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1.
ChemMedChem ; : e202400307, 2024 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-39022854

RESUMO

Carbon dioxide (CO2) is an economically viable and abundant carbon source that can be incorporated into compounds such as 1,3-azoles relevant to the pharmaceutical, cosmetics, and pesticide industries. Of the 2.4 million commercially available C2-unsubstituted 1,3-azole compounds, less than 1 % are currently purchasable as their C2-carboxylated derivatives, highlighting the substantial gap in compound availability. This availability gap leaves ample opportunities for exploring the synthetic accessibility and use of carboxylated azoles in bioactive compounds. In this study, we analyze and quantify the relevance of C2-carboxylated 1,3-azoles in small-molecule research. An analysis of molecular databases such as ZINC, ChEMBL, COSMOS, and DrugBank identified relevant C2-carboxylated 1,3-azoles as anticoagulant and aroma-giving compounds. Moreover, a pharmacophore analysis highlights promising pharmaceutical potential associated with C2-carboxylated 1,3-azoles, revealing the ATP-sensitive inward rectifier potassium channel 1 (KATP) and Kinesin-like protein KIF18A as targets that can potentially be addressed with C2-carboxylated 1,3-azoles. Moreover, we identified several bioisosteres of C2-carboxylated 1,3-azoles. In conclusion, further exploration of the chemical space of C2-carboxylated 1,3-azoles is encouraged to harness their full potential in drug discovery and related fields.

2.
Microbiol Res ; 286: 127816, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-38964072

RESUMO

Apple scab, caused by the hemibiotrophic fungus Venturia inaequalis, is currently the most common and damaging disease in apple orchards. Two strains of V. inaequalis (S755 and Rs552) with different sensitivities to azole fungicides and the bacterial metabolite fengycin were compared to determine the mechanisms responsible for these differences. Antifungal activity tests showed that Rs552 had reduced sensitivity to tebuconazole and tetraconazole, as well as to fengycin alone or in a binary mixture with other lipopeptides (iturin A, pumilacidin, lichenysin). S755 was highly sensitive to fengycin, whose activity was close to that of tebuconazole. Unlike fengycin, lipopeptides from the iturin family (mycosubtilin, iturin A) had similar activity on both strains, while those from the surfactin family (lichenysin, pumilacidin) were not active, except in binary mixtures with fengycin. The activity of lipopeptides varies according to their family and structure. Analyses to determine the difference in sensitivity to azoles (which target the CYP51 enzyme involved in the ergosterol biosynthesis pathway) showed that the reduced sensitivity in Rs552 is linked to (i) a constitutive increased expression of the Cyp51A gene caused by insertions in the upstream region and (ii) greater efflux by membrane pumps with the involvement of ABC transporters. Microscopic observations revealed that fengycin, known to interact with plasma membranes, induced morphological and cytological changes in cells from both strains. Sterol and phospholipid analyses showed a higher level of ergosta-7,22-dien-3-ol and a lower level of PI(C16:0/C18:1) in Rs552 compared with S755. These differences could therefore influence the composition of the plasma membrane and explain the differential sensitivity of the strains to fengycin. However, the similar antifungal activities of mycosubtilin and iturin A in the two strains indirectly indicate that sterols are probably not involved in the fengycin resistance mechanism. This leads to the conclusion that different mechanisms are responsible for the difference in susceptibility to azoles or fengycin in the strains studied.


Assuntos
Ascomicetos , Azóis , Lipopeptídeos , Malus , Doenças das Plantas , Lipopeptídeos/farmacologia , Malus/microbiologia , Doenças das Plantas/microbiologia , Ascomicetos/efeitos dos fármacos , Ascomicetos/metabolismo , Ascomicetos/genética , Azóis/farmacologia , Farmacorresistência Fúngica/genética , Testes de Sensibilidade Microbiana , Antifúngicos/farmacologia , Antifúngicos/metabolismo , Fungicidas Industriais/farmacologia , Regulação Fúngica da Expressão Gênica/efeitos dos fármacos , Proteínas Fúngicas/genética , Proteínas Fúngicas/metabolismo
3.
Expert Rev Anti Infect Ther ; 22(6): 399-412, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38841996

