Artículo IndizadoNovel oxazolidin-2-one-linked 1,2,3-triazole derivatives (4a–k) were synthesized by straightforward and versatile azide–enolate (3 + 2) cycloaddition. The series of compounds was screened for antifungal activity against four filamentous fungi as well as six yeast species of Candida spp. According to their efficiency and breadth of scope, they can be ordered as 4k > 4d > 4h > 4a, especially in relation to the activity displayed against Candida glabrata ATCC-34138, Trichosporon cutaneum ATCC-28592 and Mucor hiemalis ATCC-8690, i.e. compounds 4d, 4h and 4k showed excellent activity against C. glabrata (MIC 0.12, 0.25 and 0.12 μg mL−1, respectively), better than that of itraconazole (MIC 1 μg ml−1). The activity of compound 4d (MIC = 2 μg mL− 1) was higher than that observed for the standard antifungal drug (MIC = 8 μg mL−1) against Trichosporon cutaneum, while compound 4k displayed an excellent antimycotic activity against Mucor hiemalis (MIC = 2 μg mL−1 vs. 4 μg mL−1 for itraconazole). In addition, we describe herein a novel mild and eco-friendly synthetic protocol for obtaining β-ketosulfones (adducts to afford compounds 4a–k) from α-brominated carbonyls in an aqueous nanomicellar medium at room temperature.CONACYT, Secretaría de Investigación de Estudios Avanzados de la UAE

