14α-demethylase Inhibitors Research Articles

Sensitivity Analysis of Pyrenophora tritici-repentis to Quinone-Outside Inhibitor and 14α-Demethylase Inhibitor Fungicides in Latvia

Tan spot caused by Pyrenophora tritici-repentis is a severe threat to wheat production in all major wheat-growing regions. Sustainable tan spot control can be achieved by an integrated approach, including responsible management of fungicide sprays. The data about the sensitivity of P. tritici-repentis to various fungicides in the Baltic Sea region are rare. In this study, we described the variation of P. tritici-repentis sensitivity to four fungicide active ingredients to detect the formation of resistance to the most commonly used quinone-outside inhibitor (QoI) and 14α-demethylase inhibitor (DMI) fungicides in the pathogen’s population in Latvia. The effect of prothioconazole, mefentrifluconazole, pyraclostrobin, and azoxystrobin on 93 P. tritici-repentis strains from various hosts was tested in vitro by assessing mycelium linear growth inhibition at three different active ingredient concentrations (0 0.01, 0.1 and 0.5 mg L−1). Pathogen sensitivity significantly (p < 0.001) varied between the fungicide active ingredients and strains. The prothioconazole (concentration 0.5 mg L−1) had the most significant effect, with a median mycelial growth inhibition of 70.34%, followed by pyraclostrobin (47.02%), azoxystrobin (24.24%), and mefentrifluconazole (11.11%). Mutation G143A was detected in cytb gene sequences and confirmed the resistance formation in Latvia’s P. tritici-repentis population, while F129L and G137R mutations were absent. This study provided insight into P. tritici-repentis population’s sensitivity to active ingredients of DMI and OoI fungicide groups, helping to fill the knowledge gap about the pathogen fungicide sensitivity in this region.

Design, Synthesis, Investigation, and Biological Activity Assessments of (4-Substituted-Phenyl)-N-(3-morpholinopropyl)-3-phenylthiazol-2(3H)-imine Derivatives as Antifungal Agents.

In this study, a series of novel thiazol-2(3H)-imine (2a-2j) were designed, synthesized, and characterized by means of 1H NMR, 13C NMR, and HRMS spectral analyses. In vitro antifungal activity was performed using a modified EUCAST protocol. Two of the synthesized compounds (2d and 2e) showed activity against Candida albicans and Candida parapsilosis. Compound 2e showed activity against C. parapsilosis (MIC50 = 1.23 μg/mL) for 48 h. This value is very similar to ketoconazole. The dynamic analysis of the potential compounds 2d and 2e revealed notable stability while interacting with the 14α-demethylase enzyme substrate. The absorption, distribution, metabolism, and excretion (ADME) studies of the candidate compound showed acceptable ADME parameter data and verified their drug-likeness characteristics. According to the results of this study, compound 4-(4-fluorophenyl)-N-(3-morpholinopropyl)-3-phenylthiazol-2(3H)-imine (2e) and its derivatives as 14α-demethylase inhibitors can be used as a new antifungal for further structural improvements and additional research.

Novel Pyrido[4,3-d]pyrimidine Derivatives as Potential Sterol 14α-Demethylase Inhibitors: Design, Synthesis, Inhibitory Activity, and Molecular Modeling.

Thirty-four new pyrido[4,3-d]pyrimidine analogs were designed, synthesized, and characterized. The crystal structures for compounds 2c and 4f were measured by means of X-ray diffraction of single crystals. The bioassay results showed that most target compounds exhibited good fungicidal activities against Pyricularia oryzae, Rhizoctonia cerealis, Sclerotinia sclerotiorum, Botrytis cinerea, and Penicillium italicum at 16 μg/mL. Compounds 2l, 2m, 4f, and 4g possessed better fungicidal activities than the commercial fungicide epoxiconazole against B. cinerea. Their half maximal effective concentration (EC50) values were 0.191, 0.487, 0.369, 0.586, and 0.670 μg/mL, respectively. Furthermore, the inhibitory activities of the bioactive compounds were determined against sterol 14α-demethylase (CYP51). The results displayed that they had prominent activities. Compounds 2l, 2m, 4f, and 4g also showed better inhibitory activities than epoxiconazole against CYP51. Their half maximal inhibitory concentration (IC50) values were 0.219, 0.602, 0.422, 0.726, and 0.802 μg/mL, respectively. The results of molecular dynamics (MD) simulations exhibited that compounds 2l and 4f possessed a stronger affinity to CYP51 than epoxiconazole.

