In vitro evaluation of arylsubstituted imidazoles derivatives as antiprotozoal agents and docking studies on sterol 14α-demethylase (CYP51) from Trypanosoma cruzi, Leishmania infantum, and Trypanosoma brucei

Vargas, Julio Alberto Rojas; López, Alexander; Pérez, Yulier; Cos, Paul; Froeyen, Matheus

doi:10.1007/s00436-019-06206-z

Cited by 15 publications

(4 citation statements)

References 28 publications

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“…After 3 days of incubation, cell viability was assessed using 10-g/ml resazurin. After an additional incubation of 4 h, fluorescence was measured at an emission of 590 nm and an excitation of 550 nm using a spectrophotometer (Promega Discover), as described earlier (109). A compound was classified to be nontoxic when the IC 50 was greater than 20 M. Tamoxifen was used as a positive control.…”

Section: Methodsmentioning

confidence: 99%

Combination of Miconazole and Domiphen Bromide Is Fungicidal against Biofilms of Resistant Candida spp

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Cremer

et al. 2020

Antimicrob Agents Chemother

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The occurrence and recurrence of mucosal biofilm-related Candida infections, such as oral and vulvovaginal candidiasis, is a serious clinical issue. Vaginal infections caused by Candida spp., for example, affect 70-75% of women at least once during their lives. Miconazole (MCZ) is the preferred topical treatment against these fungal infections, yet it has only moderate antibiofilm activity. Through screening of a drug repurposing library we identified the quaternary ammonium compound domiphen bromide (DB) as a MCZ potentiator against Candida biofilms. DB displayed synergistic C. albicans antibiofilm activity with MCZ, reducing viable biofilm cells 1000-fold. In addition, the MCZ-DB combination also resulted in significant killing of biofilm cells of azole-resistant C. albicans, C. glabrata, and C. auris isolates. In vivo, the MCZ-DB combination had significantly improved activity in a vulvovaginal candidiasis rat model as compared to single compound treatments. Data from an artificial evolution experiment indicated that resistance development against the combination was not occurring, highlighting the potential of MCZ-DB combination therapy to treat Candida biofilm-related infections.

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Section: Methodsmentioning

confidence: 99%

Combination of Miconazole and Domiphen Bromide Is Fungicidal against Biofilms of Resistant Candida spp

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Cools

Cremer

et al. 2020

Antimicrob Agents Chemother

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“…belong to the family of kinetoplastids [ 109 ] and some compounds have been shown to inhibit the survival of both Leishmania parasites and Trypanosoma spp. [ 110 , 111 , 112 ]. Compound SQ10, which suppressed the growth of L. donovani , was also reported to possess activity against T. cruzi [ 112 ].…”

Section: Resultsmentioning

confidence: 99%

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

et al. 2023

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The recent outlook of leishmaniasis as a global public health concern coupled with the reportage of resistance and lack of efficacy of most antileishmanial drugs calls for a concerted effort to find new leads. The study combined In silico and in vitro approaches to identify novel potential synthetic small-molecule inhibitors targeting the Leishmania donovani sterol methyltransferase (LdSMT). The LdSMT enzyme in the ergosterol biosynthetic pathway is required for the parasite’s membrane fluidity, distribution of membrane proteins, and control of the cell cycle. The lack of LdSMT homologue in the human host and its conserved nature among all Leishmania parasites makes it a viable target for future antileishmanial drugs. Initially, six known inhibitors of LdSMT with IC50 < 10 μM were used to generate a pharmacophore model with a score of 0.9144 using LigandScout. The validated model was used to screen a synthetic library of 95,630 compounds obtained from InterBioScreen limited. Twenty compounds with pharmacophore fit scores above 50 were docked against the modelled three-dimensional structure of LdSMT using AutoDock Vina. Consequently, nine compounds with binding energies ranging from −7.5 to −8.7 kcal/mol were identified as potential hit molecules. Three compounds comprising STOCK6S-06707, STOCK6S-84928, and STOCK6S-65920 with respective binding energies of −8.7, −8.2, and −8.0 kcal/mol, lower than 22,26-azasterol (−7.6 kcal/mol), a known LdSMT inhibitor, were selected as plausible lead molecules. Molecular dynamics simulation studies and molecular mechanics Poisson–Boltzmann surface area calculations showed that the residues Asp25 and Trp208 were critical for ligand binding. The compounds were also predicted to have antileishmanial activity with reasonable pharmacological and toxicity profiles. When the antileishmanial activity of the three hits was evaluated in vitro against the promastigotes of L. donovani, mean half-maximal inhibitory concentrations (IC50) of 21.9 ± 1.5 μM (STOCK6S-06707), 23.5 ± 1.1 μM (STOCK6S-84928), and 118.3 ± 5.8 μM (STOCK6S-65920) were obtained. Furthermore, STOCK6S-84928 and STOCK6S-65920 inhibited the growth of Trypanosoma brucei, with IC50 of 14.3 ± 2.0 μM and 18.1 ± 1.4 μM, respectively. The identified compounds could be optimised to develop potent antileishmanial therapeutic agents.

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“…Fungal lanosterol 14α-demethylase (CYP51) is an attractive therapeutic target for the development of antifungal drugs [28, 29]. This enzyme catalyzes an essential step in the synthesis of ergosterol which is an essential component of fungal cell membrane.…”

Section: Resultsmentioning

confidence: 99%

Identification of novel antifungal agents: antimicrobial evaluation, SAR, ADME–Tox and molecular docking studies of a series of imidazole derivatives

et al. 2019

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Thirty-four imidazole-based compounds synthesized by one-pot catalytic method were evaluated for their antifungal and antibacterial activities against several fungal and bacterial strains. None of the compounds had antibacterial activity. Interestingly, compounds 1 , 2 , 3 , 10 and 15 displayed a strong antifungal activity against all the tested fungal species, while compounds 5 , 7 , 9 , 11 , 21 and 27 showed a moderate antifungal activity. To better understand the biological activity of the most active compounds ADME–Tox and molecular docking studies were carried out. Interestingly, compounds 1 , 2 , 3 , 7 , 10 and 15 showed excellent bioavailability. In addition, compounds 1 , 2 and 3 , exhibited good toxicity profiles. Docking studies of the two most active compounds 2 (IC 50 of 95 ± 7.07 μM) and 10 (IC 50 of 235 ± 7.07 μM) suggested that they might act by inhibiting the fungal lanosterol 14α-demethylase. Therefore, these novel antifungal agents merit further characterization for the development of new antifungal therapeutics. Electronic supplementary material The online version of this article (10.1186/s13065-019-0623-6) contains supplementary material, which is available to authorized users.

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In vitro evaluation of arylsubstituted imidazoles derivatives as antiprotozoal agents and docking studies on sterol 14α-demethylase (CYP51) from Trypanosoma cruzi, Leishmania infantum, and Trypanosoma brucei

Abstract: In vitro evaluation of arylsubstituted imidazoles derivatives as antiprotozoal agents and docking studies on Sterol 14α-demethylase (CYP51) fromTrypanosoma cruzi, Leishmania infantum and Trypanosoma brucei.

Cited by 15 publications

References 28 publications

Combination of Miconazole and Domiphen Bromide Is Fungicidal against Biofilms of Resistant Candida spp

Combination of Miconazole and Domiphen Bromide Is Fungicidal against Biofilms of Resistant Candida spp

Inhibiting Leishmania donovani Sterol Methyltransferase to Identify Lead Compounds Using Molecular Modelling

Identification of novel antifungal agents: antimicrobial evaluation, SAR, ADME–Tox and molecular docking studies of a series of imidazole derivatives

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