Click chemistry beyond metal-catalyzed cycloaddition as a remarkable tool for green chemical synthesis of antifungal medications.

Click chemistry is widely used for the efficient synthesis of 1,4-disubstituted-1,2,3-triazole, a well-known scaffold with widespread biological activity in the pharmaceutical sciences. In recent years, this magic ring has attracted the attention of scientists for its potential in designing and synthesizing new antifungal agents. Despite scientific and medical advances, fungal infections still account for more than 1.5 million deaths globally per year, especially in people with compromised immune function. This increasing trend is definitely related to a raise in the incidence of fungal infections and prevalence of antifungal drug resistance. In this condition, an urgent need for new alternative antifungals is undeniable. By focusing on the main aspects of reaction conditions in click chemistry, this review was conducted to classify antifungal 1,4-disubstituted-1,2,3-triazole hybrids based on their chemical structures and introduce the most effective triazole antifungal derivatives. It was notable that in all reactions studied, Cu(I) catalysts generated in situ by the reduction in Cu(II) salts or used copper(I) salts directly, as well as mixed solvents of t-BuOH/H2O and DMF/H2O had most application in the synthesis of triazole ring. The most effective antifungal activity was also observed in fluconazole analogs containing 1,2,3-triazole moiety and benzo-fused five/six-membered heterocyclic conjugates with a 1,2,3-triazole ring, even with better activity than fluconazole. The findings of structure-activity relationship and molecular docking of antifungal derivatives synthesized with copper-catalyzed azide-alkyne cycloaddition (CuAAC) could offer medicinal chemistry scientists valuable data on designing and synthesizing novel triazole antifungals with more potent biological activities in their future research.

Evaluation of Anti-Bacterial and Anti-Biofilm Activity of Native Probiotic Strains of Lactobacillus Extracts.

Background: Lactic acid bacteria produce various beneficial metabolites, including antimicrobial agents. Owing to the fast-rising antibiotic resistance among pathogenic microbes, scientists are exploring antimicrobials beyond antibiotics. In this study, we examined four Lactobacillus strains, namely L. plantarum 42, L. brevis 205, L. rhamnosus 239, and L. delbrueckii 263, isolated from healthy human microbiota, to evaluate their antibacterial and antifungal activity. Methods: Lactobacillus strains were cultivated, and the conditioned media were obtained. The supernatant was then used to treat pathogenic bacteria and applied to the growth media containing fungal and bacterial strains. Additionally, the supernatant was separated to achieve the organic and aqueous phases. The two phases were then examined in terms of bacterial and fungal growth rates. Disk diffusion and MIC tests were conducted to determine strains with the most growth inhibition potential. Finally, the potent strains identified through the MIC test were tested on the pathogenic microorganisms to assess their effects on the formation of pathogenic biofilms. Results: The organic phase of L. rhamnosus 239 extracts exhibited the highest antibacterial and antibiofilm effects, while that of L. brevis 205 demonstrated the most effective antifungal impact, with a MIC of 125 µg/mL against Saccharomyces cerevisiae. Conclusion: This study confirms the significant antimicrobial impacts of the lactic acid bacteria strains on pathogenic bacteria and fungi; hence, they could serve as a reliable alternative to antibiotics for a safe and natural protection against pathogenic microorganisms.

Synthesis and biological activity profile of novel triazole/quinoline hybrids.

Based on the significant and diverse pharmacophore features of triazole ring and considering the potent antimicrobial properties of quinoline scaffold, a novel series of 1,2,3-triazole-based polyaromatic compounds containing chloroquinoline moiety were synthesized through a well-established synthetic methodology, named click chemistry. The structure of the synthetic compounds was characterized by various spectroscopic methods. The final products of triazole/quinoline hybrids and ((prop-2-yn-1-yloxy)methyl)benzene intermediates were screened for their antibacterial (Staphylococcus aureus, Escherichia coli, Shigella flexneri, and Salmonella enterica), antifungal (Candida albicans, Saccharomyces cerevisiae, and Aspergillus fumigatus), and cytotoxic activities. The best antifungal compounds exhibited minimum inhibitory concentration (MIC), in the range of 0.35-0.63 µM, against S. cerevisiae without any cytotoxic effect. These compounds can be selected as the potential candidates for treating invasive fungal infections caused by S. cerevisiae, after further investigation. Preliminary in silico ADME studies also predicted the favorable pharmacokinetic attributes of most compounds.

Synthesis, antimycobacterial and anticancer activity of novel indole-based thiosemicarbazones.