FUENTES BENITES, MARIA PAULINA AYDEE GRACIA

GONZALEZ CALDERON, DAVIR

GONZALEZ ROMERO, CARLOS

MORALES RODRIGUEZ, MACARIO

RAMIREZ VILLALVA, ALEJANDRA

Rojas García, Roxana

TAMARIZ MASCARUA, JOAQUIN

ZAVALA SEGOVIA, MARÍA DE LAS NIEVES

MedChemComm

English

Repositorio Institucional de la Universidad Autónoma del Estado de México

MedChemCommRESEARCH ARTICLECite this: Med. Chem. Commun.,2017, 8, 2258Received 28th August 2017,Accepted 14th October 2017DOI: 10.1039/c7md00442grsc.li/medchemcommSynthesis and antifungal activity of noveloxazolidin-2-one-linked 1,2,3-triazole derivatives†Alejandra Ramírez-Villalva,a Davir González-Calderón, a Roxana I. Rojas-García,aCarlos González-Romero, a Joaquín Tamaríz-Mascarúa,cMacario Morales-Rodríguez,b Nieves Zavala-Segoviad and Aydeé Fuentes-Benítes *aNovel oxazolidin-2-one-linked 1,2,3-triazole derivatives (4a–k) were synthesized by straightforward andversatile azide–enolate (3 + 2) cycloaddition. The series of compounds was screened for antifungal activityagainst four filamentous fungi as well as six yeast species of Candida spp. According to their efficiency andbreadth of scope, they can be ordered as 4k > 4d > 4h > 4a, especially in relation to the activity displayedagainst Candida glabrata ATCC-34138, Trichosporon cutaneum ATCC-28592 and Mucor hiemalis ATCC-8690, i.e. compounds 4d, 4h and 4k showed excellent activity against C. glabrata (MIC 0.12, 0.25 and 0.12μg mL−1, respectively), better than that of itraconazole (MIC 1 μg ml−1). The activity of compound 4d (MIC =2 μg mL−1) was higher than that observed for the standard antifungal drug (MIC = 8 μg mL−1) againstTrichosporon cutaneum, while compound 4k displayed an excellent antimycotic activity against Mucorhiemalis (MIC = 2 μg mL−1 vs. 4 μg mL−1 for itraconazole). In addition, we describe herein a novel mild andeco-friendly synthetic protocol for obtaining β-ketosulfones (adducts to afford compounds 4a–k) fromα-brominated carbonyls in an aqueous nanomicellar medium at room temperature.1. IntroductionBoth oxazolidin-2-one1 and 1,2,3-triazole2 cores are very well-recognized pharmacophores in the literature. They have be-come extremely versatile in medicinal chemistry, featuringa number of clinically used drugs (e.g. Linezolid 1 orTazobactam 2, Fig. 1). Consequently, several antimicrobialsbased on one or the other scaffold have been reported in theliterature.3 On the other hand, the study of both cores in thesame molecule (3) as an antibacterial agent has been reported4and patented (e.g. 3a (ref. 5) and 3b (ref. 6)). This year – 2017– Melinta Therapeutics Inc. announced the acceptance of FDAof the Investigational New Drug (IND) application for topicalRadezolid 3c, a second-generation oxazolidinone/triazole com-pound discovered by Melinta scientists as a novel antibioticto treat serious bacterial infections.7 Curiously, antifungal ac-tivity has not been demonstrated for these kinds of com-pounds to the best of our knowledge.Even though the mechanism of action of oxazolidinone8and triazole9 cores has been described, the inhibition ofmonoamine oxidase A (MAO-A)4a as well as the RNA-bindingprocess4g has been proposed as the mode of action foroxazolidin-2-one-linked 1,2,3-triazole.Due to the strong resistance of fungi to current drugs,there is a continuous search for antifungal agents. As part ofour ongoing research, we herein describe the synthesis andbiological evaluation of novel oxazolidin-2-one-linked 1,2,3-triazole derivatives (4).2. ChemistryOur initial study began by obtaining the starting materials,azide/oxazolidin-2-one 8 and ketones 11 (Scheme 1). Firstly,chlorine derivative 7 was synthesized (61%) by couplingbetween 2-chloroethyl isocyanate 6 and benzoin 5.10 Subse-quently, the nucleophilic substitution of 7 by the azide ionfurnished compound 8 (58%).Ketones 11a–11g were synthesized since, unlike 11i–11j,they are not commercially available (ketone 11h was kindlydonated by Syntex-La Roche). For these purposes, we havedeveloped a novel organic solvent-free synthesis of2258 | Med. Chem. Commun., 2017, 8, 2258–2262 This journal is © The Royal Society of Chemistry 2017aDepartamento de Química Orgánica, Facultad de Química, UniversidadAutónoma del Estado de México, Paseo Colón/Paseo Tollocan s/n, Toluca, Estadode México, 50120, Mexico. E-mail: mpagfuentesb@uaemex.mx;Fax: +52 722 217 3890; Tel: +52 722 217 5109x113bDepartamento de