presented the thiazole compounds 1, 2, 3, and 4 as promising antifungal agents with low toxicity to mammalian Vero and peritoneal macrophage cells and interesting antifungal activity in vitro against C. neoformans-C. gattii species complex (26). In this work, we were able to correlate in vitro activity with disturbances of the fungal antioxidant system.…”

Section: Discussionmentioning

confidence: 74%

“…Some studies have reported the synthesis of new thiazoles with anti-inflammatory, antibacterial, anticancer, and anti-HIV activities (22)(23)(24)(25). As one of the groups involved in this work, we investigated novel thiazole heterocyclic compounds, which are easy to synthesize, have antifungal activity against C. gattii and C. neoformans with MICs ranging from 0.25 to 1.25 g/ml, and display low cytotoxicity in Vero cells and murine macrophages, presenting 50% inhibitory concentrations (IC 50 s) up to 32 g/ml (26). In that previous study (26), we provided evidence that the thiazole fungicides 1, 2, 3, and 4 ( Fig.…”

mentioning

confidence: 99%

“…As one of the groups involved in this work, we investigated novel thiazole heterocyclic compounds, which are easy to synthesize, have antifungal activity against C. gattii and C. neoformans with MICs ranging from 0.25 to 1.25 g/ml, and display low cytotoxicity in Vero cells and murine macrophages, presenting 50% inhibitory concentrations (IC 50 s) up to 32 g/ml (26). In that previous study (26), we provided evidence that the thiazole fungicides 1, 2, 3, and 4 ( Fig. 1) are promising compounds for the development of new drugs for the treatment of cryptococcosis.…”

mentioning

confidence: 99%

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Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex

Sá

Lima

Lino

et al. 2017

Antimicrob Agents Chemother

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Human cryptococcosis can occur as a primary or opportunistic infection and develops as an acute, subacute, or chronic systemic infection involving different organs of the host. Given the limited therapeutic options and the occasional resistance to fluconazole, there is a need to develop novel drugs for the treatment of cryptococcosis. In this report, we describe promising thiazole compounds 1, 2, 3, and 4 and explore their possible modes of action against Cryptococcus. To this end, we show evidence of interference in the Cryptococcus antioxidant system. The tested compounds exhibited MICs ranging from 0.25 to 2 g/ml against Cryptococcus neoformans strains H99 and KN99␣. Interestingly, the knockout strains for Cu oxidase and sarcosine oxidase were resistant to thiazoles. MIC values of thiazole compounds 1, 2, and 4 against these mutants were higher than for the parental strain. After the treatment of C. neoformans ATCC 24067 (or C. deneoformans) and C. gattii strain L27/01 (or C. deuterogattii) with thiazoles, we verified an increase in intracellular reactive oxygen species (ROS). Also, we verified the synergistic interactions among thiazoles and menadione, which generates superoxides, with fractional inhibitory concentrations (FICs) equal to 0.1874, 0.3024, 0.25, and 0.25 for the thiazole compounds 1, 2, 3, and 4, respectively. In addition, thiazoles exhibited antagonistic interactions with parasulphonatephenyl porphyrinato ferrate III (FeTPPS). Thus, in this work, we showed that the action of these thiazoles is related to an interference with the antioxidant system. These findings suggest that oxidative stress may be primarily related to the accumulation of superoxide radicals.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 74%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex

Sá

Lima

Lino

et al. 2017

Antimicrob Agents Chemother

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“…In Vitro Cytotoxicity The heterocyclic compounds, prepared in this study, were evaluated according to standard protocols for their in vitro cytotoxicity [23][24][25] against six human cancer cell lines including cells derived from human gastric cancer (NUGC), human colon cancer (DLD1), human liver cancer (HA22T and HEPG2), human breast cancer (MCF) and nasopharyngeal carcinoma (HONE1) as well as a normal fibroblast cells (WI38). The reference compound used is the CHS-828 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Multicomponent Reactions of Acetoacetanilide Derivatives with Aromatic Aldehydes and Cyanomethylene Reagents to Produce 4<i>H</i>-Pyran and 1,4-Dihydropyridine Derivatives with Antitumor Activities

Azzam

Mohareb

2015

Chem. Pharm. Bull.

