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Molecules
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Design, Synthesis, and Biological Evaluation of Novel Antifungals
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Design, Synthesis, and Biological Evaluation of Novel Antifungals

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (15 November 2021) | Viewed by 7104

Special Issue Editor

Prof. Dr. Sławomir Milewski

E-Mail Website
Guest Editor
Department of Pharmaceutical Technology and Biochemistry, Gdańsk University of Technology, 80-233 Gdańsk, Poland
Interests: antifungal agents; multidrug resistance; enzyme inhibitors; rational drug design

Special Issue Information

Dear Colleagues,

Infections caused by human pathogenic fungal micro-organisms affect more than 300 million people every year, and systemic mycoses—mainly in immunocompromised patients—are responsible for the death of 1.5 million individuals globally. These diseases are difficult to treat for several reasons, including the emergence of new fungal pathogens, fungal drug resistance, and last but not least, a very limited set of effective antifungal chemotherapeutics. There is little doubt that the development of novel antifungal drugs is an urgent need.

The main aim of this Issue is to collect contributions describing molecules that could be developed as antifungal drugs. These may include either entirely novel, rationally designed compounds or modifications of established antifungals, aimed at the improvement of their biological properties—especially selective toxicity. Review articles by experts in the field are particularly welcomed.

Prof. Dr. Sławomir Milewski
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Antifungals
  • Drug design
  • Antibiotic modification

Published Papers (3 papers)

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Research

26 pages, 2351 KiB  
Article
Molecular Umbrella as a Nanocarrier for Antifungals
by Andrzej S. Skwarecki, Dorota Martynow, Maria J. Milewska and Sławomir Milewski
Molecules 2021, 26(18), 5475; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185475 - 08 Sep 2021
Cited by 3 | Viewed by 1951
Abstract
A molecular umbrella composed of two O-sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a “trimethyl lock” (TML) or o-dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates demonstrated antifungal in vitro activity [...] Read more.
A molecular umbrella composed of two O-sulfated cholic acid residues was applied for the construction of conjugates with cispentacin, containing a “trimethyl lock” (TML) or o-dithiobenzylcarbamoyl moiety as a cleavable linker. Three out of five conjugates demonstrated antifungal in vitro activity against C. albicans and C. glabrata but not against C. krusei, with MIC90 values in the 0.22–0.99 mM range and were not hemolytic. Antifungal activity of the most active conjugate 24c, containing the TML–pimelate linker, was comparable to that of intact cispentacin. A structural analogue of 24c, containing the Nap-NH2 fluorescent probe, was accumulated in Candida cells, and TML-containing conjugates were cleaved in cell-free extract of C. albicans cells. These results suggest that a molecular umbrella can be successfully applied as a nanocarrier for the construction of cleavable antifungal conjugates. Full article
(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Novel Antifungals)
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20 pages, 7279 KiB  
Article
The Antifungal Action Mode of N-Phenacyldibromobenzimidazoles
by Monika Staniszewska, Łukasz Kuryk, Aleksander Gryciuk, Joanna Kawalec, Marta Rogalska, Joanna Baran and Anna Kowalkowska
Molecules 2021, 26(18), 5463; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26185463 - 08 Sep 2021
Cited by 4 | Viewed by 1927
Abstract
Our study aimed to characterise the action mode of N-phenacyldibromobenzimidazoles against C. albicans and C. neoformans. Firstly, we selected the non-cytotoxic most active benzimidazoles based on the structure–activity relationships showing that the group of 5,6-dibromobenzimidazole derivatives are less active against C. [...] Read more.
Our study aimed to characterise the action mode of N-phenacyldibromobenzimidazoles against C. albicans and C. neoformans. Firstly, we selected the non-cytotoxic most active benzimidazoles based on the structure–activity relationships showing that the group of 5,6-dibromobenzimidazole derivatives are less active against C. albicans vs. 4,6-dibromobenzimidazole analogues (5e–f and 5h). The substitution of chlorine atoms to the benzene ring of the N-phenacyl substituent extended the anti-C. albicans action (5e with 2,4-Cl2 or 5f with 3,4-Cl2). The excellent results for N-phenacyldibromobenzimidazole 5h against the C. albicans reference and clinical isolate showed IC50 = 8 µg/mL and %I = 100 ± 3, respectively. Compound 5h was fungicidal against the C. neoformans isolate. Compound 5h at 160–4 µg/mL caused irreversible damage of the fungal cell membrane and accidental cell death (ACD). We reported on chitinolytic activity of 5h, in accordance with the patterns observed for the following substrates: 4-nitrophenyl-N-acetyl-β-d-glucosaminide and 4-nitrophenyl-β-d-N,N′,N″-triacetylchitothiose. Derivative 5h at 16 µg/mL: (1) it affected cell wall by inducing β-d-glucanase, (2) it caused morphological distortions and (3) osmotic instability in the C. albicans biofilm-treated. Compound 5h exerted Candida-dependent inhibition of virulence factors. Full article
(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Novel Antifungals)
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21 pages, 1750 KiB  
Article
In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives
by Monika Staniszewska, Łukasz Kuryk, Aleksander Gryciuk, Joanna Kawalec, Marta Rogalska, Joanna Baran, Edyta Łukowska-Chojnacka and Anna Kowalkowska
Molecules 2021, 26(16), 5008; https://0-doi-org.brum.beds.ac.uk/10.3390/molecules26165008 - 18 Aug 2021
Cited by 9 | Viewed by 2644
Abstract
A newly synthetized series of N-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone (5d), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone (5i), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone (5k) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone (6a [...] Read more.
A newly synthetized series of N-phenacyl derivatives of 2-mercaptobenzoxazole, including analogues of 5-bromo- and 5,7-dibromobenzoxazole, were screened against Candida strains and the action mechanism was evaluated. 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanone (5d), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichloro-phenyl)ethanone (5i), 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,4,6-trichlorophenyl)ethanone (5k) and 2-[(5-bromo-1,3-benzoxazol-2-yl)sulfanyl]-1-phenylethanone (6a) showed anti-C. albicans SC5314 activity, where 5d displayed MICT = 16 µg/mL (%R = 100) and a weak anti-proliferative activity against the clinical strains: C. albicans resistant to azoles (Itr and Flu) and C. glabrata. Derivatives 5k and 6a displayed MICP = 16 µg/mL and %R = 64.2 ± 10.6, %R = 88.0 ± 9.7, respectively, against the C. albicans isolate. Derivative 5i was the most active against C. glabrata (%R = 53.0 ± 3.5 at 16 µg/mL). Benzoxazoles displayed no MIC against C. glabrata. Benzoxazoles showed a pleiotropic action mode: (1) the total sterols content was perturbed; (2) 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(3,4-dichlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(2,3,4-trichlorophenyl)ethanol (8h–i) at the lowest fungistatic conc. inhibited the efflux of the Rho123 tracker during the membrane transport process; (3) mitochondrial respiration was affected/inhibited by the benzoxazoles: 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-chlorophenyl)ethanol and 2-(1,3-benzoxazol-2-ylsulfanyl)-1-(4-bromophenyl)ethanol 8c–d and 8i. Benzoxazoles showed comparable activity to commercially available azoles due to (1) the interaction with exogenous ergosterol, (2) endogenous ergosterol synthesis blocking as well as (3) membrane permeabilizing properties typical of AmB. Benzoxazoles display a broad spectrum of anti-Candida activity and action mode towards the membrane without cross-resistance with AmB; furthermore, they are safe to mammals. Full article
(This article belongs to the Special Issue Design, Synthesis, and Biological Evaluation of Novel Antifungals)
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