Design, Synthesis and Anticandidal Evaluation of Indazole and Pyrazole Derivatives

Candidiasis, caused by yeasts of the genus Candida, is the second cause of superficial and mucosal infections and the fourth cause of bloodstream infections. Although some antifungal drugs to treat candidiasis are available, resistant strains to current therapies are emerging. Therefore, the search for new candicidal compounds is certainly a priority. In this regard, a series of indazole and pyrazole derivatives were designed in this work, employing bioisosteric replacement, homologation, and molecular simplification as new anticandidal agents. Compounds were synthesized and evaluated against C. albicans, C. glabrata, and C. tropicalis strains. The series of 3-phenyl-1H-indazole moiety (10a–i) demonstrated to have the best broad anticandidal activity. Particularly, compound 10g, with N,N-diethylcarboxamide substituent, was the most active against C. albicans and both miconazole susceptible and resistant C. glabrata species. Therefore, the 3-phenyl-1H-indazole scaffold represents an opportunity for the development of new anticandidal agents with a new chemotype.

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Synergistic anticandidal activity of etomidate and azoles against clinical fluconazole-resistant Candida isolates

Future Microbiology ◽

10.2217/fmb-2019-0075 ◽

2019 ◽

Vol 14 (17) ◽

pp. 1477-1488 ◽

Cited By ~ 4

Author(s):

Lívia G do AV Sá ◽

Cecília R da Silva ◽

Rosana de S Campos ◽

João B de A Neto ◽

Letícia S Sampaio ◽

...

Keyword(s):

Antifungal Activity ◽

Antifungal Drugs ◽

Planktonic Cells ◽

Candida Spp ◽

Flow Cytometric ◽

Fluconazole Resistant ◽

Anticandidal Activity ◽

Checkerboard Assay ◽

Resistant Strains ◽

Radical Generation

Aim: The purpose of this study was to evaluate the effect of etomidate alone and in combination with azoles on resistant strains of Candida spp. in both planktonic cells and biofilms. Materials & methods: The antifungal activity of etomidate was assessed by the broth microdilution test; flow cytometric procedures to measure fungal viability, mitochondrial transmembrane potential, free radical generation and cell death; as well detection of DNA damage using the comet assay. The interaction between etomidate and antifungal drugs (itraconazole and fluconazole) was evaluated by the checkerboard assay. Results: Etomidate showed antifungal activity against resistant strains of Candida spp. in planktonic cells and biofilms. Etomidate also presented synergism with fluconazole and itraconazole in planktonic cells and biofilms. Conclusion: Etomidate showed antifungal activity against Candida spp., indicating that it is a possible therapeutic alternative.

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Privileged Structures in the Design of Potential Drug Candidates for Neglected Diseases

Current Medicinal Chemistry ◽

10.2174/0929867324666171023163752 ◽

2019 ◽

Vol 26 (23) ◽

pp. 4323-4354 ◽

Cited By ~ 9

Author(s):

Ana Cristina Lima Leite ◽

José Wanderlan Pontes Espíndola ◽

Marcos Veríssimo de Oliveira Cardoso ◽

Gevanio Bezerra de Oliveira Filho

Keyword(s):

Biologically Active ◽

Neglected Diseases ◽

Financial Return ◽

Drug Candidates ◽

Lead Compounds ◽

Wide Range ◽

Methods Of Synthesis ◽

Current Therapies ◽

Resistant Strains ◽

Privileged Structures

Background: Privileged motifs are recurring in a wide range of biologically active compounds that reach different pharmaceutical targets and pathways and could represent a suitable start point to access potential candidates in the neglected diseases field. The current therapies to treat these diseases are based in drugs that lack of the desired effectiveness, affordable methods of synthesis and allow a way to emergence of resistant strains. Due the lack of financial return, only few pharmaceutical companies have been investing in research for new therapeutics for neglected diseases (ND). Methods: Based on the literature search from 2002 to 2016, we discuss how six privileged motifs, focusing phthalimide, isatin, indole, thiosemicarbazone, thiazole, and thiazolidinone are particularly recurrent in compounds active against some of neglected diseases. Results: It was observed that attention was paid particularly for Chagas disease, malaria, tuberculosis, schistosomiasis, leishmaniasis, dengue, African sleeping sickness (Human African Trypanosomiasis - HAT) and toxoplasmosis. It was possible to verify that, among the ND, antitrypanosomal and antiplasmodial activities were between the most searched. Besides, thiosemicarbazone moiety seems to be the most versatile and frequently explored scaffold. As well, phthalimide, isatin, thiazole, and thiazolidone nucleus have been also explored in the ND field. Conclusion: Some described compounds, appear to be promising drug candidates, while others could represent a valuable inspiration in the research for new lead compounds.

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Bioisosteric Replacement and Related Analogs in the Design, Synthesis and Evaluation of Ligands for Muscarinic Acetylcholine Receptors

Medicinal Chemistry ◽

10.2174/15734064113096660043 ◽

2014 ◽

Vol 10 (4) ◽

pp. 361-375 ◽

Cited By ~ 2

Author(s):

Richie Bhandare ◽

Daniel Canney

Keyword(s):

Acetylcholine Receptors ◽

Muscarinic Acetylcholine Receptors ◽

Design Synthesis ◽

Muscarinic Acetylcholine ◽

Bioisosteric Replacement

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Design, Synthesis and Antiplasmodial Evaluation of Sulfoximine-triazole Hybrids as Potential Antimalarial Prototypes

Medicinal Chemistry ◽

10.2174/1573406415666190206232308 ◽

2019 ◽

Vol 15 (6) ◽

pp. 685-692 ◽

Cited By ~ 1

Author(s):