Based on the structural elements of bioactive indole-based compounds, a series of novel 1-substituted indole-3-carboxaldehyde thiosemicarbazones were synthesized as potential antimycobacterial and anticancer agents. The derivatives were prepared via a two-step methodology including N-alkylation(benzylation) of indole-3-carboxaldehyde and conversion of the intermediate aldehydes to corresponding thiosemicarbazones. The derivatives were evaluated for their antimycobacterial activity and compounds 3d (R = propyl) and 3q (R = 4-nitrobenzyl) were among the most potent and selective derivatives with IC50 values of 0.9 and 1.9 µg/mL respectively. The anticancer activity of the derivatives was also assessed against a panel of tumor cell lines. Compounds 3t, 3u, 3v and 3w efficiently inhibited the majority of the cancer cell lines with considerable selectivity.

Design and Synthesis of New Antifungals Based on N-Un-substituted Azoles as 14α Demethylase Inhibitor.

OBJECTIVE: Azole antifungal agents, which are widely used as antifungal antibiotics, inhibit cytochrome P450 sterol 14α-demethylase (CYP51). Nearly all azole antifungal agents are Nsubstituted azoles. In addition, an azolylphenalkyl pharmacophore is uniquely shared by all azole antifungals. Due to the importance of nitrogen atom of azoles (N-3 of imidazole and N-4 of triazole) in coordination with heme in the binding site of the enzyme, here a group of N- un-substituted azoles in which both nitrogen are un-substituted was reported. MATERIALS AND METHODS: Designed compounds were synthesized by the reaction of imidazole-4- carboxaldehyde with appropriate arylamines and subsequently reduced to desired amine derivatives. Antifungal activity against Candida albicans and Saccharomyces cervisiae was done using a broth micro-dilution assay. Docking studies were done using AutoDock. RESULTS: Antimicrobial evaluation revealed that some of these compounds exhibited moderate antimicrobial activities against tested pathogenic fungi, wherein compounds 3, 7, and 8 were potent. Docking studies propose that all of the prepared azoles interacted with 14α-DM, wherein azoleheme coordination played the main role in drug-receptor interaction. CONCLUSION: Our results offer some useful references for molecular design performance or modification of this series of compounds as a lead compound to discover new and potent antimicrobial agents.

Molecular Characterization of a Fungus Producing Membrane Active Metabolite and Analysis of the Produced Secondary Metabolite

Background: The majority of studies on soil Aspergillus concern the isolation and characterization of the antimicrobial compounds produced by this organism. Our previous studies indicated an isolated Aspergillus strain soil to be of interest, and this subject is further investigated here. Methods: Soil samples of various locations in Iran were collected. Extract from Aspergillus sp. culture was obtained using ethyl acetate fractionation. Antimicrobial activity testing was performed using broth microdilution assay against Escherichia coli, Candida albicans, and Staphylococcus aureus microorganisms. One metabolite PA3-d10 was isolated from these active extracts and identified using thin layer chromatography, preparative thin-layer chromatography, HPLC, 1HNMR (proton nuclear magnetic resonance), 2D NMR, and LC-MS (liquid chromatography-mass spectrometry). Results: According to morphological and biochemical properties as well as ITS rDNA sequencing, we identified an isolate of Aspergillus flavus. The ethyl acetate fraction of the fermentation medium containing membrane active metabolites showed antimicrobial effects against different bacterial and yeast indicator strains. One metabolite from these active extracts was finally identified. Conclusion: Membrane active fraction produced by Aspergillus strain in this research demonstrated antimicrobial activities against bacteria and yeast strains. Therefore, this metabolite can be considered as a potential antimicrobial membrane active agent.

Synthesis and Antimicrobial Evaluation of 4H-Pyrans and Schiff Bases Fused 4H-Pyran Derivatives as Inhibitors of Mycobacterium bovis (BCG).

The focus of our study is the synthesis and biological activity evaluation of a series of 4H-Pyran compounds and schiff bases fused 4H-Pyran derivatives which are known to possess a wide variety of biological activities. In this paper at first a simple and efficient one-pot synthesis of 4H-Pyran s from the three-component reaction between malononitrile, aldehydes, and active methylene compounds in the presence of N-methylmorpholine (NMM) as catalyst at room temperature is reported, the reaction between these synthesized products and trimethylorthoformateor triethylorthoformateto produce schiff base compounds were also considered. The key advantages of synthesis of 4H-Pyran derivatives are short reaction time, high yield, and simple work-up. Then, these compounds were evaluated for anti-Mycobacterium activity against Mycobacterium bovis (Bacillus Calmette-Guerin). The preliminary results indicated that most of the tested compounds showed relatively good activity against the test organism. Moreover, antifungal activities of these compounds were evaluated. Finally, their effect was more noticeable on Mycobacterium bovis (BCG).

