Antifungal activity of 6-quinolinyl N-oxide chalcones against Paracoccidioides

Sá, Nívea Pereira de; Cisalpino, Patrícia Silva; Tavares, Luciana de Carvalho; Espíndola, Leandro; Pizzolatti, Moacir Geraldo; Santos, Patrícia Campi; Paula, Talles Prosperi de; Rosa, Carlos A.; Souza, Daniele G.; Santos, Danielle Anjos dos; Johann, Susana

doi:10.1093/jac/dku427

Cited by 16 publications

(11 citation statements)

References 15 publications

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“…The efficiency of CP1 in reducing the lung fungal burden was very similar to that of treatment with ITZ, but the host inflammatory response was better controlled in the animals treated with CP1. Similar results were found with treatment with chalcone (compound 4c), which presented pulmonary parenchyma preserved with mild areas of inflammation (31). Although ITZ is an oral drug with good activity against P. brasiliensis, it leads to important adverse reactions (33).…”

Section: Discussionsupporting

confidence: 68%

“…Finally, the antifungal activity of a synthetic compound derived from chalcones was analyzed. This 6-quinolinyl N-oxide could inhibit the growth of many Paracoccidioides isolates, with a MIC of 5.9 mg/liter against Pb18 (31). In comparison with these recent reports, the MIC determined for CP1 (2 mg/liter) against P. brasiliensis isolate Pb18 indicates superior antifungal activity, encouraging future efforts to target CS.…”

Section: Discussionmentioning

confidence: 67%

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Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

Rodrigues-Vendramini

Marschalk

Toplak

et al. 2019

Antimicrob Agents Chemother

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Paracoccidioidomycosis (PCM), caused by Paracoccidioides, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics testing to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacological criteria (adsorption, distribution, metabolism, excretion, and toxicity) and was therefore used in in vitro experiments. Here we demonstrate that CP1 binds with a dissociation constant of 64 ± 1 μM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity, with a 50% inhibitory concentration (IC50) of 47 ± 5 μM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with a lower inflammatory response and is thus a promising candidate and lead structure for the development of drugs useful in PCM treatment.

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Section: Discussionsupporting

confidence: 68%

Section: Discussionmentioning

confidence: 67%

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

Rodrigues-Vendramini

Marschalk

Toplak

et al. 2019

Antimicrob Agents Chemother

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“…The 6-quinolinyl and quinolinyl N-oxide chalcones, specifically those named 4c and 4e, presented strong activity against P. brasiliensis. Histopathological analysis and a progression score of the disease in mice showed that the 4c compound was able to control inflammation and resolved the infection with better results than treatment with Itraconazole and 4e, while avoiding granuloma formation and preservation of lung tissue ( de Sá et al, 2015 ).…”

Section: Facing the Problem: Through The Diagnostic To Treatment Of Pmentioning

confidence: 99%

Paracoccidioides-host Interaction: An Overview on Recent Advances in the Paracoccidioidomycosis

et al. 2015

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Paracoccidioides brasiliensis and P. lutzii are etiologic agents of paracoccidioidomycosis (PCM), an important endemic mycosis in Latin America. During its evolution, these fungi have developed characteristics and mechanisms that allow their growth in adverse conditions within their host through which they efficiently cause disease. This process is multi-factorial and involves host–pathogen interactions (adaptation, adhesion, and invasion), as well as fungal virulence and host immune response. In this review, we demonstrated the glycoproteins and polysaccharides network, which composes the cell wall of Paracoccidioides spp. These are important for the change of conidia or mycelial (26°C) to parasitic yeast (37°C). The morphological switch, a mechanism for the pathogen to adapt and thrive inside the host, is obligatory for the establishment of the infection and seems to be related to pathogenicity. For these fungi, one of the most important steps during the interaction with the host is the adhesion. Cell surface proteins called adhesins, responsible for the first contact with host cells, contribute to host colonization and invasion by mediating this process. These fungi also present the capacity to form biofilm and through which they may evade the host’s immune system. During infection, Paracoccidioides spp. can interact with different host cell types and has the ability to modulate the host’s adaptive and/or innate immune response. In addition, it participates and interferes in the coagulation system and phenomena like cytoskeletal rearrangement and apoptosis. In recent years, Paracoccidioides spp. have had their endemic areas expanding in correlation with the expansion of agriculture. In response, several studies were developed to understand the infection using in vitro and in vivo systems, including alternative non-mammal models. Moreover, new advances were made in treating these infections using both well-established and new antifungal agents. These included natural and/or derivate synthetic substances as well as vaccines, peptides, and anti-adhesins sera. Because of all the advances in the PCM study, this review has the objective to summarize all of the recent discoveries on Paracoccidioides-host interaction, with particular emphasis on fungi surface proteins (molecules that play a fundamental role in the adhesion and/or dissemination of the fungi to host-cells), as well as advances in the treatment of PCM with new and well-established antifungal agents and approaches.

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“…Other works have identified molecules showing more promising results; for instance, a derivative of 6-quinolinyl N-oxide chalcones showed antifungal activity similar to that of itraconazole in in vivo tests in mice, obtaining an MIC 50 and an MIC 90 of 7.8 and 23.4 g · ml Ϫ1 , respectively (40). Itraconazole inhibits the fungus-mediated synthesis of ergosterol via inhibition of the enzyme lanosterol 14␣-demethylase in a way that alters the permeability of the fungal cell membrane.…”

Section: Fig 4 In Vitro Cytotoxicity For Hela Cells Compounds Hs1 (Amentioning

confidence: 99%

Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections

Bagatin

Pimentel

Biavatti

et al. 2017

Antimicrob Agents Chemother

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This work evaluated new potential inhibitors of the enzyme homoserine dehydrogenase (HSD) of Paracoccidioides brasiliensis, one of the etiological agents of paracoccidioidomycosis. The tertiary structure of the protein bonded to the analogue NAD, and L-homoserine was modeled by homology. The model with the best output was subjected to gradient minimization, redocking, and molecular dynamics simulation. Virtual screening simulations with 187,841 molecules purchasable from the Zinc database were performed. After the screenings, 14 molecules were selected and analyzed by the use of absorption, distribution, metabolism, excretion, and toxicity criteria, resulting in four compounds for in vitro assays. The molecules HS1 and HS2 were promising, exhibiting MICs of 64 and 32 g · ml Ϫ1 , respectively, for the Pb18 isolate of P. brasilensis, 64 g · ml Ϫ1 for two isolates of P. lutzii, and also synergy with itraconazole. The application of these molecules to human-pathogenic fungi confirmed that the HSD enzyme may be used as a target for the development of drugs with specific action against paracoccidioidomycosis; moreover, these compounds may serve as leads in the design of new antifungals.

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Antifungal activity of 6-quinolinyl N-oxide chalcones against Paracoccidioides

Abstract: The results presented in this paper confirm the antifungal potential of the chalcones tested. The chalcone 4c was the more effective at controlling the disease in mice and this compound could be a candidate for future studies of the treatment of paracoccidioidomycosis.

Cited by 16 publications

References 15 publications

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

Promising New Antifungal Treatment Targeting Chorismate Synthase from Paracoccidioides brasiliensis

Paracoccidioides-host Interaction: An Overview on Recent Advances in the Paracoccidioidomycosis

Targeting the Homoserine Dehydrogenase of Paracoccidioides Species for Treatment of Systemic Fungal Infections

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