Design, Synthesis, Bioactive Evaluation, and Molecular Dynamics Simulation of Novel 4H-Pyrano[3,2-c]pyridine Analogues as Potential Sterol 14α-Demethylase (CYP51) Inhibitors.

To discover potential sterol 14α-demethylase (CYP51) inhibitors, thirty-four unreported 4H-pyrano[3,2-c]pyridine derivatives were designed and synthesized. The assay results indicated that most compounds displayed significant fungicidal activity against Sclerotinia sclerotiorum, Colletotrichum lagenarium, Botrytis cinerea, Penicillium digitatum, and Fusarium oxysporum at 16 μg/mL. The half maximal effective concentration (EC50) values of compounds 7a, 7b, and 7f against B. cinerea were 0.326, 0.530, and 0.610, respectively. Namely, they had better antifungal activity than epoxiconazole (EC50 = 0.670 μg/mL). Meanwhile, their half maximal inhibitory concentration (IC50) values against CYP51 were 0.377, 0.611, and 0.748 μg/mL, respectively, representing that they also possessed better inhibitory activities than epoxiconazole (IC50 = 0.802 μg/mL). The fluorescent quenching tests of proteins showed that 7a and 7b had similar quenching patterns to epoxiconazole. The molecular dynamics simulations indicated that the binding free energy of 7a and epoxiconazole to CYP51 was -35.4 and -27.6 kcal/mol, respectively.

Molecular Docking as a Method to Identify Prospective Compounds from Ocimum sanctum with Anti-Candidal Properties

Background:: To search for antifungal bioactive molecules from Ocimum sanctum, we used a molecular docking approach to identify the natural compound responsible for the property with a specific target. Our goal is to identify the potential antifungal compounds based on computational screening from reported chemical constituents of Tulsi as potential inhibitors of 14α- demethylase. Method:: Molecular docking was performed using Molergo Virtual docker software and validated based on the Root Mean Square Deviation (RMSD) value. Result:: The compounds were docked to the pocket of the enzyme, and the docking results depicted that only oxygenated compounds were important for an antifungal profile with a good docking score and interaction with the enzyme molecule. Conclusion:: The results suggest the availability of significant compounds with high potential for antifungal properties from O. sanctum. This suggests isolating these compounds for further lead identification to develop new antifungal compounds with specific targets.

Molecular Mechanisms and Biological Characteristics of Botrytis cinerea Field Isolate Resistance to Pyrisoxazole in Liaoning Province.

Botrytis cinerea is a broad-host-range necrotrophic phytopathogen responsible for serious diseases in leading crops worldwide. The novel sterol 14α-demethylase inhibitor (DMI) pyrisoxazole was recently registered for the control of tomato gray mold caused by B. cinerea in China. One hundred fifty-seven isolates of B. cinerea were collected from tomato greenhouses in 14 cities of Liaoning Province from 2016 to 2021 and examined for sensitivity to pyrisoxazole, with a mean EC50 value of 0.151 μg/ml. Three highly resistant isolates, XD-5, DG-4, and GQ-3, were screened, and the EC50 values were 0.734, 0.606, and 0.639 μg/ml with corresponding resistance factors of 12.88, 10.63, and 11.21, respectively. Compared with field-sensitive strains, the highly resistant isolate XD-5 exhibited fitness defects in traits, including mycelial growth, conidial production, and pathogenicity, but DG-4 and GQ-3 did not experience fitness costs. Positive cross-resistance was observed only between pyrisoxazole and the DMIs tebuconazole and prochloraz but not between pyrisoxazole and the non-DMIs iprodione, procymidone, pyrimethanil, fludioxonil, fluazinam, and fluopyram. Sequence alignment of the CYP51 gene indicated that three point mutations were observed in the highly resistant mutant, namely, V24I in XD-5, G461S in GQ-3, and R464K in DG-4. When exposed to pyrisoxazole, the induced expression levels of the ABC transporter AtrD and MFS transporter Mfs1 increased in the resistant isolates compared with those in the sensitive isolates, whereas the expression level of the CYP51 gene did not change significantly. Molecular docking suggested that the G461S and R464K mutations both led to a decrease in the binding energy between CYP51 and pyrisoxazole, whereas no change was found with the V24I mutation. Thus, two point mutations in the CYP51 protein combined with induced expression of the Mfs1 and AtrD genes appeared to mediate the pyrisoxazole resistance of the highly resistant mutants DG-4 and GQ-3, while the overexpression of the Mfs1 and AtrD genes was responsible for the highly resistant mutant XD-5.

