Synthesis and in vitro antifungal activities of new 3-substituted benzopyrone derivatives

A series of new benzopyrone compounds were designed and synthesized and their antifungal activities in vitro were evaluated. The results showed that the benzopyrone derivatives with short terminal alkyl chain exhibited potent antifungal activity, which represent a novel class of promising leads for the development of novel non-azole antifungal agents. Compound 5j is the most potent one with MIC(80) value 1.5 μg/mL against Trichophyton rubrum. Flexible molecular docking was used to analyze the structure-activity relationships (SARs) of the compounds. The designed compounds interact with CA-CYP51 through hydrophobic and van der Waals interactions.     

Novel antifungal beta-amino acids: synthesis and activity against Candida albicans

A series of novel beta-amino acids has been synthesized and tested for their in vitro antifungal activity against Candida albicans. A steep SAR was observed. beta-Amino acid 21 (BAY 10-8888/PLD-118) revealed the most favourable activity-tolerability profile and was selected for clinical studies as a novel antifungal for the oral treatment of yeast infections.     

Organometallic-based antibacterial and antifungal compounds: transition metal complexes of 1,1'-diacetylferrocene-derived thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone

Organometallic-based, 1,1'-diacetylferrocene-derived antibacterial and antifungal thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone have been prepared by condensing equimolar amount of 1,1'-diacetylferrocene with thiocarbohydrazide, carbohydrazide thiosemicarbazide and semicarbazide, respectively. These were used as ligands for the preparation of their cobalt (II), copper (II), nickel (II) and zinc (II) metal complexes. All the synthesized ligands and their complexes were characterized by IR, NMR, elemental analyses, molar conductances, magnetic moments and electronic spectral data. These synthesized compounds were screened for their antibacterial activity against Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi, and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata using the agar-well diffusion method. All the compounds showed good antibacterial and antifungal activity which increased on coordination with the metal ions thus, introducing a novel class of organometallic-based antibacterial and antifungal agents.     

Novel N'-benzylidene benzofuran-3-carbohydrazide derivatives as antitubercular and antifungal agents

Tuberculosis constitutes today a serious threat to human health worldwide, aggravated by the increasing number of identified multi-drug resistant strains of Mycobacterium tuberculosis (Mtb), its causative agent, as well as by the lack of development of novel mycobactericidal compounds for the last few decades. A novel series of benzofuran-3-carbohydrazide and its analogs was synthesized and characterized spectroscopically. All the compounds were characterized and screened for in vitro anti-tuberculosis (anti-TB) activity against Mycobacterium tuberculosis H37Rv strains by using resazurin assay utilizing microtiter-plate method (REMA). These compounds also showed good antifungal activity against Candida albicans. Thus, the high level of activity shown by the compounds (8a, 8k) suggests that these compounds could serve as leads for development of novel synthetic compounds with enhanced anti-TB and antifungal activity.     

Synthesis and in vitro activity of 2-thiazolylhydrazone derivatives compared with the activity of clotrimazole against clinical isolates of Candida spp

In this paper, we report on the synthesis of a novel series of 2-thiazolylhydrazone derivatives and the influence of the substituents on the thiazole ring on antifungal activity. All synthesized compounds were screened for their in vitro activities against 22 clinical isolates of Candida spp., representing six different species, compared to clotrimazole as a reference compound. Some of the tested compounds were found to possess significant antifungal activity when compared to clotrimazole, in particular compound 14 which exhibited higher potency against most of the Candida spp. considered. The compounds that were most active as anti-Candida agents were also submitted to cytotoxic screening by the Trypan Blue dye exclusion assay and in general they were shown to induce low cytotoxic effects.     

Synthesis and antimicrobial activity of some novel phenyl and benzimidazole substituted benzyl ethers

In this study, a series of novel phenyl- and benzimidazole-substituted benzyl ethers were synthesized and evaluated for antibacterial and antifungal activities against Staphylococcus aureus, Methicillin-resistant S. aureus (MRSA), Escherichia coli, Candida albicans, and Candida krusei. Compound 6g exhibited the most potent antibacterial activity with lowest MIC values of 3.12 and 6.25 microg/mL against S. aureus and MRSA, respectively.     

