Novel hybrids of fluconazole and furanones: Design, synthesis and antifungal activity (original) (raw)
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Molecules, 2020
The frequency of mycoses caused by drug-resistant fungal pathogen Candida albicans has increased drastically over the last two decades. The spread of drug-resistant strains, along with the limitations of currently available antifungals, complicates the management of fungal infections, thereby representing great challenges for clinical healthcare. Among various antimicrobial pharmacophores, 2(5H)-furanone derivatives have demonstrated antimicrobial, antifungal, and antibiofilm activities. In this study, we report the antifungal activity of the 2(5H)-furanone derivative F105, consisting of three pharmacophores, namely chlorinated 2(5H)-furanone, sulfonyl group, and l-menthol moiety. Although exhibiting moderate antifungal activity alone with the minimum inhibitory concentration (MIC) values of 32–256 μg/mL, F105 potentiates the activity of fluconazole and terbinafine with fractional inhibitory concentration index (FICI) values of 0.27–0.50. Thus, 16 μg/mL of F105 reduced the MICs of t...
American Journal of Advanced Drug Delivery, 2013
The antifungal activity of α, β-unsaturated carbonyl compounds has been recognized generally due to their ability to react with sulfhydryl containing system of fungi essential for normal metabolism.In view of this, number of enones and related compounds were synthesized and evaluated for the antifungal properties. In the present investigation, a series of some novel furfurylidene derivatives of 2,6diphenyl piperidin-4-one have been synthesized. All compounds were prepared by Claisen-Schmidt condensation between piperidin-4-one derivatives and furfuraldehyde in the basic medium; led to formation of furfurylidene derivatives. N-aryl sulphonyl and benzoyl derivatives were prepared by reacting furfurylidene piperidin-4-one with aryl sulphonyl chloride and benzoyl chloride. The newly synthesized compounds were found to havepractical yield in range of 68-96% with high purity and their characterization was done using M.P., TLC, FTIR and 1 HNMR spectral analysis.All these newly synthesized compounds were then evaluated for their in-vitro antifungal activity against Candida albicans and Aspergillus niger fungal strains in which most of the compounds showed potent activity. The present results may be used as key step for the construction of novel chemical entities with better pharmacological profiles than standard drugs.
ACS Omega, 2021
Demand has arisen for developing new azole antifungal agents with the growth of the resistant rate of infective fungal species to current azole antifungals in recent years. Accordingly, the present study reports the synthesis of novel fluconazole (FLC) analogues bearing urea functionality that led to discovering new azole agents with promising antifungal activities. In particular, compounds 8b and 8c displayed broad-spectrum activity and superior in vitro antifungal capabilities compared to the standard drug FLC against sensitive and resistant Candida albicans (C. albicans). The highly active compounds 8b and 8c had potent antibiofilm properties against FLC-resistant C. albicans species. Additionally, these compounds exhibited very low toxicity for three mammalian cell lines and human red blood cells. Time-kill studies revealed that our synthesized compounds displayed a fungicidal mechanism toward fungal growth. Furthermore, a density functional theory (DFT) calculation, additional docking, and independent gradient model (IGM) studies were performed to analyze their structure−activity relationship (SAR) and to assess the molecular interactions in the related target protein. Finally, in vivo results represented a significant reduction in the tissue fungal burden and improvements in the survival rate in a mice model of systemic candidiasis along with in vitro and in silico studies, demonstrating the therapeutic efficiency of compounds 8b and 8c as novel leads for candidiasis drug discovery.
Novel fluconazole derivatives with promising antifungal activity
Bioorganic & medicinal chemistry, 2018
The fungistatic nature and toxicity concern associated with the azole drugs currently on the market have resulted in an increased demand for new azole antifungal agents for which these problematic characteristics do not exist. The extensive use of azoles has resulted in fungal strains capable of resisting the action of these drugs. Herein, we report the synthesis and antifungal activity of novel fluconazole (FLC) analogues with alkyl-, aryl-, cycloalkyl-, and dialkyl-amino substituents. We evaluated their antifungal activity by MIC determination and time-kill assay as well as their safety profile by hemolytic activity against murine erythrocytes as well as cytotoxicity against mammalian cells. The best compounds from our study exhibited broad-spectrum activity against most of the fungal strains tested, with excellent MIC values against a number of clinical isolates. The most promising compounds were found to be less hemolytic than the least hemolytic FDA-approved azole antifungal ag...