Synthesis, antifungal, antibacterial activity, and computational evaluations of some novel coumarin-1,2,4-triazole hybrid compounds

Effective plant pathogen control presents an important challenge. Pesticide resistance and associated health and environmental problems demonstrate the need for novel, safe active ingredients for plant protection. Since both coumarins and 1,2,4-triazoles show pesticidal activity, in this study, we evaluated the antimicrobial activity of coumarin-1,2,4-triazole hybrids against plant pathogenic fungi (Fusarium oxysporum, Fusarium culmorum, Macrophomina phaseolina and Sclerotinia sclerotiorum), bacterial plant pathogens (Pseudomonas syringae and Rhodococcus fascians), and beneficial bacteria (Bacillus mycoides and Bradyrhizobium japonicum). Coumarin-1,2,4-triazoles inhibited the growth of S. sclerotiorum and F. oxysporum, while no antibacterial effect on either pathogens or soil-beneficial bacteria was observed. A quantitative structure–activity relationship models for antifungal activities on S. sclerotiorum and F. oxysporum, developed using Dragon descriptors, can explain 79% and 77% of the compounds inhibitory activity, respectively. According to molecular docking, title compounds are potential sterol 14α-demethylase inhibitors, with 7-((5-mercapto-4-(p-tolyl)-4H-1,2,4-triazol-3-yl)methoxy)-4-methyl-2H-chromen-2-one as the promising candidate for further research in plant protection.

Controlling antifungal activity with light: Optical regulation of fungal ergosterol biosynthetic pathway with photo-responsive CYP51 inhibitors.

Invasive fungal infections (IFIs) have been associated with high mortality, highlighting the urgent need for developing novel antifungal strategies. Herein the first light-responsive antifungal agents were designed by optical control of fungal ergosterol biosynthesis pathway with photocaged triazole lanosterol 14α-demethylase (CYP51) inhibitors. The photocaged triazoles completely shielded the CYP51 inhibition. The content of ergosterol in fungi before photoactivation and after photoactivation was 4.4% and 83.7%, respectively. Importantly, the shielded antifungal activity (MIC80≥64μg/mL) could be efficiently recovered (MIC80=0.5-8μg/mL) by light irradiation. The new chemical tools enable optical control of fungal growth arrest, morphological conversion and biofilm formation. The ability for high-precision antifungal treatment was validated by invivo models. The light-activated compound A1 was comparable to fluconazole in prolonging survival in Galleria mellonella larvae with a median survival of 14 days and reducing fungal burden in the mouse skin infection model. Overall, this study paves the way for precise regulation of antifungal therapy with improved efficacy and safety.

In silico and in vitro evaluation of designed fluconazole analogues as lanosterol 14α-demethylase inhibitors