Design,synthesis, and structure-activity relationship studies of novel triazole agents with strong antifungal activity against Aspergillus fumigatus

The incidence of invasive fungal infections has dramatically increased for several decades. In order to discover novel antifungal agents with broad spectrum and anti-Aspergillus efficacy, a series of novel triazole derivatives containing 1,2,3-benzotriazin-4-one was designed and synthesized. Most of the compounds exhibited stronger in vitro antifungal activities against tested fungi than fluconazole. Moreover, 6m showed comparable antifungal activity against seven pathogenic strains as voriconazole and albaconazole, especially against Aspergillus fumigatus (MIC = 0.25 μg/ml), and displayed moderate antifungal activity against fluconazole-resistant strains of Candida albicans. A clear SAR study indicated that compounds with groups at the 7-position resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.     

The comparison of characteristics between membrane-active antifungal peptide and its pseudopeptides

By the introduction of various amide surrogates, novel pseudopeptides corresponding to a membrane active depsipeptide were synthesized and their native characteristics compared with that of the peptide. The pseudopeptides had more resistance to serum proteases than the peptide and similar antimicrobial activities to that of the peptide without hemolytic activity. The pseudopeptides like the peptide were active against current drug resistant fungi and pathogenic fungi isolated from patients, and also had a strong synergism with current antifungal drugs against Candida albicans. The leakage assay suggested that the pseudopeptides also acted on the lipid membrane of pathogenic cells. These results indicated that the novel pseudopeptides had advantages over the peptide as a candidate for a novel antifungal drug and backbone modifications can be a tool in the development of a novel antifungal agent from membrane-active peptides isolated from natural sources or chemically synthesized.     

Structure-based rational design,synthesis and antifungal activity of oxime-containing azole derivatives

In an attempt to find novel azole antifungal agents with improved activity and broader spectrum, computer modeling was used to design a series of new azoles with piperidin-4-one O-substituted oxime side chains. Molecular docking studies revealed that they formed hydrophobic and hydrogen-bonding interactions with lanosterol 14α-demethylase of Candida albicans (CACYP51). In vitro antifungal assay indicates that most of the synthesized compounds showed good activity against tested fungal pathogens. In comparison with fluconazole, itraconazole and voriconazole, several compounds (such as 10c, 10e, and 10i) show more potent antifungal activity and broader spectrum, suggesting that they are promising leads for the development of novel antifungal agents.     

Synthesis,Antifungal Activity,and Molecular Simulation Study of L–Carvone-Derived 1,3,4-Oxadiazole-Thioether Compounds

To discover potent antifungal molecules with new and distinctive structures, 20 novel L-carvone-derived 1,3,4-oxadiazole-thioether compounds 5 a – 5 t were synthesized through multi-step reaction of L-carvone, and their structures were confirmed by FT-IR, ¹H-NMR, ¹³C-NMR, and HR-MS. The antifungal activities of compounds 5 a – 5 t were preliminarily tested by in vitro method, and the results indicated that all of the title compounds displayed certain antifungal activities against the eight tested plant fungi, especially for P. piricola. Among them, compound 5 i (R=p-F) with the most significant antifungal activity deserved further study for discovering and developing novel natural product-based antifungal agents. Moreover, two molecular simulation technologies were employed for the investigation of their structure–activity relationships (SARs). Firstly, a reasonable and effective 3D-QSAR model was established by the comparative molecular field (CoMFA) method, and the relationship of the substituents linked with the benzene rings and the inhibitory activities of the title compounds against P. piricola was elucidated. Then, the binding mode of compound 5 i (R=p-F) and its potential biological target (CYP51) was simulated by molecular docking, and it was found that compound 5 i could readily bind with CYP51 in the active site, and the ligand-receptor interactions involved three hydrogen bonds and several hydrophobic effects.     

Design,synthesis, and in vitro evaluation of novel antifungal triazoles

Twenty-nine novel triazole analogues of ravuconazole and isavuconazole were designed and synthesized. Most of the compounds exhibited potent in vitro antifungal activities against 8 fungal isolates. Especially, compounds a10, a13, and a14 exhibited superior or comparable antifungal activity to ravuconazole against all the tested fungi. Structure-activity relationship study indicated that replacing 4-cyanophenylthioazole moiety of ravuconazole with fluorophenylisoxazole resulted in novel antifungal triazoles with more effectiveness and a broader-spectrum.     