Microbiología, Facultad de Química, Universidad Autónomadel Estado de México, Paseo Colón/Paseo Tollocan s/n, Toluca, Estado de México,50120, Mexicoc Departamento de Química Orgánica, Escuela Nacional de Ciencias Biológicas,Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala, Ciudad de México,11340, MexicodCentro Conjunto de Investigación en Química Sustentable UAEM-UNAM,Carretera Toluca-Atlacomulco Km 14.5, Toluca, 52000, Mexico† Electronic supplementary information (ESI) available: Supplementary data(experimental procedures, characterization data of all compounds and copiesof 13C, 1H, and spectra, as well as the study on the synthesis of β-ketosulfones).See DOI: 10.1039/c7md00442gPublished on 17 October 2017. Downloaded by FAC DE QUIMICA on 14/12/2017 16:02:56. View Article OnlineView Journal  | View IssueMed. Chem. Commun., 2017, 8, 2258–2262 | 2259This journal is © The Royal Society of Chemistry 2017β-ketosulfones in an aqueous nanomicellar medium by theconcomitant use of the surfactant reagent SPGS-550-M or‘Nok’ (now available at Sigma-Aldrich11) and sodiump-toluenesulfinate from α-bromoketones. The surfactant na-ture of NOK (a third generation surfactant) allows it to act asan efficient nanoreactor in catalytic amounts. The study andscope of this novel methodology are described in the ESI† ingreater detail. Therefore, we decided to apply such a method-ology in the synthesis of compound 11 from 10, which inturn was accomplished by reported protocols12 withN-bromosuccinimide (NBS) as the bromine source.Although Cu-catalyzed azide–alkyne cycloaddition(CuAAC) is the conventional method for obtaining 1,2,3-triazole moieties,13 other strategies have emerged as alterna-tives for such a purpose. We previously reported14 a novelsynthetic protocol to achieve the efficient assembly of 1,4,5-trisubstituted 1,2,3-triazole cores through azide–enolatecycloaddition. In consequence, oxazolidin-2-one-linked 1,2,3-triazole derivatives (4) were synthesized by the efficient1,3-dipolar cycloaddition of azide/oxazolidin-2-one in thepresence of enolates prepared in situ from ketones 11 acti-vated by DBU as the base. Table 1 summarizes theseoutcomes.3. MicrobiologyCompounds 4a–k were tested for their in vitro activity againstfour filamentous fungi: Aspergillus fumigatus ATCC-16907,Trichosporon cutaneum ATCC-28592, Rhizopus oryzae ATCC-10329 and Mucor hiemalis ATCC-8690. These compoundswere also evaluated, employing standardized microbiologicalmethods developed by the CLSI, against six yeast specimens:Candida albicans ATCC-10231, Candida utilis ATCC-9226, Can-dida tropicalis ATCC-13803, Candida parapsilopsis ATCC-22019,Fig. 1 The novel series of compounds 4 involves the extremelyimportant oxazolidin-2-one and 1,2,3-triazole pharmacophoric cores.A similar feature is found in antimicrobial oxazolidin-2-one-linked1,2,3-triazole 3, including lead compounds 1 and 2.Scheme 1 Reagents and conditions: (i) N2, 180 °C, 24 h. (ii) NaN3 (1.1 eq.), DMF anh., 60 °C, 12 h, N2. (iii) NBS (1.1 eq.), TsOH·H2O (1.0 eq.), MeCN,60 °C, 4 h. (iv) SPGS-550-M aq. (2% w/w), p-Tol-SO2Na (1.5 eq.), r.t., 12 h.MedChemComm Research ArticlePublished on 17 October 2017. Downloaded by FAC DE QUIMICA on 14/12/2017 16:02:56. View Article Online2260 | Med. Chem. Commun., 2017, 8, 2258–2262 This journal is © The Royal Society of Chemistry 2017Candida glabrata ATCC-34138, and Candida krusei ATCC-14243.Then, the sensitivity of the filamentous microorganisms wasdetermined by the microdilution M38-A method,15 and that ofthe yeast fungi with the M27-A3 method.16Such antifungal activity was compared to that ofitraconazole as the standard antifungal drug. The minimuminhibitory concentration (MIC) values of the standard andcompounds 4a–k, expressed in micrograms per milliliter,were determined in 96-well plates using MOPS (3-[N-morpholino]propanesulfonic acid buffered RPMI-1640 me-dium, Sigma-Aldrich).4. Results and discussionThe antifungal activity of the test compounds is summa-rized in Table 2. Compounds 4d, 4h and 4k showed ex-cellent activity against C. glabrata (MIC 0.12, 0.25 and0.12 μg mL−1, respectively), better than that ofitraconazole (MIC 1 μg ml−1). The activity of compound4d (MIC = 2 μg mL−1) was higher than that observed forthe standard antifungal drug (MIC = 8 μg mL−1) againstTrichosporon cutaneum, while compound 4k displayed anexcellent antimycotic activity against Mucor hiemalis (MIC= 2 