2020-02-27 09:26:59
Priscilla Maciel Quatrin, Daiane Flores Dalla Lana, Luana Candice Genz Bazana, Luis Fla´vio Souza de Oliveira, Mario Lettieri Teixeira,d Edilma Elaine Silva, William Lopes, Roˆmulo Faria Santos Canto, Gustavo Pozza Silveiraae and Alexandre Meneghello Fuentefria
1.Introduction
In 1993, 2-((phenylsulfinyl)methyl)-3-(phenylthio)-1H-indole was identified as a potent HIV reverse transcriptase inhibitor.9 Since then, several libraries of 3-thio-indole derivatives have been synthesized as new anti-retroviral agents10,11 and as strong poxvirus inhibitors.12 Also, arylthioindoles, such as 5-bromo-3-((3,4,5- trimethoxyphenyl)thio)-1H-indole (1) (Fig. 1), have been proposed as anti-tubulin inhibitors to be used as new antitumor drugs.
Commercially available drugs that are first prescribed to treat cancer, including 5-fluorouracil, gallium compounds, and mito- mycin C, are being repurposed as antibacterials.15 With these points in mind, we demonstrate that a library of 3-calcogenyl-indoles 3 (Fig. 1) presents good activities against Staphylococcus aureus isolates.16 Similarly, anticancer drugs are being repurposed as new antifungals. For instance, the geldanamycin derivative 17-AAG, which is an Hsp90 inhibitor, dramatically improves the fluconazole activity in a Galleria mellonella model of systemic candidiasis.17
Organoselenium compounds have several chemical and pharmacological applications18–22 due to their unique mechanisms of action including broad antimicrobial activity.23 For instance, diphenyl diselenide and its analogues showed growth-inhibition and fungistatic activity against filamentous fungi and pathogenic Candida spp.24 2,20-Dithienyl diselenide demonstrated fungistatic activity toward C. albicans.25 Ebselen analogues presented activity against C. albicans and filamentous fungi.26–28 Selenocyanates have a vast range of biological applications and can be prepared using different methodologies.29 Efficient preparation of 3-selenocyanate- indoles has been reported in the literature by the use of diverse selenocyanate species.
Recently, a library of allylic-selenocyanates, such as 3, was prepared by us as new agents to combat Fusarium spp. involved in human infections.35 Based on these previous studies and with our ongoing program seeking new molecules with anti- microbial properties16,35–37 that can be developed as new leads for future in vivo studies, we decided to prepare a collection of seven 3-selenocyanate-indoles 4 (Fig. 1) and screen them against Candida spp. and dermatophytes. Therefore, this work discloses the results of these screening tests and toxicological studies (cytotoxicity, genotoxicity, mutagenicity, and allergeni- city) to the best hit identified. The results are shown in the following sections.
2.Results and discussion
Seven 3-selenocyanate-indoles, 4a–g (Table 1), were synthesized in one chemical step by an electrophilic aromatic substitution of the respective indole with electrophilic selenocyanate species. Triselenium dicyanide (TSD), which can be easily prepared in situ from malononitrile and selenium dioxide in dimethyl- sulfoxide, was chosen as the electrophilic selenium reagent.32 So, the indoles reacted with TSD in dimethylsulfoxide at room temperature to yield the target indole selenocyanides in excel- lent yields (78–99%, ESI†). In a total, five new compounds, 4c–g, were prepared.
It has been identified that a halogen atom at the 5-position of the indole ring of 3-arylthioindoles results in a reduction of the free energy associated with the binding of the compounds to tubulin, which decreases their cytotoxicity.13 It is known that several compounds presenting anti-cancer activity also demonstrate antimicrobial capacity.15,17,38–40 Preliminary results of our group demonstrated that 3-chalcogenyl-indoles are active toward Gram- positive bacteria (Fig. 1). The lead compound in these screening tests presents a 5-bromoindole moiety.16 Similarly, this work shows the 3-selenocyanate-indoles 4a and 4b as lead compounds for further broad-spectrum antifungal drug development toward Candida spp. and dermatophytes of the genera Trichophyton and Microsporum. These fungi are typical dermatomycosis agents. Noteworthy, compound 4a also has a 5-bromoindole moiety as observed in the previous studies with different targets. The presence of iodine (4c) or other electron withdrawing groups such as CO2CH3 (4d) at the fifth position of the indole ring was deleterious to the activities (Table 1).