RESUMO

INTRODUCTION: Terbinafine is considered the gold standard for treating skin fungal infections and onychomycosis. However, recent reports suggest that dermatophytes are developing resistance to terbinafine and the other traditional antifungal agents, itraconazole and fluconazole. When there is resistance to terbinafine, itraconazole or fluconazole, or when these agents cannot used, for example, due to potential drug interactions with the patient's current medications, clinicians may need to consider off-label use of new generation azoles, such as voriconazole, posaconazole, fosravuconazole, or oteseconazole. It is essential to emphasize that we do not advocate the use of newer generation azoles unless traditional agents such as terbinafine, itraconazole, or fluconazole have been thoroughly evaluated as first-line therapies. AREAS COVERED: This article reviews the clinical evidence, safety, dosage regimens, pharmacokinetics, and management algorithm of new-generation azole antifungals. EXPERT OPINION: Antifungal stewardship should be the top priority when prescribing new-generation azoles. First-line antifungal therapy is terbinafine and itraconazole. Fluconazole is a consideration but is generally less effective and its use may be off-label in many countries. For difficult-to-treat skin fungal infections and onychomycosis, that have failed terbinafine, itraconazole and fluconazole, we propose consideration of off-label voriconazole or posaconazole.


Assuntos
Antifúngicos , Azóis , Farmacorresistência Fúngica , Onicomicose , Humanos , Antifúngicos/administração & dosagem , Antifúngicos/efeitos adversos , Antifúngicos/farmacologia , Onicomicose/tratamento farmacológico , Onicomicose/microbiologia , Azóis/administração & dosagem , Azóis/farmacologia , Dermatomicoses/tratamento farmacológico , Dermatomicoses/microbiologia , Uso Off-Label , Interações Medicamentosas , Arthrodermataceae/efeitos dos fármacos
4.
Pharmaceuticals (Basel) ; 17(6)2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38931390

RESUMO

A series of hybrid compounds with triazole and thiazolidine nuclei connected by a linker has been synthesized and extensively studied. Various synthetic methods for the target compounds have been tested. A microbiological assessment of the obtained compounds was carried out on strains of pathogenic fungi C. albicans, C. non-albicans, multidrug-resistant C. auris, Rhizopus arrhizus, Aspergillus spp. and some dermatophytes and other yeasts. The lowest obtained MIC values for target compounds lie between 0.003 µg/mL and 0.5 µg/mL and therefore the compounds are not inferior or several times better than commercial azole drugs. The length of the acylpiperazine linker has a limited effect on antifungal activity. Some bioisosteric analogues were tested in microbiological analysis, but turned out to be weaker than the leader in activity. The highest activity was demonstrated by a compound with para-chlorobenzylidene substituent in the thiazolidine fragment. Molecular modelling was used to predict binding modes of synthesized molecules and rationalize experimentally observed SAR. The leader compound is twice more effective in inhibiting the formation of germ tubes by Candida albicans yeast cells compared to voriconazole. An increased level of Pdr5, an azoles drug efflux pump was observed, but the increase is lower than that caused by azoles. The results can be useful for further development of more powerful and safe antifungal agents.

