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The prevalence of invasive fungal infections has been dramatically increased as the size of the immunocompromised population worldwide has grown. Aspergillus fumigatus is characterized as one of the most widespread and ubiquitous fungal pathogens. Among antifungal drugs, azoles have been the most widely used category for the treatment of fungal inf...
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... to the absence of a crystal structure of Aspergillus fumigatus CYP51A enzyme, a ligand-based pharmacophore model was generated based on the common features of commercially available active compounds against the tested fungus. Particularly, the training set of 22 active compounds was comprised of five commercially available antifungal drugs from the drug class of azoles (clotrimazole, ketoconazole, oxiconazole, fluconazole, and voriconazole) and 17 active compounds against the tested fungus (1.0 nmol•mL −1 < MIC < 305 nmol•mL −1 ), bearing characteristic imidazole and triazole rings (Figure 2, Figure S1, and Table S1 see Supplementary Materials). According to this set, the common chemical features of the compounds were identified, and the pharmacophore model was created. ...
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... to the absence of a crystal structure of Aspergillus fumigatus CYP51A enzyme, a ligand-based pharmacophore model was generated based on the common features of commercially available active compounds against the tested fungus. Particularly, the training set of 22 active compounds was comprised of five commercially available antifungal drugs from the drug class of azoles (clotrimazole, ketoconazole, oxiconazole, fluconazole, and voriconazole) and 17 active compounds against the tested fungus (1.0 nmol·mL −1 < MIC < 305 nmol·mL −1 ), bearing characteristic imidazole and triazole rings (Figure 2, Figure S1, and Table S1 see Supplementary Materials). According to this set, the common chemical features of the compounds were identified, and the pharmacophore model was created. ...
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... Figure S3 (see Supplementary Materials) the pharmacophore-fit of the selected compounds on the features of the optimum model is depicted. Additionally, the docking analysis suggested that the selected compounds may coordinate the heme metal ion as in the case of azoles binding (Figures 8-10). Specifically, compounds 1 ( Figure 7) and 7 (Figure 8) develop π-π stacking with the aromatic rings of Tyr107 and Tyr121, as in the case of R-econazole ( Figure 9) and both coordinate ferric ion with the sulfonyl group oxygen atom. ...
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... oxygen atom of the sulfonyl group of compound 4 develops metal coordination with the heme iron atom, as in the case of compound 1, 3, and 7. Additionally, a salt bridge is created between the Natom and the heme ring. The methoxy benzene moiety of this compound interacts via a π-π stacking with Tyr107 and its carbonyl group forms two hydrogen bonds with the backbone of Val120 and with Additionally, the docking analysis suggested that the selected compounds may coordinate the heme metal ion as in the case of azoles binding (Figures 8-10). Specifically, compounds 1 ( Figure 7) and 7 (Figure 8) develop π-π stacking with the aromatic rings of Tyr107 and Tyr121, as in the case of R-econazole ( Figure 9) and both coordinate ferric ion with the sulfonyl group oxygen atom. ...
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... order to evaluate the stability of compounds 1, 2, and 4, compared to R-econazole, the docking poses of the four molecules were subjected to unconstrained molecular dynamics simulations for 1 μs each. In all cases, the RMSD of the structural model backbone was reasonable ( Figure 10A), as well as the ligand RMSD ( Figure 10B). ...
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... order to evaluate the stability of compounds 1, 2, and 4, compared to R-econazole, the docking poses of the four molecules were subjected to unconstrained molecular dynamics simulations for 1 μs each. In all cases, the RMSD of the structural model backbone was reasonable ( Figure 10A), as well as the ligand RMSD ( Figure 10B). ...
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... indicate ( Figure 10C) that the imidazole nitrogen of R-econazole, the sulfonyl group oxygens of compounds 1 and 4 and nitro group oxygens of compound 2 were found in constant proximity to Fe 3+ . Although these interactions with heme iron remain stable for all tested compounds as shown in the distance profiles along their trajectories ( Figure 10C), we postulate that the forces maintaining such a stable binding profile are hydrophobic. ...
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... indicate ( Figure 10C) that the imidazole nitrogen of R-econazole, the sulfonyl group oxygens of compounds 1 and 4 and nitro group oxygens of compound 2 were found in constant proximity to Fe 3+ . Although these interactions with heme iron remain stable for all tested compounds as shown in the distance profiles along their trajectories ( Figure 10C), we postulate that the forces maintaining such a stable binding profile are hydrophobic. This could be explained by the fact that the RMSD of these three compounds was stable along the trajectories as shown in Figure 10B. ...