The lead compounds 4a and 4b were screened against a panel of 25 Candida strains and 15 filamentous fungi. These compounds presented a broad spectrum fungicidal profile against both genera tested and geometric means of 4.1 and 6.0 mg mL—1 toward Candida spp. and 1.2 and 2.2 mg mL—1 against Trichophyton and Microsporum (Table 2). These results are similar to the ones obtained using FCZ (2.5 mg mL—1), which is the prescribed drug in the treatment of candidiasis.41 Meanwhile, the selenocyanates 4a and 4b were 50–100 times less active than TBF (0.02 mg mL—1) against dermatophytes. However, since resistance to these micro- organisms is continuously observed,42–44 4a and 4b might be an alternative for the reference drug (TBF), especially considering that they do not share the same mechanism of action as that of TBF. The MIC of anidulafungin against yeasts and MEC for filamentous fungi increased significantly in the presence of sorbitol after 7 and 8 days, respectively, as an indication of its fungal cell wall activity. This was not observed for 3-selenocyanate-indoles 4a and 4b, since their MICs did not change (Table S1, ESI†). Similarly, ergo- sterol (100, 150, 200, and 250 mg mL—1) was added into the culture medium to verify if the compounds have action on the fungal cell
membrane. Amphotericin B was used as the control. The MICs also did not vary for the selenocyanate-indoles 4a and 4b (Table S2, ESI†). The ergosterol and sorbitol assays indicated that the broad- spectrum antifungal mechanism of action of compounds 4a and 4b are not related to interactions with the membrane and fungal cell wall chemicals. Hence, scanning electron microscopy (SEM) allowed us to visualize the effects of the 3-selenocyanate- indole 4a on the morphology and amount of C. albicans cells after in vitro treatment. A considerable reduction in the number of blastoconidia, hyphae, and pseudohyphae was evidenced by SEM images after exposure to 4a (Fig. 4). The fungicidal activity of this compound may be related to this effect. The formation of hyphae and pseudohyphae by yeast is considered an important mechanism of pathogenicity, which facilitates tissue invasion, colonization, and infection of mucous membranes.45,46 There-
fore, this information might be clinically relevant.
The fungal cells were exposed for 4, 12, 24, and 48 h (C. albicans) (Fig. 3A and C) and 4b (Fig. 3B and D) at concentrations MIC/2, MIC, MICx2, and MICx4 in a time-kill assay. Compound 4a presented a fungicidal profile (a reduction of 499.9% in log10 relative to the initial inoculum) against C. albicans (ATCC 18804) at MICx2 and MICx4 after 4 h of treatment. Meanwhile, at MIC/2 and MIC, microbial inhibition was observed after 12 h of experiment followed by cell proliferation equivalent to the positive control (Fig. 3A). A fungicidal effect was also observed toward T. rubrum at all concentrations over the initial 8 h of experiment (Fig. 3C). This complete inhibition of their growth in the early hours demonstrates an excellent fungicidal effect and could be further related to a possible high level of clinical efficacy. The time-kill assay demonstrated that 4b exhibits a fungistatic effect (a reduction of o99.9% in log10 in relation to the initial inoculum) against C. albicans (ATCC 18804) at MICx2 and MICx4 after 12 and 24 h of treatment, respectively. However, a significant reduction in the activity after 12 to 24 h of treatment followed by cell proliferation can be observed (Fig. 3B). This effect is noted with azole antifungals. These drugs do not completely eliminate fungal cells but inhibit their growth. The fungistatic mechanism usually works in conjunction with the immune system of the host, killing pathogenic or opportunistic microorganisms. However, this mechanism of action might be a major concern in immunocompromised, patients leading to a persistent infection.47 Meanwhile, the selenocyanate-indole 4b presented a fungicidal profile against T. rubrum (45) at MIC and MICx2 after 24 h and at MICx4 after 8 h of treatment. Cell proliferation is observed at MIC and MICx2 after 8 h of treatment, which would suggest the need for a new therapeutic dose. A dose-dependent effect was noted in the first few hours of the experiment with T. rubrum, which required a new therapeutic dose for complete microbial inhibition, as noticed at MIC and MICx2 concentrations after 24 h of treatment (Fig. 3D).
Selenocyanate-indoles 4a and 4b (32 mg mL—1) were not cytotoxic to human leukocyte cells, since no statistical differences were observed compared to phosphate-buffered saline (PBS, negative control). Bleomycin (BLE, positive control) reduced the cell viability to approximately 20% (Fig. 4A). Similarly, significant micronucleus frequency, as well as apoptotic and necrotic processes for compounds 4a and 4b (32 mg mL—1), was not noticed, inferring a non-mutagenic potential (Fig. 4B). However, the comet assay showed that 4a and 4b (32 mg mL—1) caused significant DNA damage (Fig. 4C).