5.
Front Vet Sci ; 11: 1376851, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38903684

RESUMO

Introduction: Fungal diseases are frequently associated with elevated mortality rates in elasmobranchs. Currently, there is a notable absence of scientifically validated therapeutic medications that can ensure both effectiveness and safety when administered to this group of animals. The empirical prescription of azole antifungal agents, particularly voriconazole, has been posited as a potentially efficacious treatment approach for addressing most common mycoses in sharks and rays. However, there are still no published pharmacokinetic studies supporting its use in elasmobranchs and there is a lack of scientific base for its utilization in elasmobranchs. Methods: For this study, voriconazole was administered intravenously (IV) and intramuscularly (IM), at a single dose of 4 mg/kg to six adult undulate skates (Raja undulata). A washout period of 8 weeks was left between each route of administration. Blood samples were collected both before and at ten predetermined intervals after each dosing (0.25, 0.5, 1, 1.5, 2, 4, 8, 12, 24, and 36 h after drug administration). Plasma concentrations were quantified using a validated high-performance liquid chromatography method, and pharmacokinetic (PK) data was analyzed through non-compartmental methods. Results: The mean extrapolated concentration at 0 h (C0) after IV administration was 27.19 ± 7.15 µg/mL and the mean peak plasma concentrations (Cmax) ± SEM after IM administration resulted 2.98 ± 0.28 µg/mL at a mean time to maximum concentration (T max) of 1.33 ± 0.17 h. Terminal half-lives were calculated and resulted 11.18 ± 1.32 h for IV injections and 9.59 ± 1.38 h for IM injections. The area under the curve extrapolated to infinity was determined as 58.14 ± 2.79 h·µg/ml following IV injections and 37.60 ± 6.67 h·µg/ml following IM injections. The IM-administered voriconazole exhibited a mean absolute bioavailability of 64.67 ± 11.47%. Discussion: These discoveries provide backing for the possible application of voriconazole through the intramuscular route in undulate skates and support using lower dosage regimens compared to those required for oral administration, emphasizing the importance of conducting further pharmacokinetic studies with antifungals in elasmobranchs.

6.
Biochem Pharmacol ; 226: 116400, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38945275

RESUMO

The emergence of multidrug-resistant fungi is of grave concern, and its infections are responsible for significant deaths among immunocompromised patients. The treatment of fungal infections primarily relies on a clinical class of antibiotics, including azoles, polyenes, echinocandins, polyketides, and a nucleotide analogue. However, the incidence of fungal infections is increasing as the treatment for human and plant fungal infections overlaps with antifungal drugs. The need for new antifungal agents acting on different targets than known targets is undeniable. Also, the pace at which loss of fungal susceptibility to antibiotics cannot be undermined. There are several modes by which fungi can develop resistance to antibiotics, including reduced drug uptake, drug target alteration, and a reduction in the cellular concentration of the drug due to active extrusions and biofilm formation. The efflux pump's overexpression in the fungi primarily reduced the antibiotic's concentration to a sub-lethal concentration, thus responsible for developing resistant fungus strains. Several strategies are used to check antibiotic resistance in multi-drug resistant fungi, including synthesizing antibiotic analogs and giving antibiotics in combination therapies. Among them, the efflux pump protein inhibitors are considered potential adjuvants to antibiotics and can block the efflux of antibiotics by inhibiting efflux pump protein transporters. Moreover, it can sensitize the antifungal drugs to multi-drug resistant fungi with overexpressed efflux pump proteins. This review discusses the natural lead molecules, repurposable drugs, and formulation strategies to overcome the efflux pump activity in the fungi.


Assuntos
Antifúngicos , Farmacorresistência Fúngica Múltipla , Fungos , Antifúngicos/farmacologia , Humanos , Fungos/efeitos dos fármacos , Fungos/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Animais , Micoses/tratamento farmacológico , Micoses/microbiologia
7.
Chem Asian J ; : e202400481, 2024 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-38856102

RESUMO

Zwitterionic compounds are an emergent class of energetic materials and have gained synthetic interest of many in the recent years. Due to their better packing efficiencies and strong inter/intramolecular electrostatic interactions, they often ensue superior energetic properties than their salt analogues. A systematic review from the perspective of design, synthesis, and physicochemical properties evaluation of the zwitterionic energetic materials is presented. Depending on the parent ring(s) used for the synthesis and the type of moieties bearing positive and negative charges, different classes of energetic materials, such as primary explosives, secondary explosives, heat resistant explosives, oxidizers, etc., may result. The properties of some of the energetic zwitterionic compounds are also compared with analogous energetic salts. This review will encourage readers to explore the possibility of designing new zwitterionic energetic materials.