The drugs fighting against aggressive fungal infections are in limited number, therefore, extensive research is obligatory to develop new therapeutic strategies. Fluconazole (FLZ) is a clinically approved drug, but resistant drug against most fungal pathogens, thus it is vital to identify more compounds that can better check the fungal growth. Analogue-based drug designing is a quick and economical way since it has inherent drug-like properties of marketed drugs. This study aims to generate and evaluate analogues of FLZ with better potency against fungal-borne infections. A total of 3307 analogues of FLZ were developed from six scaffold structures. Only 390 compounds passed Lipinski’s rule, of which 247 analogues exhibited lower docking scores than FLZ with 5FSA. These inhibitors were further subjected to pharmacokinetics property evaluation and cytotoxicity test and it was found that only 46 analogues were suitable for further evaluation. Based on the molecular docking score of the best two analogues, 6f (−12.7 kcal/mol) and 8f (−12.8 kcal/mol) were selected for molecular dynamics and in-vitro studies. Antifungal activities of both compounds against 4 strains of Candida albicans were evaluated by disc diffusion assay and micro broth dilution assay and Minimum inhibitory concentrations (MICs) for 6f and 8f were observed as 256 µg/ml against 4719, 4918 and 5480 strains but the MIC was extended to 512 µg/ml for strain 3719. Both analogues exhibited low antifungal activities as compared to FLZ (8–16 µg/ml). The interaction of 6f with Mycostatin was also performed using a chequerboard assay that was found additive. Communicated by Ramaswamy H. Sarma

New pyrrole derivatives as DNA gyrase and 14α-demethylase inhibitors: Design, synthesis, antimicrobial evaluation, and molecular docking.

An efficient one-pot reaction utilizing readily available chemical reagents was used to prepare novel 2-amino-1,5-diaryl-1H-pyrrole-3-carbonitrile derivatives and the structures of these compounds were validated by spectroscopic data and elemental analyses. All the synthetic compounds were evaluated for their antimicrobial activities (MZI assay). The tested compounds proved high activities on Staphylococcus aureus (Gram-positive bacteria) and Candida albicans (Pathogenic fungi). However, they did not show any activity on Escherichia coli (Gram-negative bacteria). The most effective compounds in MZI assay 7c, 9a, 9b, 11a, and 11b were selected to determine their MIC on S. aureus and C. albicans. Furthermore, DNA gyrase and 14-α demethylase inhibitory assays were performed to study the inhibitory activities of 7c, 9a, 9b, 11a, and 11b. The results illustrated that compound 9b was the most DNA gyrase inhibitor (IC50 of 0.0236 ± 0.45 µM, which was 1.3- fold higher than gentamicin reference IC50 values of 0.0323 ± 0.81 µM). In addition, compound 9b demonstrated the highest 14-α demethylase inhibitory effect with IC50 of 0.0013 ± 0.02 µM, compared to ketoconazole (IC50 of 0.0008 ± 0.03 µM) and fluconazole (IC50 of 0.00073 ± 0.01 µM), as antifungal reference drugs. Lastly, docking studies were performed to rationalize the dual inhibitory activities of the highly active compounds on both DNA gyrase and 14-α demethylase enzymes.

Targeted deletion of three CYP51s in Fusarium fujikuroi and their different roles in determining sensitivity to 14α-demethylase inhibitor fungicides.

Fusarium fujikuroi is the pathogenic agent of rice bakanae disease and has developed serious resistance to prochloraz, a 14α-demethylase inhibitor (DMI). Prochloraz resistance in F. fujikuroi is caused by cooperation between FfCyp51B with Cyp51A and shows cross-resistance only to prothioconazole but not to tebuconazole, difenoconazole, propiconazole, metconazole, hexaconazole, and triadimefon. This study aimed to analyze the functions of the three Cyp51s in F. fujikuroi, especially their role in determining sensitivity to DMIs. The respective deletion of FfCyp51A, Cyp51B, and Cyp51C had no obvious effect on morphology, conidium germination, or pathogenicity. The involvement of growth, growth and ergosterol biosynthesis, and conidium production and ergosterol biosynthesis was observed for FfCyp51A, Cyp51B, and Cyp51C, respectively. Compared with the sensitive isolate of F. fujikuroi, the effect on sensitivity to the tested DMIs was divided into four groups: (i) both of Cyp51A and Cyp51B positively regulate the sensitivity to prochloraz and prothioconazole; (ii) Cyp51B positively regulate the sensitivity to tebuconazole and metconazole, but negatively regulate the sensitivity to difenoconazole; (iii) Cyp51A and Cyp51B play opposite roles in the sensitivity to triadimefon. Therefore, deletion of Cyp51A in F. fujikuroi confers a higher sensitivity to triadimefon, while deletion of Cyp51B results in a triadimefon-resistant mutant isolate; (iv) deletion of Cyp51B yielded a mutant isolate that was more resistant to propiconazole and hexaconazole. Sophisticated interactions exist within the three Cyp51 genes to DMIs fungicides sensitivity in F. fujikuroi, and Cyp51B probably plays a more critical role than Cyp51A and Cyp51C. © 2022 Society of Chemical Industry.