As disclosed by Pukalskien˙e et al.,48 the divergence in comet and micronucleus results can be explained by the fact that proliferating leukocytes were used for the micronucleus assay. Leukocyte cells have higher repair capacity than cells in the comet’s G0 phase (resting cells). Therefore, the DNA damage observed in the comet assay can be repaired during the micro- nucleus experiment.49 Since the nuclei of the fungal and mammalian cells have similarities, it is believed that the targets of the compounds are the nucleic acids. Further experiments might be conducted to confirm this hypothesis.
Most imidazole antifungals present cell toxicity or bioavail- ability problems and are formulated for topical use.50 Ketoconazole is cytotoxic and presents a possible mechanism of mitochondrial dysfunction in liver cells, compromising mitochondrial DNA synthesis, resulting in induced apoptosis.51 Thus, even drugs demonstrating cellular toxicity for systemic use are prescribed for topical administration. In addition, in the present study, the toxicity of the selenocyanate-indoles 4a and 4b was evaluated at 32 mg mL—1 and the MICs (geometric mean) determined were in the range of 1.2 to 6.0 mg mL—1. Thus, DNA damage is being observed at higher concentrations of the compounds compared to the MICs.
The selenocyanate-indoles 4a and 4b (32 mg mL—1) are found to be non-irritant (IS = 2.19 and 3.01, respectively) through the HET-CAM assay (Fig. S15, ESI†). The chorioallantoic membrane is highly vascularized and responds to injuries caused by processes, such as inflammation, similar to that observed in the conjunctival tissue of rabbit eyes.52 This is an indication that formulations for topical administration might be developed without further mucous irritation.
Synergistic effects as a consequence of coinfection of Candida spp. with Staphylococcus have been demonstrated by invitro and ex vivo54 studies. It is assumed that Gram-positive bacteria adhere or bind to the hyphae of Candida spp. For instance, it has been shown that C. albicans can transport S. aureus into tissues disseminating the infection in an oral co-colonization model. Therefore, co-infection of Candida spp. and S. aureus results in a more serious infection than that caused by each microorganism individually.54 3-Selenocyanate-indoles 4a and 4b were also screened against S. aureus (ATCC 25923) and the MICs determined were 8 mg mL—1 (see the ESI†), indicating that the compounds might have antimicrobial capacities, avoiding this kind of co-infection.
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4-ISOPROPYL-1-(2-METHOXYPHENYL)-1H-PYRAZOLO[3,4-D]PYRIDAZINE-7-THIOLCatalog No.:AA01ARO8 CAS No.:1105198-11-5 MDL No.:MFCD11986588 MF:C15H16N4OS MW:300.3787 |
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2-Hydrazino-6-isopropylpyrimidin-4(3H)-oneCatalog No.:AA01AQJ9 CAS No.:1105198-36-4 MDL No.:MFCD16631650 MF:C7H12N4O MW:168.1964 |
(7-ISOPROPYL-5-OXO-2,3-DIHYDRO-5H-[1,3]THIAZOLO[3,2-A]PYRIMIDIN-3-YL)ACET+Catalog No.:AA01ARPE CAS No.:1105198-41-1 MDL No.:MFCD11986597 MF:C11H14N2O3S MW:254.3055 |