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... these interactions with heme iron remain stable for all tested compounds as shown in the distance profiles along their trajectories ( Figure 10C), we postulate that the forces maintaining such a stable binding profile are hydrophobic. This could be explained by the fact that the RMSD of these three compounds was stable along the trajectories as shown in Figure 10B. ...
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... the three compounds under investigation share common binding characteristics. Reconazole forms steady hydrophobic contacts between the two-chlorine bearing aromatic rings with mainly Thr289, Leu110, and Val120 and the imidazole ring is stabilized by Ala293 ( Figure 10D). Compound 1, as a larger in size compound, besides hydrophobic contacts between its aromatic groups and mainly Thr289, Leu110, and Val120, bears an extra benzo-dioxole group, which penetrates deeper to interact with the two prolines Pro394 and Pro446, as well as Ile364 and Ser362 ( Figure 10E). ...
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... forms steady hydrophobic contacts between the two-chlorine bearing aromatic rings with mainly Thr289, Leu110, and Val120 and the imidazole ring is stabilized by Ala293 ( Figure 10D). Compound 1, as a larger in size compound, besides hydrophobic contacts between its aromatic groups and mainly Thr289, Leu110, and Val120, bears an extra benzo-dioxole group, which penetrates deeper to interact with the two prolines Pro394 and Pro446, as well as Ile364 and Ser362 ( Figure 10E). Compound 2 forms similar hydrophobic interactions with Val120, Tyr121, as well as Tyr107. ...
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... 2 forms similar hydrophobic interactions with Val120, Tyr121, as well as Tyr107. The benzyl group attached to the Fe interacting nitro group is also stabilized by Ala239 ( Figure 10F). Compound 4 has a similar interaction profile, forming aromatic-hydrophobic interactions with Thr289, Val120, and Ile364, and hydrophobic interactions with Met286 ( Figure 10G). ...
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... benzyl group attached to the Fe interacting nitro group is also stabilized by Ala239 ( Figure 10F). Compound 4 has a similar interaction profile, forming aromatic-hydrophobic interactions with Thr289, Val120, and Ile364, and hydrophobic interactions with Met286 ( Figure 10G). A general observation is that the MIC and MFC values of the hit compounds were remarkably different from those of econazole compared to the predictions of the molecular docking. ...
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... order to evaluate the stability of compounds 1, 2, and 4, compared to R-econazole, the docking poses of the four molecules were subjected to unconstrained molecular dynamics simulations for 1 µs each. In all cases, the RMSD of the structural model backbone was reasonable ( Figure 10A), as well as the ligand RMSD ( Figure 10B). ...
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... order to evaluate the stability of compounds 1, 2, and 4, compared to R-econazole, the docking poses of the four molecules were subjected to unconstrained molecular dynamics simulations for 1 µs each. In all cases, the RMSD of the structural model backbone was reasonable ( Figure 10A), as well as the ligand RMSD ( Figure 10B). ...
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... indicate ( Figure 10C) that the imidazole nitrogen of R-econazole, the sulfonyl group oxygens of compounds 1 and 4 and nitro group oxygens of compound 2 were found in constant proximity to Fe 3+ . Although these interactions with heme iron remain stable for all tested compounds as shown in the distance profiles along their trajectories ( Figure 10C), we postulate that the forces maintaining such a stable binding profile are hydrophobic. ...
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... indicate ( Figure 10C) that the imidazole nitrogen of R-econazole, the sulfonyl group oxygens of compounds 1 and 4 and nitro group oxygens of compound 2 were found in constant proximity to Fe 3+ . Although these interactions with heme iron remain stable for all tested compounds as shown in the distance profiles along their trajectories ( Figure 10C), we postulate that the forces maintaining such a stable binding profile are hydrophobic. This could be explained by the fact that the RMSD of these three compounds was stable along the trajectories as shown in Figure 10B. ...
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... these interactions with heme iron remain stable for all tested compounds as shown in the distance profiles along their trajectories ( Figure 10C), we postulate that the forces maintaining such a stable binding profile are hydrophobic. This could be explained by the fact that the RMSD of these three compounds was stable along the trajectories as shown in Figure 10B. ...
