Antifungal screening and in silico mechanistic studies of an in‐house azole library

Sarı, Suat; Kart, Didem; Sabuncuoğlu, Suna; Doğan, İnci Selin; Özdemi̇r, Zeynep; Bozbey, İrem; Gencel, Melis; Eşsiz, Şebnem; Reynisson, Jóhannes; Karakurt, Arzu; Saraç, Selma; Dalkara, Sevim

doi:10.1111/cbdd.13587

Cited by 8 publications

(4 citation statements)

References 52 publications

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“…Melting points (mp) were determined using a Thomas-Hoover capillary melting point apparatus (USA) and uncorrected. 1 H NMR (400 MHz) and 13 C NMR (125 MHz) spectra were recorded by a Varian Mercury 400 FT (USA) and Bruker Avance 500 (Germany) NMR spectrometers, respectively. Tetramethylsilane was used as internal reference and the chemical shifts are expressed as  (ppm) values.…”

Section: Chemistrymentioning

confidence: 99%

“…The title compounds were crystallized from methanol. Their structure and purity were validated through 1 H NMR, 13 C NMR, and LC-MS spectral data.…”

Section: Synthesis Of the Compoundsmentioning

confidence: 99%

“…To date, various crystallographic studies have been reported elucidating CYP51 inhibition by azoles at molecular level [8][9][10][11]. Previously we reported a number of compounds in azole structure with antifungal effects [12,13], which include an indole derivative showing highly potent antifungal activity with a minimum inhibitory concentration (MIC) of 0.125 g/ml against C. albicans (Figure 1) [14]. Thus, we designed and synthesized two novel indole derivatives, 1-(4-chlorophenyl)-2-(1H-imidazol-1-yl)ethanol 1H-indole-2-carboxylate (4a) and 2-(1H-imidazol-1-yl)-1-(2-naphthyl)ethanol 1H-indole-2-carboxylate (4b) ( Figure 1).…”

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confidence: 99%

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Design, synthesis, antifungal activity, and QM/MM docking study of two azole derivatives with indole ring

Sarı¹,

Kart²

2020

jrp

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Systemic candidiasis is a major health issue for immunocompromised individuals due to the increase in drug-resistance among Candida spp., which are prevalent pathogenic fungi responsible for many types of fungal infections. Azoles are among the most preferred antifungal class for systemic candidiasis with broad antifungal spectrum and systemic availability. In this study, we synthesized and tested antifungal effects of two new indole derivatives to investigate the impact of indole on the activity of azole antifungal compounds and to find potent derivatives against Candida spp. including resistant strains and biofilms. 1-(4-Chlorophenyl)-2-(1H-imidazol-1yl)ethanol 1H-indole-2-carboxylate (4a) showed excellent antifungal profile with several times more potent activity against the tested species including a fluconazole-resistant C. tropicalis isolate. The minimum inhibitory concentration (MIC) of 4a was 0.03125 µg/ml against C. albicans, which was 0.5 µg/ml for fluconazole. The compound also showed promising biofilm inhibitory effect compared to amphotericin B. The importance of indole was demonstrated through molecular docking studies with the structure of C. albicans CYP51, the established target of azole antifungals, using different protocols. QM/MM docking approach yielded excellent results and accuracy, especially regarding metal interactions. As a result, indole could be a very useful fragment to design new and highly potent antifungal compounds in azole structure.