Identification of novel antifungal nonapeptides through the screening of combinatorial peptide libraries based on a hexapeptide motif

Four sets of mixture based nonapeptide libraries derived from an antifungal hexapeptide pharmacophore Arg-D-Trp-D-Phe-Ile-D-Phe-His-NH(2) (II) have been synthesized. The three C-terminal positions 7, 8 and 9 were subject to randomization using 19 genetically coded amino acids. They were then screened for their antifungal activity against Candida albicans and Cryptococcus neoformans in order to quantify inhibition at each step of the nonapeptide sublibrary deconvolution. The studies led to the identification of several novel nonapeptides with potent antifungal activity. Two of the nonapeptides exhibited approximately 17-fold increase in the activity in comparison to the lead hexapeptide motif His-D-Trp-D-Phe-Phe-D-Phe-Lys-NH(2) (I) against C. albicans.     

Synthesis and biological evaluation of novel 3-substituted amino-4-hydroxylcoumarin derivatives as chitin synthase inhibitors and antifungal agents

A series of novel 3-substituted amino-4-hydroxycoumarin derivatives have been designed and synthesized as chitin synthase (CHS) inhibitors. All the synthesized compounds have been screened for their CHS inhibition activity and antimicrobial activity in vitro. The enzymatic assay indicated that most of the compounds have good inhibitory activity against CHS, in which compound 6o with IC₅₀ of 0.10?mmol/L had stronger activity than that of polyoxins B, which acts as control drug with IC₅₀ of 0.18?mmol/L. As far as the antifungal activity is concerned, most of the compounds possessed moderate to excellent activity against some representative pathogenic fungi. Especially, compound 6b was found to be the most potent agent against Cryptococcus neoformans with minimal inhibitory concentration (MIC) of 4?μg/mL. Moreover, the results of antibacterial screening showed that these compounds have negligible actions to some tested bacteria. Therefore, these compounds would be promising to develop selective antifungal agents.     

Synthesis and biological evaluation of vinyl ether-containing azole derivatives as inhibitors of Trichophyton rubrum

In an attempt to search for many target compounds with excellent activities, a series of vinyl ether-containing azole derivatives were designed, synthesized, and evaluated as antifungal agents. Results of preliminary antifungal tests against Trichophyton rubrum in vitro indicated that most of the synthesized compounds showed excellent activities. In comparison with fluconazole, itraconazole, voriconazole, omoconazole and amphotericin B, several compounds (such as 7d, 7g and 7h) exhibited more potent inhibitory activities, suggesting that they were promising leads for the development of novel antifungal agents.     

Synthesis and Antifungal Activity of Curcumol Derivatives

To discover novel and effective antifungal candidates, a series of new curcumol derivatives were designed, synthesized, and evaluated their antifungal activity against five phytopathogenic fungi by the mycelium growth rate method. Derivatives c4 , c22 and c23 exhibited excellent antifungal activity against Phomopsis sp. with EC₅₀ values of 3.06, 3.07, and 3.16 μM, respectively. Specifically, compound c4 exhibited the strongest antifungal activity against Phomopsis sp., which was 44 times that of pyrimethanil (EC₅₀=134.37 μM). The results of scanning electron microscopy (SEM) and transmission electron microscopy (TEM) indicated that compound c4 could cause cell senescence and death of Phomopsis sp. by changing the normal hyphal morphology and disrupting the normal metabolism of hyphal cells. Moreover, compound c4 showed excellent curative effect against Phomopsis sp. on kiwifruit. These findings confirmed that compound c4 has great potential as a potent antifungal agent.     