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... the three compounds under investigation share common binding characteristics. R-econazole forms steady hydrophobic contacts between the two-chlorine bearing aromatic rings with mainly Thr289, Leu110, and Val120 and the imidazole ring is stabilized by Ala293 ( Figure 10D). Compound 1, as a larger in size compound, besides hydrophobic contacts between its aromatic groups and mainly Thr289, Leu110, and Val120, bears an extra benzo-dioxole group, which penetrates deeper to interact with the two prolines Pro394 and Pro446, as well as Ile364 and Ser362 ( Figure 10E). ...
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... forms steady hydrophobic contacts between the two-chlorine bearing aromatic rings with mainly Thr289, Leu110, and Val120 and the imidazole ring is stabilized by Ala293 ( Figure 10D). Compound 1, as a larger in size compound, besides hydrophobic contacts between its aromatic groups and mainly Thr289, Leu110, and Val120, bears an extra benzo-dioxole group, which penetrates deeper to interact with the two prolines Pro394 and Pro446, as well as Ile364 and Ser362 ( Figure 10E). Compound 2 forms similar hydrophobic interactions with Val120, Tyr121, as well as Tyr107. ...
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... 2 forms similar hydrophobic interactions with Val120, Tyr121, as well as Tyr107. The benzyl group attached to the Fe interacting nitro group is also stabilized by Ala239 ( Figure 10F). Compound 4 has a similar interaction profile, forming aromatic-hydrophobic interactions with Thr289, Val120, and Ile364, and hydrophobic interactions with Met286 ( Figure 10G). ...
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... benzyl group attached to the Fe interacting nitro group is also stabilized by Ala239 ( Figure 10F). Compound 4 has a similar interaction profile, forming aromatic-hydrophobic interactions with Thr289, Val120, and Ile364, and hydrophobic interactions with Met286 ( Figure 10G). Figure 10. ...
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... 4 has a similar interaction profile, forming aromatic-hydrophobic interactions with Thr289, Val120, and Ile364, and hydrophobic interactions with Met286 ( Figure 10G). Figure 10. RMSD of (Α) Cα atoms of CYP51A, (Β) ligands along the MD trajectory. ...
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... test set contained 3 commercially available antifungal drugs (miconazole, econazole, and bifonazole) and 19 active compounds (19 nmol•mL −1 ≤ MIC ≤ 350 nmol•mL −1 ) (Figure 3). All compounds were converted from Figure 10. RMSD of (A) Cα atoms of CYP51A, (B) ligands along the MD trajectory. ...
Citations
... Compounds were tested for their antifungal activity against eight fungal species using the microdilution method, [46,47] and the results are presented in Table 3. According to the obtained results, all compounds showed very good activity with MIC ranging from 0.042-0.443 ...
... The antibacterial assay was carried out using the microdilution method [46,47] (http://www.dntpasteur.ru/metodic2_4_2_2.php/). All experiments were conducted in duplicate and repeated three times. ...
Thirteen new 1H‐1,2,4‐triazolyl derivatives were synthesized, and six of them were selected based on docking prediction for the investigation of their antimicrobial activity against five bacterial and eight fungal strains. All compounds demonstrated antibacterial activity with MIC lower than that of the ampicillin and chloramphenicol. In general, the most sensitive bacteria appeared to be P.fluorescens, while the plant pathogen X.campestris was the most resistant. The antifungal activity of the compounds was much better than the antibacterial activity. All compounds were more potent (6 to 45 times) than reference drugs ketoconazole and bifonazole with the best activity achieved by compound 4a A.versicolor, A.ochraceus, A.niger, and T.viride showed the highest sensitivity to compound 4b, while, T.viride,P. funiculosum, and P.ochrochloron showed good sensitivity to compound 4a. Molecular docking studies suggest that the probable mechanism of antibacterial activity involves the inhibition of the MurB enzyme of E.coli, while CYP51 of C. albicans appears to be involved in the mechanism of antifungal activity. It is worth mentioning that none of the tested compounds violated Lipinski's rule of five.
... The organisms were obtained from the Mycological Laboratory, Department of Plant Physiology, Institute for Biological Research 'Siniša Stankovic', Belgrade, Serbia. The antifungal assay was carried out using microdilution method as previously reported [53,54]. All experiments were performed in duplicate and repeated three times. ...