Azole fungicide sensitivity and molecular mechanisms of reduced sensitivity in Irish Pyrenopeziza brassicae populations.

Light leaf spot, caused by Pyrenopeziza brassicae, is amongst the most damaging diseases of winter oilseed rape (Brassica napus), and currently the sterol 14α-demethylase (CYP51) inhibitors (azoles) represent the main class of fungicides used to control light leaf spot development. However, a shift in sensitivity to azole fungicides in P. brassicae populations has been observed in different European countries, including Ireland. To assess the sensitivity status of Irish P. brassicae populations to azole fungicides, three collections of P. brassicae from 2018-2020 were tested in vitro against tebuconazole and prothioconazole-desthio, and the PbCYP51 gene targeted by this class of fungicides was genotyped in different isolates. A change in sensitivity to azole fungicides was observed and differences in sensitivity to tebuconazole between Irish populations were present. There were two substitutions within PbCYP51 (G460S and S508T) and inserts of different sizes in its promoter region. The presence of the G460S/S508T double mutant was reported for the first time, and the diversity in insert size was greater than previously known. Compared to wild type isolates, those carrying G460S or S508T were less sensitive to both fungicides and, where inserts were also identified, they further reduced sensitivity to azole fungicides. The results of this study suggest that azole fungicides are still very effective in controlling light leaf spot in Ireland. However, using azole fungicides in mixtures of fungicides with different modes of action is recommended. © 2022 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Phenylhydrazone linked 1,2,3-triazole hybrids: synthesis, antimicrobial evaluation and docking studies as dual inhibitors of DNA gyrase and lanosterol 14-α demethylase

Phenylhydrazone linked 1,2,3-triazole hybrids: synthesis, antimicrobial evaluation and docking studies as dual inhibitors of DNA gyrase and lanosterol 14-α demethylase

Discovery of inhibitors against SARS-CoV-2 associated fungal coinfections via virtual screening, ADMET evaluation, PASS, molecular docking, dynamics and pharmacophore studies

The black fungus is a SARS-CoV-2-associated fungal co-infection. Mechanisms by which antifungal drugs act against Mucormycosis are by inhibition of enzymes implicated in ergosterol biosynthesis or cell wall formation or the drug interaction directly with ergosterol. Since it has been shown that the reduction of ergosterol biosynthesis prevents this infection, we carried out a virtual screening with molecular docking analysis and tested a dataset of 880 molecules for its effects on an enzyme involved in ergosterol biosynthesis (CYP51) and fungal infection (lipase), as well as ADMET and toxicity properties of the studied molecules. We calculated the stability of the complex’s inhibitor-enzyme throughout the time using molecular dynamics simulations. From this, initial screening indicated that 600 out of a total of 880 compounds have a good affinity towards sterol 14α-demethylase. The two compounds ZINC95486139 and ZINC33833639 were determined as safe and have good drug-likeness properties, and have binding energies of −75.07 and −83.89 kcal/mol, respectively by MMGBSA and create strong and stable interactions with the residues of the active site of the enzyme. To the best of our knowledge, ZINC95486139 and ZINC33833639 have not yet been described in the literature as anti-sterol 14α-demethylase inhibitors or evaluated for their anti-fungal activity.