Synthesis and Biological Evaluation of Thiosemicarbazide Derivatives Endowed with High Activity toward Mycobacterium Bovis.

Thiosemicarbazides are potent intermediates for the synthesis of pharmaceutical and bioactive materials and thus, they are used extensively in the field of medicinal chemistry. The imine bond (-N=CH-) in this compounds are useful in organic synthesis, in particular for the preparation of heterocycles and non-natural ß-aminoacids. In this paper the synthesis of some new thiosemicarbazide derivatives by condensation reaction of various aldehydes or ketones with 4-phenylthiosemicarbazide or thiosemicarbazide is reported. This synthesis method has the advantages of high yields and good bioactivity. The structures of these compounds were confirmed by IR, mass, 1H NMR, 13C NMR, and single-crystal X-ray diffraction studies. All of these compounds were tested for their in-vitro anti-mycobacterial activity. The influence of the functional group and position of substituent on anti-bacterial activity of compounds is investigated too. The preliminary results indicated that all of the tested compounds showed good activity against the test organism. The compounds 11 and 30 showed the highest anti-tubercular activity (0.39 µg/mL). This synthesis method has the advantages of high yields and good bioactivity.

Synthesis of Novel Fluorene Bisamide Derivatives via Ugi Reaction and Evaluation their Biological Activity against Mycobacterium species.

A series of new fluorene bisamide derivatives were synthesized through multi-component Ugi reaction and tested for their in-vitro anti-mycobacterial activity. The structures of the products 5a-w were deduced from their IR, 1H NMR, and 13C NMR spectra. Elemental analyses (CHN) for novel compounds (5a, 5d, 5f, 5h, 5k, 5l, 5p, 5s, 5t, 5v, 5w) was done. These compounds were evaluated as anti-bacterial agents against Mycobacterium bovis and M. tuberculosis, while their activity expressed as the minimum inhibitory concentration (MIC) in µg/mL. Among the twenty-three synthesized compounds, 5a was found to be the most active compound in vitro with MIC of 1.95 µg/mL against Mycobactrium bovis and compound 5k showed greatest potency against sensitive and resistant strains of M.tuberculosis (H37Rv, IHMT149/09, HPV115/08, and HPV65/08).

Identification and Evaluation of Novel Drug Targets against the Human Fungal Pathogen Aspergillus fumigatus with Elaboration on the Possible Role of RNA-Binding Protein.

BACKGROUND: Aspergillus fumigatus is an airborne opportunistic fungal pathogen that can cause fatal infections in immunocompromised patients. Although the current anti-fungal therapies are relatively efficient, some issues such as drug toxicity, drug interactions, and the emergence of drug-resistant fungi have promoted the intense research toward finding the novel drug targets. METHODS: In search of new antifungal drug targets, we have used a bioinformatics approach to identify novel drug targets. We compared the whole proteome of this organism with yeast Saccharomyces cerevisiae to come up with 153 specific proteins. Further screening of these proteins revealed 50 potential molecular targets in A. fumigatus. Amongst them, RNA-binding protein (RBP) was selected for further examination. The aspergillus fumigatus RBP (AfuRBP), as a peptidylprolyl isomerase, was evaluated by homology modeling and bioinformatics tools. RBP-deficient mutant strains of A. fumigatus were generated and characterized. Furthermore, the susceptibility of these strains to known peptidylprolyl isomerase inhibitors was assessed. RESULTS: AfuRBP-deficient mutants demonstrated a normal growth phenotype. MIC assay results using inhibitors of peptidylprolyl isomerase confirmed a higher sensitivity of these mutants compared to the wild type. CONCLUSION: Our bioinformatics approach revealed a number of fungal-specific proteins that may be considered as new targets for drug discovery purposes. Peptidylprolyl isomerase, as a possible drug target, was evaluated against two potential inhibitors and the promising results were investigated mechanistically. Future studies would confirm the impact of such target on the antifungal discovery investigations.

Design, Synthesis and Anti-Tubercular Activity of Novel 1, 4-Dihydropyrine-3, 5-Dicarboxamide Containing 4(5)-Chloro-2-Ethyl- 5(4)-Imidazolyl Moiety.