Heterocyclic Communications, 2002
A number of new 5-nitro-2-furfurylidene derivatives 9a-k were synthesized by the reaction of 2-methy1-4-(5-nitro-2-furfurylmethyliden)-A 2-oxazolin-5-one 6 or 2-phenyl-4-(2-furfurylmethyliden)-A 2-oxazolin-5-one 7 with appropriate 2-aminobenzothiazole. The compounds synthesized were identified by 'H-NMR, IR, MS and micro analysis. All compounds studied in this work were screened for their in vitro antimicrobial and antifungal activities against the standard strains: Bacillus subtilis, Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, Salmonella typhimurium, and the yeast Candida albicans.
Discovery and Development of Antifungal Compounds
Current Medicinal Chemistry -Anti-Infective Agents, 2003
Antifungal agents constitute a major part of antiinfective drugs and have been in practice since 16 th century. Antifungal agents generally belong to the class of polyenes, azoles, apart from other heterocycles, organometallics, etc. Polyenes & azoles as basic moieties act by disrupting the cell wall or cell membrane or protein synthesis. The recent increase in the number of antifungal agents and the discovery that some of the older ones have properties which allow them to be used in new ways led to the development of several new therapeutic regimes. Moreover, various modifications have been attempted to achieve an optimal blend of favourable properties together with minimal potential for undesirable side effects. Thus, it is important to learn the mode of action of these agents, their advantages, and their limitations as this information will be helpful in determining the indications for use of one regimes over the others. In this review, we summarize antifungal agents which are of utmost importance clinically.
Synthesis and biological activity studies of furan derivatives
Medicinal Chemistry Research, 2010
The organic compounds, 4-Ethyl-2synthesized and purified through column chromatography and preparative TLC. All compounds were characterized by IR, 1 H, 13 C NMR, MS, and microanalysis. The in vitro antibacterial and antifungal activities of these compounds were investigated against some bacteria and fungi. The antibacterial and antifungal activities were measured by using the disc-diffusion method against gram-positive bacteria, i.e., Staphylococcus aureus ATCC 25923, Staphylococcus enteritidis ATCC1376, Psydomamonas aeruginosa ATCC 29212, Bacillus subtilis RSKK 244, Bacillus megaterium gram-negative bacteria Escherichia coli ATCC 27853, Listeria monocytogenes ATCC 7644, and as fungus Micrococcus Luteus NRRLB was used. All compounds in this study showed activity against test bacteria. Their antibiogram tests showed better results than some known antibiotics.
Recent Advances in Antifungal Agents
Mini-Reviews in Medicinal Chemistry, 2007
New antifungals are needed in the medicine because of more aggressive and invasive diagnostic and therapeutic methods used, rapid emergence of resistant and new opportunistic fungi, increasing number of patients suffering from immunosuppressive situations e.g., AIDS, transplantation, cancer, etc. Several classes of new antifungal agents are discussed here including some new members of known families. Voriconazole, posaconazole and ravuconazole, are novel triazoles that inhibit the ergosterol synthesis. These drugs overcome problems associated with the ineffectivity of fluconazole against some Aspergillus spp. or the variable bioavailability of itraconazole. Echinocandins (caspofungin, anidulafungin and micafungin) represent a new family of antifungal agents that inhibit 1,3-glucan synthase. Nikkomycins targeting the chitin synthase, show activity against Histoplasma capsulatum and Blastomyces dermatitidis. Sordarin derivatives that block the fungal protein synthesis can be considered as a promising new class of antifungal agents for the treatment of Candida and Pneumocystis infections.