Sterol profiling of Leishmania parasites using a new HPLC-tandem mass spectrometry-based method and antifungal azoles as chemical probes reveals a key intermediate sterol that supports a branched ergosterol biosynthetic pathway

Human leishmaniasis is an infectious disease caused by Leishmania protozoan parasites. Current chemotherapeutic options against the deadly disease have significant limitations. The ergosterol biosynthetic pathway has been identified as a drug target in Leishmania. However, remarkable differences in the efficacy of antifungal azoles that inhibit ergosterol biosynthesis have been reported for the treatment of leishmaniasis. To better understand the sterol biosynthetic pathway in Leishmania and elucidate the mechanism underlying the differential efficacy of antifungal azoles, we developed a new LC-MS/MS method to study sterol profiles in promastigotes of three Leishmania species, including two L. donovani, one L. major and one L. tarentolae strains. A combination of distinct precursor ion masses and LC retention times allowed for specific detection of sixteen intermediate sterols between lanosterol and ergosterol using the newly developed LC-MS/MS method. Although both posaconazole and fluconazole are known inhibitors of fungal lanosterol 14α-demethylase (CYP51), only posaconazole led to a substantial accumulation of lanosterol in azole-treated L. donovani promastigotes. Furthermore, a key intermediate sterol accumulated by 40- and 7-fold when these parasites were treated with posaconazole and fluconazole, respectively, which was determined as 4α,14α-dimethylzymosterol by high resolution mass spectrometry and NMR spectroscopy. The identification of 4α,14α-dimethylzymosterol supports a branched ergosterol biosynthetic pathway in Leishmania, where lanosterol C4- and C14-demethylation reactions occur in parallel rather than sequentially. Our results suggest that selective inhibition of leishmanial CYP51 is insufficient to effectively prevent parasite growth and dual inhibitors of both CYP51 and the unknown sterol C4-demethylase may be required for optimal antiparasitic effect.

Prediction of novel and potent inhibitors of lanosterol 14-α demethylase

Lanosterol 14-α demethylase (LDM) is one of the promising drug targets of azoles antifungal. In this study, we have screened a large number of small molecules from different chemical databases (ZINC, DrugBank, ChEMBL, and ChemDiv) to find out novel and potential inhibitors of LDM. As a result, from more than a hundred thousand molecules, the two best candidates, C1 (ZINC000299817826) and C3 (ZINC000095786149), were selected from the top-scoring compounds and further validated in Molecular Dynamic (MD) simulation. The Glide scores of C1 and C3 were −19.33 kcal/mol and −19.13 kcal/mol, suggesting that these compounds bind with LDM with higher binding affinity than the benchmark compound (itraconazole), which has a Glide score of −6.85 kcal/mol. Docking poses reveal that the compounds C1 and C3 bind to the outermost region of the LDM binding site, which can prevent the lanosterol from getting into the catalytic pocket. Furthermore, MD simulation studies were performed to assess the stability of C1 and C3 in complex with LDM and were found to be stable over the 100 nanosecond simulation time. Binding free energy calculated by the MMPBSA method suggested that the C3 forms a more stable complex with the LDM as close to the benchmark compounds. Among the top selected molecules, C1 and C3 were predicted to be the significant inhibitors of LDM. Communicated by Ramaswamy H. Sarma

Bioactivity of mefentrifluconazole against different Fusarium spp.

Emergence and development of resistance to 14α-demethylase inhibitors (DMIs) have become a critical issue in both agriculture and medical fields. Mefentrifluconazole, the first isopropanol triazole fungicide belonging to a new subclass of DMIs, has been proposed to show high activity, minimal adverse side effects, and inconsistent cross resistance with other DMIs due to its high structural flexibility. In this study, mefentrifluconazole showed disparate inhibitory activity against the mycelium growth of seven tested Fusarium species. The most sensitive species included F. oxysporum, F. proliferatum, F. commuae, and F. fujikuroi, followed by F. equiseti and F. graminearum, while F. solani was most insensitive. Consistently, mefentrifluconazole presented the strongest inhibiting effects on conidium germination, cell membrane integrity, and ergosterol biosynthesis in F. fujikuroi, followed by F. graminearum, while F. solani ranked last. Further results indicated that all F. fujikuroi isolates causing rice bakanae disease (RBD) were sensitive to mefentrifluconazole regardless of their resistance to prochloraz, tebuconazole, carbendazim, and phenamacril. Additionally, the inoculation tests found that mefentrifluconazole presented a better protective efficacy on rice seedlings when applied 12 h before the F. fujikuroi inoculation, compared to applied 12 h post the inoculation. Overall, this study demonstrated the various bioactivity of mefentrifluconazole combating Fusarium spp. and put new insights into RBD management as well as the applications of DMIs.