8.
Beilstein J Org Chem ; 20: 891-897, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38711595

RESUMO

A stereoselective N-alkenylation of azoles with alkynes and iodine(III) electrophile is reported. The reaction between various azoles and internal alkynes is mediated by benziodoxole triflate as the electrophile in a trans-fashion, affording azole-bearing vinylbenziodoxoles in moderate to good yields. The tolerable azole nuclei include pyrazole, indazole, 1,2,3-triazole, benzotriazole, and tetrazole. The iodanyl group in the product can be leveraged as a versatile synthetic handle, allowing for the preparation of hitherto inaccessible types of densely functionalized N-vinylazoles.

9.
Chemphyschem ; 25(12): e202400105, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38721760

RESUMO

Pentazole is regarded as a unique inorganic molecule that possess organic heterocyclic structure. Therefore, the research on pentazolyl derivatives represents a cutting-edge direction in both contemporary inorganic chemistry and heterocyclic chemistry. Moreover, their synthesis is regarded as the most significant research topic in the field of energetic materials due to the great potential of pentazolyl derivatives to breakthrough the energy bottleneck of CHNO-based energetic materials. However, synthesizing pentazolyl derivatives is challenging. To provide a theoretical support for the synthesis, we conducted theoretical studies on six single-ring pentazolyl derivatives with different functional groups. The results suggest that derivatization reduces the bond strength and weakens the aromaticity of the pentazolate ring. Further analysis showed that derivatization mainly affects the π aromaticity of the pentazolate ring, and ultimately causing poor stability of the pentazolyl derivatives. Among the six derivatives investigated in this study, fluoro pentazole (cyclo-N5-F) and hydroxyl pentazole (cyclo-N5-OH) possess good aromaticity, which is similar to the reported cyclo-N5-NCHN(CH3)2. Further calculations show that the kinetic stability of cyclo-N5-OH is higher than that of cyclo-N5-F. These results collectively indicate that cyclo-N5-OH is a promising candidate for synthesizing single-ring pentazolyl derivatives.

10.
Life Sci ; 348: 122699, 2024 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-38718854

RESUMO

AIMS: Azoles have been widely employed for the treatment of invasive fungal diseases; however, their efficacy is diminished as pathogenic fungi tolerate them due to their fungistatic properties. Geldanamycin (GdA) can render azoles fungicidal by inhibiting the ATPase and molecular chaperone activities of heat shock protein 90 (Hsp90). Nonetheless, the clinical applicability of GdA is restricted due to its cytotoxic ansamycin scaffold structure, its induction of cytoprotective heat shock responses, and the conservative nature of Hsp90. Hence, it is imperative to elucidate the mechanism of action of GdA to confer fungicidal properties to azoles and mitigate the toxic adverse effects associated with GdA. MATERIALS AND METHODS: Through various experimental methods, including the construction of gene-deleted Candida albicans mutants, in vitro drug sensitivity experiments, Western blot analysis, reactive oxygen species (ROS) assays, and succinate dehydrogenase activity assays, we identified Hsp90 client proteins associated with the tolerance of C. albicans to azoles. KEY FINDINGS: It was observed that GdA effectively hindered the entry of Hsp90 into mitochondria, resulting in the alleviation of inhibitory effect of Hsp90 on succinate dehydrogenase. Consequently, the activation of succinate dehydrogenase led to an increased production of ROS. within the mitochondria, thereby facilitating the antifungal effects of azoles against C. albicans. SIGNIFICANCE: This research presents a novel approach for conferring fungicidal properties to azoles, which involves specifically disrupting the interaction of between Hsp90 and succinate dehydrogenase rather than employing a non-specific inhibition of ATPase activity of Hsp90.


Assuntos
Antifúngicos , Azóis , Benzoquinonas , Candida albicans , Proteínas de Choque Térmico HSP90 , Lactamas Macrocíclicas , Espécies Reativas de Oxigênio , Succinato Desidrogenase , Benzoquinonas/farmacologia , Lactamas Macrocíclicas/farmacologia , Candida albicans/efeitos dos fármacos , Antifúngicos/farmacologia , Proteínas de Choque Térmico HSP90/metabolismo , Succinato Desidrogenase/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Azóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Testes de Sensibilidade Microbiana , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Proteínas Fúngicas/metabolismo , Proteínas Fúngicas/genética , Farmacorresistência Fúngica/efeitos dos fármacos
11.
Antimicrob Agents Chemother ; : e0161923, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38712935