Nine new functionally substituted derivatives of 2-aminothiazole were evaluated for antimicrobial activity using microdilution method against the panel of eight bacterial and eight fungal strains. Evaluation of antibacterial activity revealed that compounds are potent antibacterial agents, more active than ampicillin and streptomycin except of some compounds against B. cereus and En. cloacae. The best compound appeared to be compound 8. The most sensitive bacteria appeared to be En. cloacae, while L. monocytogenes was the most resistant. Compounds also exhibited good antifungal activity much better than two reference drugs, ketoconazole and bifonazole. Compound 1 exhibited the best antifungal activity. The most sensitive fungus was T. viride, while A. fumigatus was the most resistant. Bacteria as well as fungi in general showed different sensitivity towards compounds tested. Molecular docking studies revealed that MurB inhibition is probably involved in the mechanism of antibacterial activity, while CYP51 of C. albicans is responsible for the mechanism of antifungal activity. Finally, it should be mentioned that all compounds displayed very good druglikeness scores.
... cyclopium (food isolates) and Candida albicans (ATCC 10231) were tested. The detailed explanation is given in our previous papers [32,33]. ...
Twelve steroid based hydrazones were in silico evaluated using computer program PASS as antimicrobial agents. The experimental evaluation revealed that all compounds have low to moderate antibacterial activity against all bacteria tested, except for B.cereus with MIC at a range of 0.37–3.00 mg/mL and MBC at 0.75–6.00 mg/mL. The most potent appeared to be compound 11 with MIC/MBC of0.75/1.5 mg/mL, respectively. The evaluation of antibacterial activity against three resistant strains MRSA, E.coli and P.aeruginosa demonstrated superior activity of compounds against MRSA compared with ampicillin, which did not show bacteriostatic or bactericidal activities. All compounds exhibited good antifungal activity with MIC of 0.37–1.50 mg/mL and MFC of 1.50–3.00 mg/mL, but with different sensitivity against fungi tested. According to docking studies, 14-alpha demethylase inhibition may be responsible for antifungal activity. Two compounds were evaluated for their antibiofilm activity. Finally, drug-likeness and docking prediction were performed.
... O ergosterol é um componente importante presente na membrana celular fúngica tendo como função a regulação da fluidez, da permeabilidade e da atividade das enzimas associadas à membrana. A diminuição do ergosterol resulta em perda da integridade e funcionalidade da membrana celular fúngica, além de gerar acúmulo de esteróis tóxicos, acarretando inibição da replicação ou morte celular(DONG et al., 2019;KRITSI et al., 2019; BERKOWE et al., 2017;ARAÚJO, 2008;GREER, 2003). ...
No ambiente hospitalar, principalmente em unidades de terapia intensiva, as infecções fúngicas oportunistas representam um grande desafio a comunidade médica e científica, pois pacientes que possuem doenças de base que afetam o sistema imunológico e são submetidos a inúmeros procedimentos invasivos tem de 5 a 10 vezes maiores chances de adquirir infecções fúngicas nosocomiais. Essa problemática adquiriu características ainda mais complexas com a pandemia da COVID-19 principalmente devido ao aumento na utilização de antimicrobianos, corticosteroides e procedimentos invasivos, amplificando o risco das infecções causadas por fungos e outros patógenos. Desse modo, esta revisão narrativa tem o objetivo descrever os aspectos farmacocinéticos, farmacodinâmicos, uso clínico e interações medicamentosas dos principais agentes de uso sistêmico pertencentes a segunda geração da classe dos Azóis: fluconazol, itraconazol, posaconazol e voriconazol. O mecanismo de ação desses agentes deve-se a inibição da desmetilação da 14α-lanosterol, essencial para biossíntese de ergosterol. Diferentemente dos imidazólicos, os triazóis possuem em sua estrutura molecular dois átomos de carbono e três de nitrogênio que confere a este grupo menor toxicidade as células humanas e maior espectro de ação, tornando-os mais eficientes e seguros para uso clínico. Por fim, com o aumento da incidência de infecções fúngicas durante a Pandemia da COVID-19, os antifúngicos se tornaram alvos de atenção e preocupação devido ao número limitado de agentes que compõem esta classe. Desse modo, é imprescindível o uso seguro e racional dessa classe, bem como a ampliação nos esforços da comunidade científica na descoberta de novos agentes no intuito de combater doenças ocasionadas por microorganismos resistentes aos tratamentos tradicionais.
... cyclopium (food isolate). All experiments were performed in triplicate [64,65]. ...