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The multi-component reaction of either acetoacetanilide derivative 1a or b with any of the aldehyde derivatives 2a-d and malononitrile 3 in the presence of triethylamine as a catalyst gave the 4H-pyran derivatives 4a-g, respectively. Carrying the same reaction but using a catalytic amount of ammonium acetate gave the 1,4-dihydropyridine derivatives 5a-f, respectively. The use of ethyl cyanoacetate instead of malononitrile in the presence of a catalytic amount of triethylamine gave the 4H-pyran derivatives 7a-d, respectively. Compound 4e was used to synthesize 1,4-dihydropyridine 9a-c and arylhydraone 11a-e derivatives were synthesized from 4a and e. The anti-tumor evaluations of the newly synthesized products were tested against six human cancer and normal cell lines. The results showed that compounds 4a, b, f, 5d, f, 9 and 11a-d had optimal cytotoxic effect against cancer cell lines with IC 50 <550 nM. The toxicity of the most active compounds was further measured against shrimp larvae.Key words 4H-pyran; 1,4-dihydropyridine; cyanomethylene; cytotoxicity Multicomponent reactions (MCRs) are one-pot reactions employing more than two starting materials, e.g. 3, 4, ... , 7, where most of the atoms of the starting materials are incorporated in the final product.1) Several descriptive tags are regularly attached to MCRs they are atom economic, e.g. the majority if not all of the atoms of the starting materials are incorporated in the product; they are efficient, e.g. they efficiently yield the product since the product is formed in onestep instead of multiple sequential steps; they are convergent, e.g. several starting materials combine in one reaction to form the product; they exhibit a very high bond-forming-index (BFI), e.g. several non-hydrogen atom bonds are formed in one synthetic transformation.2,3) Therefore MCRs are often a useful alternative to sequential multistep synthesis.In view of the increasing interest in the preparation of a large variety of heterocyclic compound libraries, the development of new synthetically valuable MCRs with several diversity points remains a challenge for both academic and industrial institutions.4) 4H-Pyran and its derivatives are an important class of heterocyclic compounds possessing broad biological activities, such as anti-inflammatory, 5) analgesic, 6) antioxidant,antiamoebic 11) and oral analgesic. 12) From the aforementioned reports, it seemed that the development of an efficient, rapid, and clean synthetic route towards focused libraries of such compounds is of great importance to both medicinal and synthetic chemists. The combination of multicomponent reactions (MCR 2 ), [13][14][15] which combines different types of MCRs in one pot process inheriting the high selectivity, efficiency, and atom economy of MCR, has gained more and more attention, since Dömling and Ugi reported the first MCR 2 of a modified four-component reaction (4CR) and the Ugi 4CR.16) However, most of the reported MCR 2 cases are limited in isonitrile based multicomponent reactions. [17][18][19][20]...

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The Brazilian compound library (BraCoLi) database: a repository of chemical and biological information for drug design

et al. 2022

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The Brazilian Compound Library (BraCoLi) is a novel open access and manually curated electronic library of compounds developed by Brazilian research groups to support further computer-aided drug design works. Herein, the first version of the database is described comprising 1,176 compounds. Also, the chemical diversity and drug-like profiles of BraCoLi were defined to analyze its chemical space. A significant amount of the compounds fitted Lipinski and Veber's rules, alongside other drug-likeness properties. A comparison using principal component analysis showed that BraCoLi is similar to other databases (FDA-approved drugs and NuBBEDB) regarding structural and physicochemical patterns. Furthermore, a scaffold analysis showed that BraCoLi presents several privileged chemical skeletons with great diversity. Despite the similar distribution in the structural and physicochemical spaces, similarity analysis indicated that compounds present in the BraCoLi are generally different from the two other databases showing an interesting innovative aspect, which is a desirable feature for novel drug design purposes.

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Thiazole compounds with activity against Cryptococcus gattii and Cryptococcus neoformans in vitro

Cited by 32 publications

References 38 publications

Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex

Heterocycle Thiazole Compounds Exhibit Antifungal Activity through Increase in the Production of Reactive Oxygen Species in the Cryptococcus neoformans-Cryptococcus gattii Species Complex

Multicomponent Reactions of Acetoacetanilide Derivatives with Aromatic Aldehydes and Cyanomethylene Reagents to Produce 4<i>H</i>-Pyran and 1,4-Dihydropyridine Derivatives with Antitumor Activities

The Brazilian compound library (BraCoLi) database: a repository of chemical and biological information for drug design

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