RESUMO

We used whole-genome sequencing to analyze a collection of 35 fluconazole-resistant and 7 susceptible Candida parapsilosis isolates together with coverage analysis and GWAS techniques to identify new mechanisms of fluconazole resistance. Phylogenetic analysis shows that although the collection is diverse, two persistent clinical lineages were identified. We identified copy number variation (CNV) of two genes, ERG11 and CDR1B, in resistant isolates. Two strains have a CNV at the ERG11 locus; the entire ORF is amplified in one, and only the promoter region is amplified in the other. We show that the annotated telomeric gene CDR1B is actually an artifactual in silico fusion of two highly similar neighboring CDR genes due to an assembly error in the C. parapsilosis CDC317 reference genome. We report highly variable copy numbers of the CDR1B region across the collection. Several strains have increased the expansion of the two genes into a tandem array of new chimeric genes. Other strains have experienced a deletion between the two genes creating a single gene with a reciprocal chimerism. We find translocations, duplications, and gene conversion across the CDR gene family in the C. parapsilosis species complex, showing that it is a highly dynamic family.

12.
Molecules ; 29(9)2024 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-38731487

RESUMO

The wheat scab caused by Fusarium graminearum (F. graminearum) has seriously affected the yield and quality of wheat in China. In this study, gallic acid (GA), a natural polyphenol, was used to synthesize three azole-modified gallic acid derivatives (AGAs1-3). The antifungal activity of GA and its derivatives against F. graminearum was studied through mycelial growth rate experiments and field efficacy experiments. The results of the mycelial growth rate test showed that the EC50 of AGAs-2 was 0.49 mg/mL, and that of AGAs-3 was 0.42 mg/mL. The biological activity of AGAs-3 on F. graminearum is significantly better than that of GA. The results of field efficacy tests showed that AGAs-2 and AGAs-3 significantly reduced the incidence rate and disease index of wheat scab, and the control effect reached 68.86% and 72.11%, respectively. In addition, preliminary investigation was performed on the possible interaction between AGAs-3 and F. graminearum using density functional theory (DFT). These results indicate that compound AGAs-3, because of its characteristic of imidazolium salts, has potential for use as a green and environmentally friendly plant-derived antifungal agent for plant pathogenic fungi.


Assuntos
Antifúngicos , Azóis , Fusarium , Ácido Gálico , Triticum , Fusarium/efeitos dos fármacos , Fusarium/crescimento & desenvolvimento , Ácido Gálico/química , Ácido Gálico/farmacologia , Antifúngicos/farmacologia , Antifúngicos/química , Triticum/microbiologia , Azóis/farmacologia , Azóis/química , Doenças das Plantas/microbiologia , Doenças das Plantas/prevenção & controle , Testes de Sensibilidade Microbiana
13.
Mycoses ; 67(6): e13750, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38813959

RESUMO

BACKGROUND: The prevalence of Candida glabrata healthcare-associated infections is on the rise worldwide and in Lebanon, Candida glabrata infections are difficult to treat as a result of their resistance to azole antifungals and their ability to form biofilms. OBJECTIVES: The first objective of this study was to quantify biofilm biomass in the most virulent C. glabrata isolates detected in a Lebanese hospital. In addition, other pathogenicity attributes were evaluated. The second objective was to identify the mechanisms of azole resistance in those isolates. METHODS: A mouse model of disseminated systemic infection was developed to evaluate the degree of virulence of 41 azole-resistant C. glabrata collected from a Lebanese hospital. The most virulent isolates were further evaluated alongside an isolate having attenuated virulence and a reference strain for comparative purposes. A DNA-sequencing approach was adopted to detect single nucleotide polymorphisms (SNPs) leading to amino acid changes in proteins involved in azole resistance and biofilm formation. This genomic approach was supported by several phenotypic assays. RESULTS: All chosen virulent isolates exhibited increased adhesion and biofilm biomass compared to the isolate having attenuated virulence. The amino acid substitutions D679E and I739N detected in the subtelomeric silencer Sir3 are potentially involved- in increased adhesion. In all isolates, amino acid substitutions were detected in the ATP-binding cassette transporters Cdr1 and Pdh1 and their transcriptional regulator Pdr1. CONCLUSIONS: In summary, increased adhesion led to stable biofilm formation since mutated Sir3 could de-repress adhesins, while decreased azole susceptibility could result from mutations in Cdr1, Pdh1 and Pdr1.