Herein, we report the design, synthesis, and evaluation of the antimicrobial activity of new heteroaryl (aryl) thiazole derivatives. The design was based on a molecular hybridization approach. The in vitro evaluation revealed that these compounds demonstrated moderate antibacterial activity. The best activity was achieved for compound 3, with MIC and MBC in the range of 0.23–0.7 and 0.47–0.94 mg/mL, respectively. Three compounds (2, 3, and 4) were tested against three resistant strains, namely methicillin resistant Staphylococcus aureus, P. aeruginosa, and E. coli, which showed higher potential than the reference drug ampicillin. Antifungal activity of the compounds was better with MIC and MFC in the range of 0.06–0.47 and 0.11–0.94 mg/mL, respectively. The best activity was observed for compound 9, with MIC at 0.06–0.23 mg/mL and MFC at 0.11–0.47 mg/mL. According to docking studies, the predicted inhibition of the E. coli MurB enzyme is a putative mechanism of the antibacterial activity of the compounds, while inhibition of 14a-lanosterol demethylase is probably the mechanism of their antifungal activity.
... It was carried out with 96-well microplates containing TSB medium for the resistant P. aeruginosa strain, supplemented with examined compounds in concentrations ranging from 1/16 to 4 × MIC as described previously [60] in the checkboard manner. The fractional inhibitory concentration index (FICI) was calculated by the following equation as described in our previous paper [63]: FICI = FIC1 0 /MIC1 0 + FIC2 0 /MIC2 0 FIC1 0 and FIC2 0 are the MICs of a combination of tested compounds and antibiotics, and MIC1 0 and MIC2 0 , represent the MIC values of individual agents. The following cut-offs: FIC ≤ 0.5 synergistic, >0.5 <2 additive, ≥2 <4 indifferent, and FIC > 4 antagonistic effects were used for the discussion of obtained results. ...
Background:
Infectious diseases represent a significant global strain on public health security and impact on socio-economic stability all over the world. The increasing resistance to the current antimicrobial treatment has resulted in the crucial need for the discovery and development of novel entities for the infectious treatment with different modes of action that could target both sensitive and resistant strains.
Methods:
Compounds were synthesized using the classical organic chemistry methods. Prediction of biological activity spectra was carried out using PASS and PASS-based web applications. Pharmacophore modeling in LigandScout software was used for quantitative modeling of the antibacterial activity. Antimicrobial activity was evaluated using the microdilution method. AutoDock 4.2® software was used to elucidate probable bacterial and fungal molecular targets of the studied compounds.
Results:
All compounds exhibited better antibacterial potency than ampicillin against all bacteria tested. Three compounds were tested against resistant strains MRSA, P. aeruginosa and E. coli and were found to be more potent than MRSA than reference drugs. All compounds demonstrated a higher degree of antifungal activity than the reference drugs bifonazole (6-17-fold) and ketoconazole (13-52-fold). Three of the most active compounds could be considered for further development of the new, more potent antimicrobial agents.
Conclusion:
Compounds 5b (Z)-3-(3-hydroxyphenyl)-5-((1-methyl-1H-indol-3-yl)methylene)-2-thioxothiazolidin-4-one and 5g (Z)-3-[5-(1H-Indol-3-ylmethylene)-4-oxo-2-thioxo-thiazolidin-3-yl]-benzoic acid as well as 5h (Z)-3-(5-((5-methoxy-1H-indol-3-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)benzoic acid can be considered as lead compounds for further development of more potent and safe antibacterial and antifungal agents.
... cyclopium (food isolate). All experiments were performed in duplicate and repeated three times [83,84]. ...
This manuscript deals with the synthesis and computational and experimental evaluation of the antimicrobial activity of twenty-nine 4-(indol-3-yl)thiazole-2-amines and 4-ιndol-3-yl)thiazole acylamines. An evaluation of antibacterial activity against Gram (+) and Gram (−) bacteria revealed that the MIC of indole derivatives is in the range of 0.06–1.88 mg/mL, while among fourteen methylindole derivatives, only six were active, with an MIC in the range of of 0.47–1.88 mg/mL. S. aureus appeared to be the most resistant strain, while S. Typhimurium was the most sensitive. Compound 5x was the most promising, with an MIC in the range of 0.06–0.12 mg/mL, followed by 5d and 5m. An evaluation of these three compounds against resistant strains, namely MRSA P. aeruginosa and E. coli, revealed that they were more potent against MRSA than ampicillin. Furthermore, compounds 5m and 5x were superior inhibitors of biofilm formation, compared to ampicillin and streptomycin, in terms Compounds 5d, 5m, and 5x interact with streptomycin in additive manner. The antifungal activity of some compounds exceeded or was equipotent to those of the reference antifungal agents bifonazole and ketoconazole. The most potent antifungal agent was found to be compound 5g. Drug likeness scores of compounds was in a range of −0.63 to 0.29, which is moderate to good. According to docking studies, E. coli MurB inhibition is probably responsible for the antibacterial activity of compounds, whereas CYP51 inhibition was implicated in antifungal activity. Compounds appeared to be non-toxic, according to the cytotoxicity assessment in MRC-5 cells.