Tommy F. Mabasa ◽

Babatunde Awe ◽

Dustin Laming ◽

Henok H. Kinfe

Keyword(s):

Alkyl Substituent ◽

Antimalarial Drugs ◽

Significant Activity ◽

Design Synthesis ◽

Antimalarial Agents ◽

Falciparum Strain ◽

Physiological Properties ◽

Resistant Strains ◽

Cytotoxicity Activities ◽

Drug Resistant Strains

Background:Malaria, caused by the deadly Plasmodium falciparum strain, claims the lives of millions of people annually. The emergence of drug-resistant strains of P. falciparum to the artemisinin-based combination therapy (ACT), the last line of defense against malaria, is worrisome and urges for the development of new chemo-types with a new mode of action. In the search of new antimalarial agents, hybrids of triazoles and other known antimalarial drugs have been reported to possess better activity than either of the parent compounds administered individually. Despite their better activity, no hybrid antimalarial drugs have been developed so far.Objective:In the hope of developing new antimalarial prototypes, we propose the design, synthesis and antimalarial evaluation of novel sulfoximine-triazole hybrids owing to their interesting biological and physiological properties.Methods:The sulfoximine part of the hybrid will be synthesized via imidation of the corresponding sulfoxide. Propargylation of the NH moiety of the sulfoximine followed by copper-catalyzed click chemistry with benzyl azide was envisaged to provide the target sulfoximine-triazole hybrids.Results:Five novel sulfoximine-triazole hybrids possessing various substituents on the sulfoximine moiety have been successfully synthesized and evaluated for their antiplasmodial and cytotoxicity activities. The results revealed that the co-presence of the sulfoximine and triazole moieties along with a lipophilic alkyl substituent on the sulfur atom impart significant activity.Conclusion:Sulfoximine-triazole hybrids could be used as a prototype for the synthesis of new derivatives with better antiplasmodial activities.

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Novel Acetohydrazide Pyrazole Derivatives: Design, Synthesis, Characterization and Antimicrobial Activity

Asian Journal of Chemistry ◽

10.14233/ajchem.2019.22190 ◽

2019 ◽

Vol 31 (12) ◽

pp. 2740-2744

Author(s):

Anil Verma ◽

Vinod Kumar ◽

Ramesh Kataria ◽

Joginder Singh

Keyword(s):

Mass Spectrometry ◽

Antimicrobial Activity ◽

Antimicrobial Agents ◽

Antimicrobial Activities ◽

Pyrazole Derivatives ◽

Reaction Conditions ◽

Design Synthesis ◽

Structure Activity ◽

Electron Withdrawing Group ◽

Sar Study

Eleven acetohydrazide linked pyrazole derivatives were designed and synthesized via condensation of acetohyadrazide with different substituted formyl pyrazole derivatives under mild reaction conditions. Synthesized compounds were characterized on the basis of IR, NMR (1H & 13C) and mass spectrometry. The antimicrobial activities of all the compounds were screened against four bacterial and two fungal strains. Among the synthesized compounds, three compounds viz. 6b, 6c and 6d were found as efficient antimicrobial agents in reference to the standard drugs viz. ciprofloxacin and amphotericin-B. Further, structure-activity relationship (SAR) study revealed that electron-withdrawing group enhances the antimicrobial potential of synthesized derivatives as compared to other groups present in the ring. Hence, among compounds 6b-c, compound 6d could be explored further against other microbes to prove its vitality.

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Recent Exposure to Caspofungin or Fluconazole Influences the Epidemiology of Candidemia: a Prospective Multicenter Study Involving 2,441 Patients

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01128-10 ◽

2010 ◽

Vol 55 (2) ◽

pp. 532-538 ◽

Cited By ~ 223

Author(s):

Olivier Lortholary ◽

Marie Desnos-Ollivier ◽

Karine Sitbon ◽

Arnaud Fontanet ◽

Stéphane Bretagne ◽

...

Keyword(s):

Intensive Care Unit ◽

Odds Ratio ◽

Susceptibility Testing ◽

Antifungal Susceptibility ◽

Bloodstream Infections ◽

Antifungal Drugs ◽

Surveillance Program ◽

Prospective Multicenter Study ◽

Recent Exposure ◽

Adults And Children

ABSTRACTA prospective multicenter surveillance program on yeast bloodstream infections was implemented in the Paris, France, area without restrictions on ward of hospitalization (intensive care unit, hematology, and surgery) or age (adults and children). The present analysis concerns 2,618 isolates collected over 7 years from 2,441 patients. Centralized species identification and antifungal susceptibility testing using the EUCAST methodology were performed. Almost 10% (232/2,441) of the patients had recently (≤30 days) been treated with antifungal drugs. We analyzed the effect of recent exposure to fluconazole (n= 159) or caspofungin (n= 61) on the proportions of the five majorCandidaspecies. For both drugs, preexposure was associated with a decreased prevalence ofCandida albicansin favor of less drug-susceptible species (C. glabrataandC. kruseifor the former andC. parapsilosisand, to a lesser extent,C. glabrataandC. kruseifor the latter;P= 0.001). In the multivariate analysis, the risk of being infected with an isolate with decreased susceptibility to fluconazole was independently associated with an age of ≥15 years (odds ratio [OR] = 2.45; 95% confidence interval [CI] = 1.39 to 4.31;P= 0.002) and with recent exposure to fluconazole (OR = 2.17; 95% CI = 1.51 to 3.13;P< 0.001), while the risk of being infected with an isolate with decreased susceptibility to caspofungin was independently associated with an age <15 years (OR = 2.53; 95% CI = 1.43 to 4.48;P= 0.001) and with recent exposure to caspofungin (OR = 4.79; 95% CI = 2.47 to 9.28;P< 0.001). These findings could influence future recommendations for the management of candidemia.

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