Assuntos
Antifúngicos , Biofilmes , Candida glabrata , Candidíase , Farmacorresistência Fúngica , Mutação , Biofilmes/crescimento & desenvolvimento , Candida glabrata/genética , Candida glabrata/efeitos dos fármacos , Candida glabrata/isolamento & purificação , Candida glabrata/patogenicidade , Candida glabrata/fisiologia , Líbano , Animais , Camundongos , Farmacorresistência Fúngica/genética , Antifúngicos/farmacologia , Humanos , Virulência/genética , Candidíase/microbiologia , Proteínas Fúngicas/genética , Polimorfismo de Nucleotídeo Único , Modelos Animais de Doenças , Azóis/farmacologia , Testes de Sensibilidade Microbiana , Hospitais , Feminino
14.
Antimicrob Agents Chemother ; : e0002224, 2024 Apr 16.
Artigo em Inglês | MEDLINE | ID: mdl-38624217

RESUMO

Candida parapsilosis has recently emerged as a major threat due to the worldwide emergence of fluconazole-resistant strains causing clonal outbreaks in hospitals and poses a therapeutic challenge due to the limited antifungal armamentarium. Here, we used precise genome editing using CRISPR-Cas9 to gain further insights into the contribution of mutations in ERG11, ERG3, MRR1, and TAC1 genes and the influence of allelic dosage to antifungal resistance in C. parapsilosis. Seven of the most common amino acid substitutions previously reported in fluconazole-resistant clinical isolates (including Y132F in ERG11) were engineered in two fluconazole-susceptible C. parapsilosis lineages (ATCC 22019 and STZ5). Each mutant was then challenged in vitro against a large array of antifungals, with a focus on azoles. Any possible change in virulence was also assessed in a Galleria mellonella model. We successfully generated a total of 19 different mutants, using CRISPR-Cas9. Except for R398I (ERG11), all remaining amino acid substitutions conferred reduced susceptibility to fluconazole. However, the impact on fluconazole in vitro susceptibility varied greatly according to the engineered mutation, the stronger impact being noted for G583R acting as a gain-of-function mutation in MRR1. Cross-resistance with newer azoles, non-medical azoles, but also non-azole antifungals such as flucytosine, was occasionally noted. Posaconazole and isavuconazole remained the most active in vitro. Except for G583R, no fitness cost was associated with the acquisition of fluconazole resistance. We highlight the distinct contributions of amino acid substitutions in ERG11, ERG3, MRR1, and TAC1 genes to antifungal resistance in C. parapsilosis.

15.
Chimia (Aarau) ; 78(3): 104-107, 2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38547010

RESUMO

Aryl azoles can be found in numerous active pharmaceutical ingredients (APIs). Milvexian is a Factor Xia inhibitor currently in phase III for the treatment of thrombotic events containing an ortho-substituted 1-aryl-1H-1,2,3-triazole moiety. During the process development of Milvexian, we assessed multiple approaches for the preparation of 4-chloro-1,2,3-triazole, intermediate 1. In this review article, we will detail how we initiated several academic collaborations to speed up the selection of the best synthesis for commercial manufacturing. Ultimately, those results not only helped us to achieve our goal but yielded general methodologies for the functionalization of azoles that extended even beyond our initial scope.