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Section: Chemistrymentioning

confidence: 99%

“…The title compounds were crystallized from methanol. Their structure and purity were validated through 1 H NMR, 13 C NMR, and LC-MS spectral data.…”

Section: Synthesis Of the Compoundsmentioning

confidence: 99%

mentioning

confidence: 99%

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Design, synthesis, antifungal activity, and QM/MM docking study of two azole derivatives with indole ring

Sarı¹,

Kart²

2020

jrp

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“…The in‐house collection, which features 106 structural analogs of azole antifungals (Figure 2), was previously prepared for antifungal compound design and some of them were found highly potent against Candida sp. (Doğan et al, 2018; Sari et al, 2017; Sari, Kart, Ozturk, et al, 2019a; Sari, Kart, Sabuncuoglu, et al, 2019; Sari, Kaynak, & Dalkara, 2018). Therefore, our study also aims to find dual‐acting compounds with both antifungal and antibacterial effects.…”

Section: Introductionmentioning

confidence: 99%

Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies

Sarı

Avci

Koçak

et al. 2020

Drug Development Research

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Azole antifungal drugs are commonly used in antifungal chemotherapy. Antibacterial effects of some topical antifungals, such as miconazole and econazole, have lately been revealed, which suggests a promising venue in antimicrobial chemotherapy. In this study, we tested an in-house azole collection with antifungal properties for their antibacterial activity to identify dual-acting hits using the broth microdilution method. The in vitro screen yielded a number of potent derivatives against grampositive bacteria, Enterococcus faecalis and Staphylococcus aureus. Compound 73's minimum inhibitory concentration (MIC) value less than 1 μg/ml against S. aureus; however, none of the compounds showed noteworthy activity against methicillinresistant S. aureus (MRSA). All the active compounds were found safe at their MIC values against the healthy fibroblast cells in the in vitro cytotoxicity test. Molecular docking studies of the most active compounds using a set of docking programs with flavohemoglobin (flavoHb) structure, the proposed target of the azole antifungals with antibacterial activity, presented striking similarities regarding the binding modes and interactions between the tested compounds and the antifungal drugs with crystallographic data. In addition to being noncytotoxic, the library was predicted to be drug-like and free of pan-assay interference compounds (PAINS). As a result, the current study revealed several potential azole derivatives with both antifungal and antibacterial activities. Inhibition of bacterial flavoHb was suggested as a possible mechanism of action for the title compounds.

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New Ester‐Containing Azole Derivatives With Potent Anti‐Candida Effects: Synthesis, Antifungal Susceptibility, Cytotoxicity, and Molecular Modeling Studies

Ataker,

Öncü,

Gülmez

et al. 2024

Drug Development Research

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Mortalities due to mycoses have dramatically increased with the emergence of drug‐resistant strains and growing immune‐compromised populations globally. Azole antifungals have been the first choice against fungal infections of a wide spectrum and several azole derivatives with ester function were reported for their potentially promising and favorable activity against Candida spp. In this study, we designed and synthesized a series of 1‐(aryl)−2‐(1H‐imidazol‐1‐yl/1H‐1,2,4‐triazol‐1‐yl)ethyl esters, and tested them against seven reference Candida strains using EUCAST reference microdilution method. Among the series, 6a, 6d, and 6g proved highly potent in vitro compared to fluconazole; especially against Candida albicans and Candida tropicalis with minimum inhibitor concentration (MIC) values as low as 0.125 and 0.06 mg/L, respectively, although their activities against Candida krusei and Candida glabrata remained limited. The compounds also showed minimal toxicity to murine fibroblasts according to the in vitro cytotoxicity tests. Molecular modeling predicted 6g as an orally available druglike compound according to all parameters and CYP51 inhibition as the likely mechanism for their antifungal effects. The study underpins the promise of azoles with ester functionality as a potential scaffold for small‐molecule antifungal drug design.

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Antifungal screening and in silico mechanistic studies of an in‐house azole library

Cited by 8 publications

References 52 publications

Design, synthesis, antifungal activity, and QM/MM docking study of two azole derivatives with indole ring

Design, synthesis, antifungal activity, and QM/MM docking study of two azole derivatives with indole ring

Antibacterial azole derivatives: Antibacterial activity, cytotoxicity, and in silico mechanistic studies

New Ester‐Containing Azole Derivatives With Potent Anti‐Candida Effects: Synthesis, Antifungal Susceptibility, Cytotoxicity, and Molecular Modeling Studies

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