Development of fluorinated nicotinonitriles and fused candidates as antimicrobial, antibiofilm, and enzyme inhibitors.

The antimicrobial assessments of two new series of nicotinonitriles and pyrido[2,3-d]pyrimidines were performed using amoxicillin and nystatin as reference standards. Outstanding antifungal activities were achieved by some target compounds; for instance, compounds 7 and 9 displayed a minimal inhibitory concentration (MIC) value of 1.95 µg/ml toward Candida albicans, compound 11 showed a potent anti-Rhizopus effect (MIC 1.95 µg/ml) and compound 14 elicited remarkable antifungal effects against both Aspergillis niger and C. albicans (MIC 1.95 µg/ml). However, pyrido[2,3-d]pyrimidines 12, 14, and 16 showed moderate antibacterial activities against some gram-negative bacteria. The antibiofilm results of these compounds against resistant strains of Proteus mirabilis were better than those of Pseudomonas aeruginosa. Docking studies of these hits at the DNA gyrase active site revealed affinity and docking scores comparable to that of the reference standards. Gyrase-inhibitory activities revealed that 14 (IC50 = 0.31 µM) is the most potent hit as DNA gyrase A inhibitor; it exhibited 1.66-fold the activity of ciprofloxacin (IC50 = 0.50 µM) and it was a 44.3 times more potent gyrase B inhibitor (IC50 = 0.04 µM) than novobiocin (IC50 = 1.77 µM). Regarding its antifungal activity, it displayed 0.78% of the fluconazole activity as a 14α-demethylase inhibitor. The cytotoxicity of 12, 14, and 16 on human diploid lung fibroblasts (WI38 cells) ensured their safety. Moreover, they are orally bioavailable with no permeation of the blood-brain barrier.

Mode of action and efficacy of quinolinic acid for the control of Ceratocystis fimbriata on sweet potato.

Ceratocystis fimbriata is a hazardous fungal pathogen able to cause black rot disease on sweet potato. The management of C. fimbriata strongly relies on the use of toxic fungicides, and there is a lack of efficient alternative strategies. The antifungal properties of quinolinic acid (QA) were studied for the first time, indicating that QA shows selective antifungal activity against C. fimbriata. QA inhibited completely the mycelial growth of C. fimbriata at less than 0.8mg mL-1 concentration (pH4), and was able to produce alterations in the fungal cell wall, and to impede spore agglutination and mycelium formation. QA significantly reduced the concentration of ergosterol, and was able to associate to iron (II), suggesting that QA may be a lanosterol 14-α demethylase inhibitor. In preventive applications, QA reduced the disease incidence of C. fimbriata on sweet potato by 75%, achieving higher control efficacy in comparison with commercial fungicides prochloraz and carbendazim. The first selective antifungal agent against C. fimbriata was discovered in this work, and showed suitable antifungal properties for the management of black rot disease. © 2021 Society of Chemical Industry.

CDATA[Recent Advances in the Development of 1,2,3-Triazole-containing Derivatives as Potential Antifungal Agents and Inhibitors of Lanoster ol 14α-Demethylase.

1,2,3-Triazole, a five-membered heterocyclic nucleus, is widely recognized as a key chromophore of great value in medicinal chemistry for delivering compounds possessing innumerable biological activities, including antimicrobial, antitubercular, antidiabetic, antiviral, antitumor, antioxidants, and anti-inflammatory activities. Mainly, in the past years, diverse conjugates carrying this biologically valuable core have been reported due to their attractive fungicidal potential and potent effects on various infective targets. Hence, hybridization of 1,2,3-triazole with other antimicrobial pharmacophores appears to be a judicious strategy to develop new effective anti-fungal candidates to combat the emergence of drug-sensitive and drug-resistant infectious diseases. Thus, the current review highlights the recent advances of this promising category of 1,2,3-triazole-containing hybrids incorporating diverse varieties of bioactive heterocycles such as conozole, coumarin, imidazole, benzimidazole, pyrazole, indole, oxindole, chromene, pyrane, quinazoline, chalcone, isoflavone, carbohydrates, and amides. It underlies their inhibition behavior against a wide array of infectious fungal species during 2015-2020.