6-CYCLOPROPYL-1-(4-METHYLPHENYL)-1,5-DIHYDRO-4H-PYRAZOLO[3,4-D]PYRIMIDIN-+Catalog No.:AA01ARPF CAS No.:1105198-46-6 MDL No.:MFCD11986602 MF:C15H14N4O MW:266.2979 |
1-Phenyl-5-((pyrimidin-2-ylthio)methyl)-1H-1,2,3-triazole-4-carboxylic acidCatalog No.:AA01FMJ7 CAS No.:1105198-52-4 MDL No.:MFCD11986624 MF:C14H11N5O2S MW:313.3344 |
GLYCYRRHIZICACIDMONOSODIUMSALTCatalog No.:AA009OVB CAS No.:11052-19-0 MDL No.:MFCD03938959 MF:C42H62NaO16+ MW:845.9219 |
OligomycinCCatalog No.:AA01DZJ7 CAS No.:11052-72-5 MDL No.:MFCD00043231 MF:C45H74O10 MW:775.0631 |
Ibu-deoxycytidineCatalog No.:AA0083LA CAS No.:110522-75-3 MDL No.:MFCD00079383 MF:C13H19N3O5 MW:297.3071 |
2'-Deoxy-5'-O-DMT-N6-phenoxyacetyl-D-adenosineCatalog No.:AA008YJ9 CAS No.:110522-82-2 MDL No.:MFCD00058546 MF:C39H37N5O7 MW:687.7404 |
N4-(4-Methoxyphenyl)-n6-(pyridin-2-ylmethyl)-1h-pyrazolo[3,4-d]pyrimidine-4,6-diamineCatalog No.:AA01AS8Y CAS No.:1105224-27-8 MDL No.:MFCD12009136 MF:C18H17N7O MW:347.3739 |
4-(2-Methyl-1H-imidazol-1-yl)butanoic acidCatalog No.:AA007CO6 CAS No.:110525-54-7 MDL No.:MFCD01721737 MF:C8H12N2O2 MW:168.1931 |
4-(1H-Pyrazol-1-yl)butanoic acidCatalog No.:AA0083L7 CAS No.:110525-56-9 MDL No.:MFCD01693645 MF:C7H10N2O2 MW:154.1665 |
(S)-(+)-2-[Hydroxy(diphenyl)methyl]-1-methylpyrrolidineCatalog No.:AA003CDF CAS No.:110529-22-1 MDL No.:MFCD00145245 MF:C18H21NO MW:267.3654 |
N-{4-[(4,6-Dimethylpyrimidin-2-yl)sulfamoyl]phenyl}-4-methylbenzamideCatalog No.:AA01F4YG CAS No.:110534-79-7 MDL No.:MFCD00863108 MF:C20H20N4O3S MW:396.4628 |
Ethyl 5-acetoxy-6-bromo-2-(bromomethyl)-1-methyl-1h-indole-3-carboxylateCatalog No.:AA003Q97 CAS No.:110543-98-1 MDL No.:MFCD00407019 MF:C15H15Br2NO4 MW:433.0919 |
Boc-d-2-aminoadipic acidCatalog No.:AA007CO0 CAS No.:110544-97-3 MDL No.:MFCD00797554 MF:C11H19NO6 MW:261.2717 |
3-bromo-4-methoxythiopheneCatalog No.:AA01FMVY CAS No.:110545-69-2 MDL No.:MFCD25955496 MF:C5H5BrOS MW:193.0616 |
2,4-di-tert-butyl-6-({4-[(3,5-di-tert-butyl-2-hydroxyphenyl)methyl]piperazin-1-yl}methyl)phenolCatalog No.:AA00907O CAS No.:110546-20-8 MDL No.:MFCD14156144 MF:C34H54N2O2 MW:522.8048 |
3-Quinolinecarboxylic acid,6,7,8-trifluoro-1,4-dihydro-1-(2-hydroxy-1-methylethyl)-4-oxo-, ethylester, (R)-Catalog No.:AA01CCLL CAS No.:110548-05-5 MDL No.:MFCD30186682 MF:C15H14F3NO4 MW:329.2712 |
3-(2-methylpent-2-enoyl)-1,3-thiazolidine-4-carboxylic acidCatalog No.:AA01DU8S CAS No.:1105507-65-0 MDL No.:MFCD09932700 MF:C10H15NO3S MW:229.2960 |
Anthra[2,3-b]furan-7-carboxylic acid,5,10-dihydro-4,8,11-trimethoxy-6-methyl-5,10-dioxo-, methyl esterCatalog No.:AA01CBSN CAS No.:110551-55-8 MDL No.:MFCD30741516 MF: MW: |
2-Methyl-4,6-bis(octylsulfanylmethyl)phenolCatalog No.:AA00HBNY CAS No.:110553-27-0 MDL No.:MFCD00134699 MF:C25H44OS2 MW:424.7463 |
Budesonide-d8Catalog No.:AA01CC9N CAS No.:1105542-94-6 MDL No.:MFCD07369194 MF:C25H26D8O6 MW:438.5832 |
1-(4-cyanophenyl)-4-hydroxypyrrolidine-2-carboxylic acidCatalog No.:AA01E7UT CAS No.:1105547-86-1 MDL No.:MFCD11135473 MF:C12H12N2O3 MW:232.2353 |
(R)-(+)-3-Bromoisobutyric acid methyl esterCatalog No.:AA003RG6 CAS No.:110556-33-7 MDL No.:MFCD00010639 MF:C5H9BrO2 MW:181.0278 |
epi-SesaMin MonocatecholCatalog No.:AA008VTC CAS No.:1105568-81-7 MDL No.: MF:C19H18O6 MW:342.3426 |