Organometallic-based antibacterial and antifungal compounds: transition metal complexes of 1,1′-diacetylferrocene-derived thiocarbohydrazone,carbohydrazone, thiosemicarbazone and semicarbazone

Organometallic-based, 1,1′-diacetylferrocene-derived antibacterial and antifungal thiocarbohydrazone, carbohydrazone, thiosemicarbazone and semicarbazone have been prepared by condensing equimolar amount of 1,1′-diacetylferrocene with thiocarbohydrazide, carbohydrazide thiosemicarbazide and semicarbazide, respectively. These were used as ligands for the preparation of their cobalt (II), copper (II), nickel (II) and zinc (II) metal complexes. All the synthesized ligands and their complexes were characterized by IR, NMR, elemental analyses, molar conductances, magnetic moments and electronic spectral data. These synthesized compounds were screened for their antibacterial activity against Escherichia coli, Bacillus subtillis, Staphylococcus aureus, Pseudomonas aeruginosa and Salmonella typhi, and for antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani and Candida glaberata using the agar-well diffusion method. All the compounds showed good antibacterial and antifungal activity which increased on coordination with the metal ions thus, introducing a novel class of organometallic-based antibacterial and antifungal agents.     

Asymmetric total synthesis of 6-Tuliposide B and its biological activities against tulip pathogenic fungi

The structure-activity relationship was investigated to evaluate the antifungal activities of tuliposides and tulipalins against tulip pathogenic fungi. 6-Tuliposide B was effectively synthesized via the asymmetric Baylis-Hillman reaction. Tuliposides and tulipalins showed antifungal activities against most of the strains tested at high concentrations (2.5 mM), while Botrytis tulipae was resistant to tuliposides. Tulipalin formation was involved in the antifungal activity, tulipalin A showed higher inhibitory activity than 6-tuliposide B and tulipalin B. Both the tuliposides and tulipalins showed pigment-inducing activity against Gibberella zeae and inhibitory activity against Fusarium oxysporum f. sp tulipae. These activities were induced at a much lower concentration (0.05 mM) than the antifungal MIC values.     

Peptide dendrimers as antifungal agents and carriers for potential antifungal agent—N3‐(4‐methoxyfumaroyl)‐(S)‐2,3‐diaminopropanoic acid—synthesis and antimicrobial activity

A series of peptide dendrimers and their conjugates with antimicrobial agent FMDP (N³‐(4‐methoxyfumaroyl)‐(S)‐2,3‐diamino‐propanoic acid) were synthesized. The obtained compounds were tested for the antibacterial and antifungal activity. All novel dendrimers displayed much better activity against the tested strains than FMDP itself. Moreover, their conjugates with FMDP also exhibited antimicrobial activity. The most promising molecules were tested against a broad selection of fungal strains. The analysis of their antifungal properties indicates that the examined molecules are efficient growth inhibitors of fluconazole‐resistant hospital‐acquired strains. Moreover, an application of amphiphilic branched peptides such as FMDP carriers suggests that transport mechanism involves more likely the cell membrane perturbation than the mediation of the specific transport proteins. The activity of obtained compounds strongly depends on the specific structure of the molecule.     

Synthesis and antifungal activity of a novel series of 13-(4-isopropylbenzyl)berberine derivatives

By replacing the methyl group of 13-(4-isopropylbenzyl)berberine 2 with various acyl, alkyl, and benzyl groups via the demethylated intermediate, 13-(4-isopropylbenzyl)berberrubine 4, a novel series of 9-O-alkyl-13-(4-isopropylbenzyl)berberine derivatives was synthesized and examined for antifungal activities against various human pathogenic fungi. The introduction of various alkyl groups led to enhanced antifungal activity but that of acyl groups resulted in decrease of the activity. Among them, 9-O-butyl-13-(4-isopropylbenzyl)berberine 6d exhibited the most potent antifungal activities against Cryptococcus neoformans, Candida species (MIC=0.25-1 μg/ml), and Aspergillus species (MIC=2-4 μg/ml). The compound was found to be relatively safe up to 900 mg/kg in oral administration to mice.     

Recent advances in natural antifungal flavonoids and their derivatives

The resistance of pathogenic fungi and failure of drug therapy increased dramatically. Numerous studies have reported the individual or synergistic antifungal potency of natural and synthesized flavonoids, especially against drug-resistant fungi. This brief review summarizes the structure and individual or synergistic antifungal activity of natural and synthesized flavonoids (literatures mainly cover the past 10 years 2009–2019), with a special focus on the antifungal spectra, structure–activity relationship and mechanisms of actions. These may contribute to a better understanding of flavonoids as multi-target agents in the treatment of mycoses and provide some ideas on the development of novel flavonoids-based antifungals.