Current researches have showed that N3, N5-diaryl-2, 6-dimethyl -1, 4-dihydropyrine-3, 5- dicarboxamide analogues demonstrate notable anti-tubercular activity. In this study, Hantzsch condensation was used to design and synthesize new analogues of dihydropyridine (DHP). Different diary carboxamides were inserted at positions 3 and 5 of the DHP ring. 4(5)-chloro-2-ethyl-5(4)-imidazolyl moiety was considered at position 4 of the DHP ring. The structures of prepared ligands were characterized using TLC followed by FT-IR, elemental analysis, Mass and proton NMR. Results of anti-tubercular activity have indicated all the prepared ligands 3a-f inhibit the mycobacterium tuberculosis growth and the most potent compounds were 3c (3,4-Cl) and 3b (4-Cl). The in-vitro obtained data are agreement with our computational predictions in terms of partial atomic charge of carbonyl moieties at the positions 3 and 5 of dihydropyridine ring and the logP of the molecules.

Design, Synthesis and Evaluation of Antitubercular Activity of Novel Dihydropyridine Containing Imidazolyl Substituent.

Recent studies have indicated that 1, 4-dihydropyridine-3, 5-dicarboxamide derivatives show significant anti-tubercular activity. In this research, new derivatives of 1, 4-dihydropyridine were designed and synthesized using Hantzsch condensation in which dicyclohexyl and different dicyclohexylcarbamoyl were substituted at C-3 and C-5 positions of the DHP ring. In addition, 4 (5)-chloro-2-methyl-5 (4)-imidazolyl moiety was substituted at C-4 position of DHP. The structure of synthetized compounds were characterized by TLC, IR, elemental analysis and proton NMR. Based on the in vitro screening data, all of the designed and synthetized compounds (3a-3g) showed a good ability to inhibit the mycobacterium tuberculosis growth in terms of MIC. Aromatic carboxamide containing compounds were more potent than cyclohexyl derivative and the most potent compound was 3a (4-nitrophenyl derivative). The experimental data are in agreement with our computational predictions in terms of partial atomic charge of carbonyl moieties at the C-3 and C-5 positions of DHP ring and partition coefficient of the molecules.

Synthesis and Antimycobacterial Activity of some Triazole Derivatives-New Route to Functionalized Triazolopyridazines.

A series of cyclic analogues of bioactive thiosemicarbazide derivatives have been synthesized as potential antimycobacterial agents. The 4-amino-1,2,4-triazole-5-thione analogues (Ia-f) were prepared by heating a mixture of thiocarbohydrzide and appropriate carboxylic acids. Reaction of thiocarbohydrazide with γ-ketoesters in the presence of sodium methoxide furnished triazolopyridazine derivatives IIa-b. Finally, condensation of 4-amino-1,2,4-triazole-5-thione with some aldehydes gave Schiff bases IIIa-e. After characterization by different spectroscopic and analytical methods, the derivatives were tested for their inhibitory activity against Mycobacterium bovis BCG. Among the derivatives, compound Ib proved to be the most potent derivatives with MIC value of 31.25 µg/mL. Given the fact that 4-amino-1,2,4-triazole-5-thiones Ia-f were the most active derivatives, it could be suggested that this group of derivatives have the potential to be considered as lead compounds for future optimization efforts.

Antimycobacterial evaluation of novel [4,5-dihydro-1H-pyrazole-1-carbonyl]pyridine derivatives synthesized by microwave-mediated Michael addition.

The focus of this study is the synthesis and biological activity evaluation of a series of dibenzalaceton derivatives (3a-3n) and novel [4,5-dihydro-1H-pyrazole-1-carbonyl]pyridine derivatives (5a-5g) against Mycobacterium bovis, Bacillus Calmette-Guerin (BCG). Dibenzalacetone derivatives were synthesized by benzaldehyde derivatives. The [4,5-dihydro-1H-pyrazole-1-carbonyl]pyridine derivatives were synthesized by Michael addition reaction and using green chemistry microwave-mediated method. All compounds were evaluated against BCG and the activity expressed as minimum inhibitory concentration (MIC) in µM. The result showed good activity for all the compounds especially compounds (3a), (3n), and (5a) illustrated high activity (7.03, 8.10 and 5.37 µM, respectively).

Synthesis and antimycobacterial activity of novel thiadiazolylhydrazones of 1-substituted indole-3-carboxaldehydes.

A series of novel thiocarbohydrazones of substituted indoles and their corresponding thiadiazole derivatives were prepared, and their structures were confirmed by different analytical and spectroscopic methods. The derivatives were prepared by a sequential synthetic strategy including substitution at N-1 position of indole ring by various aliphatic and benzylic substituents, followed by condensation with thiocarbohydrazide, and finally cyclization by triethyl orthoformate. The derivatives were tested for their antimycobacterial activity against Mycobacterium bovis BCG, and the results revealed that among the synthesized compounds, thiadiazole derivatives 4e, 4f, 4n, 4p, 4q, and 4t exhibited the highest activity with IC50 value of 3.91 µg/mL. The results indicate that the thiadiazole moiety plays a vital role in exerting antimycobacterial activity.