... A modified microdilution technique was carried out [79,80]. Briefly, the fungal spores were washed from the surface of agar plates with sterile 0.85% saline containing 0.1% Tween 80 (v/v). ...
The goal of this research is to investigate the antimicrobial activity of nineteen previously synthesized 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives. The compounds were tested against a panel of three Gram-positive and three Gram-negative bacteria, three resistant strains, and six fungi. Minimal inhibitory, bactericidal, and fungicidal concentrations were determined by a microdilution method. All of the compounds showed antibacterial activity that was more potent than both reference drugs, ampicillin and streptomycin, against all bacteria tested. Similarly, they were also more active against resistant bacterial strains. The antifungal activity of the compounds was up to 80-fold higher than ketoconazole and from 3 to 40 times higher than bifonazole, both of which were used as reference drugs. The most active compounds (2, 3, 6, 7, and 19) were tested for their inhibition of P. aeruginosa biofilm formation. Among them, compound 3 showed significantly higher antibiofilm activity and appeared to be equipotent with ampicillin. The prediction of the probable mechanism by docking on antibacterial targets revealed that E. coli MurB is the most suitable enzyme, while docking studies on antifungal targets indicated a probable involvement of CYP51 in the mechanism of antifungal activity. Finally, the toxicity testing in human cells confirmed their low toxicity both in cancerous cell line MCF7 and non-cancerous cell line HK-2.
... cyclopium (food isolate). The organisms were obtained from the Mycological Laboratory, Department of Plant Physiology, Institute for Biological Research "Siniša Stankovic", Belgrade, Serbia.All experiments were performed in duplicate and repeated three times[62,63]. ...
In this study, we report the design, synthesis, computational and experimental evaluation of the antimicrobial activity, as well as docking studies of new 5-methylthiazole based thiazolidinones. All compounds demonstrated antibacterial efficacy, some of which (1,4,10 and 13) exhibited good activity against E. coli and B. cereus. The evaluation of antibacterial activity against three resistant strains, MRSA, P. aeruginosa and E. coli, revealed that compound 12 showed the best activity, higher than reference drugs ampicillin and streptomycin, which were inactive or exhibited only bacteriostatic activity against MRSA, respectively. Ten out of fifteen compounds demonstrated higher potency than reference drugs against a resistant strain of E. coli, which appeared to be the most sensitive species to our compounds. Compounds 8, 13 and 14 applied in a concentration equal to MIC reduced P. aeruginosa biofilm formation by more than 50%. All compounds displayed antifungal activity, with compound 10 being the most active. The majority of compounds showed better activity than ketoconazole against almost all fungal strains. In order to elucidate the mechanism of antibacterial and antifungal activities, molecular docking studies on E. coli Mur B and C. albicans CYP51 and dihydrofolate reductase were performed. Docking analysis of E. coli MurB indicated a probable involvement of MurB inhibition in the antibacterial mechanism of tested compounds while docking to 14α-lanosterol demethylase (CYP51) and tetrahydrofolate reductase of Candida albicans suggested that probable involvement of inhibition of CYP51 reductase in the antifungal activity of the compounds. Potential toxicity toward human cells is also reported.
... Kritsi et al. [168] used a pharmacophore screen based on five imidazole and triazole drugs to identify 1 million compounds meeting drug-likeness criteria within the 11 million compound ZINC database. They then used in silico docking with a homology model of AfCYP51A to identify eight non-azole compounds, including four that appeared to dock in close proximity to the heme iron and aromatic amino acids in the active site. ...
Antifungal drugs and antifungal agrochemicals have significant limitations. These include several unintended consequences of their use including the growing importance of intrinsic and acquired resistance. These problems underpin an increasingly urgent need to improve the existing classes of antifungals and to discover novel antifungals. Structural insights into drug targets and their complexes with both substrates and inhibitory ligands increase opportunity for the discovery of more effective antifungals. Implementation of this promise, which requires multiple skill sets, is beginning to yield candidates from discovery programs that could more quickly find their place in the clinic. This review will describe how structural biology is providing information for the improvement and discovery of inhibitors targeting the essential fungal enzyme sterol 14α-demethylase.
