In Vitro Anti-Candida Activity and Action Mode of Benzoxazole Derivatives

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) 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.

Synthesis, characterization, and biological activities of folic acid conjugates with polyvinyl alcohol, chitosan, and cellulose

“…The antifungal activity of conjugates P‐1B, P‐2B, and P‐3A against the tested species may be due the structure activity relationship for the incorporation of FA moieties on the halopolymers. Additionally, the presence of halogroups (Cl and Br) along the conjugate polymers may have an effect on the fungus species as described previously 73,74 . Thus, chemical conjugation of PVA, CS and CL with FA resulted in improving their antifungal activity.…”

“…Additionally, the presence of halogroups (Cl and Br) along the conjugate polymers may have an effect on the fungus species as described previously. 73,74 Thus, chemical conjugation of PVA, CS and CL with FA resulted in improving their antifungal activity.…”

Emerging Antifungal Targets and Strategies

“…Berberine hydrochloride, traditional Chinese medicine with antimicrobial effects, reduces intracellular efflux of fluconazole by downregulating CDR1 [ 100 ], while polyunsaturated fatty acids could reduce efflux from C. krusei cells [ 101 ]. Benzoxazole derivatives could interfere with both cell efflux and ergosterol synthesis in C. albicans [ 62 ].…”

The Application of Small Molecules to the Control of Typical Species Associated With Oral Infectious Diseases

“…Monika et al synthesized a series of benzoxazole derivatives showing equivalent effects to commercially used azoles, which either interacted with exogenous ergosterol or blocked the synthesis of endogenous ergosterol. Among the library of 23 benzoxazoles featuring 2mercaptobenzoxazole with the phenacyl moiety or respective alcohols, compound 5d showed good stability and water solubility, representing a good candidate in the treatment of andida infection (Staniszewska et al, 2021a). C. albicans can form biofilms on the mucosal surface, which not only increase its virulence but also lead to drug resistance (Lohse et al, 2018).…”