16.
Bioorg Chem ; 145: 107241, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38437761

RESUMO

The discovery of new small molecule-based inhibitors is an attractive field in medicinal chemistry. Structurally diversified heterocyclic derivatives have been investigated to combat multi-drug resistant bacterial infections and they offers several mechanism of action. Methicillin-resistant Staphylococcus aureus (MRSA) is becoming more and more deadly to humans because of its simple method of transmission, quick development of antibiotic resistance, and ability to cause hard-to-treat skin and filmy diseases. The sulfur (SVI) particularly sulfonyl and sulfonamide based heterocyclic moieties, have found to be good anti-MRSA agents. The development of new nontoxic, economical and highly active sulfur (SVI) containing derivatives has become hot research topics in drug discovery research. Presently, more than 150 FDA approved Sulfur (SVI)-based drugs are available in the market, and they are widely used to treat various types of diseases with different therapeutic potential. The present collective data provides the latest advancements in Sulfur (SVI)-hybrid compounds as antibacterial agents against MRSA. It also examines the outcomes of in-vitro and in-vivo investigations, exploring potential mechanisms of action and offering alternative perspectives on the structure-activity relationship (SAR). Sulfur (SVI)-hybrids exhibits synergistic effects with existing drugs to provide antibacterial action against MRSA.


Assuntos
Antibacterianos , Staphylococcus aureus Resistente à Meticilina , Humanos , Antibacterianos/farmacologia , Antibacterianos/química , Testes de Sensibilidade Microbiana , Relação Estrutura-Atividade , Enxofre/farmacologia
17.
Curr Rheumatol Rev ; 2024 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-38445695

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disorder where inflammation and destruc-tion of bone are the hallmarks of the disease. This review focuses on the etiology, pathophysiolo-gy, and treatment strategies for RA, along with the different approaches used for the synthesis of pyrazoles, the characterization of various properties, and their biological significance for curing RA. The activated immune system of the body causes inflammation of the synovial joint due to the interaction of immune cells, such as T and B lymphocytes, macrophages, plasma cells, den-dritic cells and mast cells. The treatment for RA has been revolutionized with the discovery of new chemical compounds and an understanding of their mechanism in the treatment of the dis-ease. Pyrazoles are the starting materials for the synthesis of heterocyclic compounds and possess great relevance in the pharmaceutical field for the development of new drugs. They are versatile bio-scaffolds in medicinal chemistry and organic synthesis. This has been followed by a deep analysis of pyrazoles and their derivatives on the basis of medical significance in the treatment of RA. This follow-up and information may help the chemists, scientists, and researchers to generate new pyrazole compounds with high efficacy for better treatment of patients with RA. We summa-rize the review with an understanding of the core of pyrazoles and a claim that their derivatives may be helpful in the development of efficient drugs against RA.

18.
Mycoses ; 67(3): e13704, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38429226

RESUMO

BACKGROUND: Meyerozyma guilliermondii is a yeast species responsible for invasive fungal infections. It has high minimum inhibitory concentrations (MICs) to echinocandins, the first-line treatment of candidemia. In this context, azole antifungal agents are frequently used. However, in recent years, a number of azole-resistant strains have been described. Their mechanisms of resistance are currently poorly studied. OBJECTIVE: The aim of this study was consequently to understand the mechanisms of azole resistance in several clinical isolates of M. guilliermondii. METHODS: Ten isolates of M. guilliermondii and the ATCC 6260 reference strain were studied. MICs of azoles were determined first. Whole genome sequencing of the isolates was then carried out and the mutations identified in ERG11 were expressed in a CTG clade yeast model (C. lusitaniae). RNA expression of ERG11, MDR1 and CDR1 was evaluated by quantitative PCR. A phylogenic analysis was developed and performed on M. guilliermondii isolates. Lastly, in vitro experiments on fitness cost and virulence were carried out. RESULTS: Of the ten isolates tested, three showed pan-azole resistance. A combination of F126L and L505F mutations in Erg11 was highlighted in these three isolates. Interestingly, a combination of these two mutations was necessary to confer azole resistance. An overexpression of the Cdr1 efflux pump was also evidenced in one strain. Moreover, the three pan-azole-resistant isolates were shown to be genetically related and not associated with a fitness cost or a lower virulence, suggesting a possible clonal transmission. CONCLUSION: In conclusion, this study identified an original combination of ERG11 mutations responsible for pan-azole-resistance in M. guilliermondii. Moreover, we proposed a new MLST analysis for M. guilliermondii that identified possible clonal transmission of pan-azole-resistant strains. Future studies are needed to investigate the distribution of this clone in hospital environment and should lead to the reconsideration of the treatment for this species.