Synthesis and Antimycobacterial Activity of Symmetric Thiocarbohydrazone Derivatives against Mycobacterium bovis BCG.

In this work, we reported the synthesis and evaluation of antimycobacterial and antifungal activity of a series of thiocarbohydrazone derivatives which are thiacetazone congeners. The target compounds were synthesized in superior yields by reacting thiocarbohydrazide with different aromatic aldehydes and methyl ketones. Compounds 8, 19 and 25 were found to be the most potent derivatives, exhibiting acceptable activity against Mycobacterium bovis BCG compared to thiacetazone and ethambutol as reference substances. Compounds 8, 15 and 25 exhibited the highest activity against Candida albicans. The most active compounds had a completely different aromatic ring system with various electronic, steric and lipophilic natures. This is understandable in light of the fact that carbohydrazone derivatives must undergo a metabolic activation step before exerting their anti-TB activity and different SAR rules govern each one of these two processes.

Antifungal indole and pyrrolidine-2,4-Dione derivative peptidomimetic lead design based on in silico study of bioactive Peptide families.

BACKGROUND: The rise of opportunistic fungal infections highlights the need for development of new antimicrobial agents. Antimicrobial Peptides (AMPs) and Antifungal Peptides (AFPs) are among the agents with minimal resistance being developed against them, therefore they can be used as structural templates for design of new antimicrobial agents. METHODS: In the present study four antifungal peptidomimetic structures named C1 to C4 were designed based on plant defensin of Pisum sativum. Minimum inhibitory concentrations (MICs) for these structures were determined against Aspergillus niger N402, Candida albicans ATCC 10231, and Saccharomyces cerevisiae PTCC 5052. RESULTS: C1 and C2 showed more potent antifungal activity against these fungal strains compared to C3 and C4. The structure C2 demonstrated a potent antifungal activity among them and could be used as a template for future study on antifungal peptidomemetics design. Sequences alignments led to identifying antifungal decapeptide (KTCENLADTY) named KTC-Y, which its MIC was determined on fungal protoplast showing 25 (µg/ml) against Aspergillus fumigatus Af293. CONCLUSION: The present approach to reach the antifungal molecules seems to be a powerful approach in design of bioactive agents based on AMP mimetic identification.

One pot synthesis and biological activity evaluation of novel Schiff bases derived from 2-hydrazinyl-1,3,4-thiadiazole.

Considering the structural features of a group of known potent inhibitors of human platelet aggregation containing hydrazone structural backbone, a series of novel hydrazone derivatives of 2-hydrazinyl-1,3,4-thiadiazole were synthesized using a one-pot process and tested for their inhibitory activity against platelet aggregation induced by arachidonic acid and ADP. Among the derivatives, compounds 3l, 3o and 3p exhibited the highest antiplatelet aggregation activity. The derivatives were also screened for their potential antimycobacterial activity and compounds 3g, 3k, 3p and 3q were among the most active compounds.

Synthesis and biological evaluation of coumarin derivatives as inhibitors of Mycobacterium bovis (BCG).

The coumarin compounds are an important class of biologically active molecules, which have attractive caught the attention of many organic and medicinal chemists, due to potential pharmaceutical implications and industrial applications. We herein report the one-pot procedure for the efficient synthesis of coumarin derivatives using commercially available substrates via isocyanide-based multicomponent condensation reactions. These compounds were evaluated for anti-mycobacterium activity against Mycobacterium bovis (Bacillus Calmette-Guerin). The preliminary results indicated that all of the tested compounds showed relatively good activity against the test organism. The compounds 7e, 7l, and 7m showed high anti-tuberculosis activity.

Synthesis and biological evaluation of propargyl acetate derivatives as anti-mycobacterial agents.

BACKGROUND: The emergence of multidrug-resistant strains of Mycobacterium tuberculosis (Mtb) has intensified efforts to discover novel drugs for tuberculosis (TB) treatment. Targeting the persistent state of Mtb, a condition in which Mtb is resistant to conventional drug therapies, is of particular interest. METHODS: This study is focused on propargyl acetate derivatives. Eight molecules were designed based on propargyl alcohols and different acid anhydrides. RESULTS: All the synthesized compounds and commercially available ones were evaluated for anti-tuberculosis activity. CONCLUSIONS: Inhibitors against Mtb have been identified and characterized for further development into potential novel anti-tubercular drugs.