Assuntos
Azóis , Farmacorresistência Fúngica , Saccharomycetales , Humanos , Azóis/farmacologia , Tipagem de Sequências Multilocus , Farmacorresistência Fúngica/genética , Antifúngicos/farmacologia , Mutação , Testes de Sensibilidade Microbiana , Fluconazol/farmacologia
19.
Sci Total Environ ; 923: 171189, 2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38447726

RESUMO

Antifungal resistance has emerged as a significant health concern with increasing reports of resistant variants in previously susceptible species. At present, little is known about occupational exposure to antifungal-resistant fungi. This study aimed to investigate Danish workers' occupational exposure to airborne fungi resistant to first-line treatment drugs. A retrospective study was performed on a unique collection of personal exposure samples gathered over a twenty-year period from Danish working environments, in sectors including agriculture, animal handling, waste management, and healthcare. A total of 669 samples were cultivated at 37 °C and fungal colonies were identified using MALDI-TOF MS. Subsequently, identification was confirmed by amplicon sequencing the genes of calmodulin and beta-tubulin to unveil potential cryptic species. Infectious fungi (495 isolates from 23 species) were tested for resistance against Itraconazole, Voriconazole, Posaconazole, and Amphotericin B. Working environments were highly variable in the overall fungal exposure, and showed vastly different species compositions. Resistance was found in 30 isolates of the species Aspergillus fumigatus (4 of 251 isolates), A. nidulans (2 of 13), A. niger complex (19 of 131), A. versicolor (3 of 18), and A. lentulus (2 of 2). Sequence analysis revealed several cryptic species within the A. niger complex including A. tubingensis, A. luchuensis, and A. phoenicis. Among the resistant A. fumigatus isolates, two contained the well-described TR34/L98H mutation in the cyp51A gene and promoter region, while the remainder harbored silent mutations. The results indicate that the working environment significantly contributes to exposure to resistant fungi, with particularly biofuel plant workers experiencing high exposure. Differences in the prevalence of resistance across working environments may be linked to the underlying species composition.


Assuntos
Antifúngicos , Proteínas Fúngicas , Antifúngicos/farmacologia , Estudos Retrospectivos , Proteínas Fúngicas/genética , Fungos , Itraconazol , Aspergillus fumigatus , Testes de Sensibilidade Microbiana , Azóis
20.
Neurosci Lett ; 828: 137750, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38548219

RESUMO

Azoles such as nafimidone, denzimol and loreclezole are known for their clinical efficacy against epilepsy, and loreclezole acts by potentiating γ-aminobutyric acid (GABA)-ergic currents. In the current study, we report a series of azole derivatives in alcohol ester and oxime ester structure showing promising anticonvulsant effects in 6 Hz and maximal electro shock (MES) models with minimal toxicity. The most promising of the series, 5f, was active in both 6 Hz and MES tests with a median effective dose (ED50) of 118.92 mg/kg in 6 Hz test and a median toxic dose (TD50) twice as high in mice. The compounds were predicted druglike and blood-brain barrier (BBB) penetrant in silico. Contrary to what was expected, the compounds showed no in vitro affinity to GABAA receptors (GABAARs) in radioligand binding assays; however, they were found structurally similar to peroxisome proliferator-activated receptors alpha (PPAR-α) agonists and predicted to show high affinity and agonist-like binding to PPAR-α in molecular docking studies. As a result, 5f emerged as a safe azole anticonvulsant with a wide therapeutic window and possible action through PPAR-α activation.


Assuntos
Anticonvulsivantes , Azóis , Camundongos , Animais , Anticonvulsivantes/farmacologia , Convulsões/tratamento farmacológico , Simulação de Acoplamento Molecular , PPAR alfa , Ácido gama-Aminobutírico , Ésteres , Relação Estrutura-Atividade
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