μg mL−1 vs. 4 μg mL−1 for itraconazole). Compounds4a, 4c and 4e proved to be moderate antifungal agentsagainst Aspergillus fumigatus strains. The current resultssuggest that the presence of either the a-CN or p-NO2Phgroup at position 5 of the triazole cores increases thebiological activity of these compounds in both yeast andfilamentous fungi.These outcomes can also be described by the ‘sensitivity’parameters of yeasts, according to the breakpoints describedin the M27-A3 document (Table 3). In general, C. glabrata,C. krusei and C. parapsilosis showed some susceptibility tothe test compounds, whereas C. albicans, C. tropicalis andC. utilis were resistant to all of them.Table 1 Synthesis of oxazolidin-2-one-linked 1,2,3-triazoles 4a–k from azide 8 by coupling with active ketones 11Entrya Ketone Triazoleb (yield%)c1 11a: R2 = Ph, R1 = SO2-p-Tol 4a (68)2 11b: R2 = p-CH3Ph, R1 = SO2-p-Tol 4b (61)3 11c: R2 = p-NO2-Ph, R1 = SO2-p-Tol 4c (74)4 11d: R2 = m-NO2Ph, R1 = SO2-p-Tol 4d (70)5 11e: R2 = p-Cl-Ph, R1 = SO2-p-Tol 4e (72)6 11f: R2 = thiophen-2-yl, R1 = SO2-p-Tol 4f (68)7 11g: R2 = 5-chlorothiophen-2-yl, R1 = SO2-p-Tol 4g (64)8 11h: R2 = pentyl, R1 = SO2Ph 4h (71)9 11i: R2 = CH3, R1 = COCH3 4i (73)10 11j: R2 = Ph, R1 = COPh 4j (71)11 11k: R2 = Ph, R1 = CN 4k (67)a Reaction conditions: To a solution of compound 8 (1.0 eq.) and 11 (1.0 eq.) in DMF anh., DBU (2.0 eq.) was added. The reaction mixture wasstirred at 50–60 °C for 12–24 h. b Confirmed by 1H-NMR, 13C-NMR and MS. c Yields refer to chromatographically pure isolated compounds.Table 2 In vitro antifungal activities of the synthetized compounds (MIC, μg mL−1)Compound C. alb C. trop C. uti C. kru C. gla C. par M. hie A. fum T. cut R. ory4a 8 8 8 0.5 1 8 4 2 8 164b 1 8 4 8 2 0.25 16 8 8 164c 4 8 4 0.25 4 8 16 2 8 164d 8 8 8 8 0.12 0.5 16 16 2 164e 8 8 8 8 4 8 16 4 8 164f 8 8 8 8 1 8 16 8 8 164g 8 8 8 2 2 4 16 16 8 164h 8 8 8 8 0.25 8 16 16 8 164i 8 8 8 8 2 4 16 16 8 84j 8 8 8 8 2 8 16 16 8 164k 8 8 8 0.5 0.12 8 2 16 8 16Standarda 0.03 0.06 0.25 0.25 1 0.06 4 1 8 1Abbreviations: C. alb., Candida albicans; C. trop., Candida tropicalis; C. uti., Candida utilis; C. kru., Candida krusei; C.gla., Candida glabrata,C. par., Candida parapsilosis; M. hie., Mucor hiemalis; A. fum., Aspergillus fumigatus; T. cut., Trichosporon cutaneum; R. ory., Rhizopusoryzae.a Itraconazole.MedChemCommResearch ArticlePublished on 17 October 2017. Downloaded by FAC DE QUIMICA on 14/12/2017 16:02:56. View Article OnlineMed. Chem. Commun., 2017, 8, 2258–2262 | 2261This journal is © The Royal Society of Chemistry 20175. ConclusionIn summary, eleven oxazolidin-2-one-linked 1,2,3-triazole de-rivatives (4a–k) were synthesized in good yields based onazide–enolate 1,3-dipolar cycloaddition. In vitro assays dem-onstrated that compound 4k is the most efficient antimicro-bial agent, since it was either better than or comparable toitraconazole against three species (C. glabrata, M. hiemalisand T. cutaneum). The second best antimicrobial activity wasexhibited by compound 4d, which was much better than thereference drug against two species (C. glabrata and T.cutaneum). In consequence, these compounds can be consid-ered as drug candidates for future complementary biologicalstudies. In addition, we have developed a novel organicsolvent-free synthesis of β-ketosulfones in an aqueous nano-micellar medium. The surfactant nature of SPGS-550-M or‘NOK’ (a third generation surfactant) allows it to act as an ef-ficient nanoreactor in catalytic amounts. The notable advan-tages of this methodology over those previously reported in-clude its simplicity of handling, mild conditions, high yields,cheap reagents and great tolerance of functional groups.Conflicts of interestThe authors declare no competing interest.AcknowledgementsWe gratefully acknowledge financial support from the Sec-retaría de Investigación y Estudios Avanzados/UAEMéx (pro-ject no. 3804/2014/CID) and CONACYT-Mexico (postgraduatescholarship no. 227581 and no. 273644). The authors wouldalso like to thank the referees for their valuable commentsand suggestions, Signa S.A. de C.V. for kindly donating somesolvents and reagents, and L. Triana-Cruz (CCIQS UAEMex–UNAM) for technical support.References1 (a) N. Pandit, R. K. Singla and B. Shrivastava, Int. J. Med.Chem., 2012, 2012, 24; (b) K. J. Shaw and M. R. Barbachyn,Ann. N. Y. Acad. 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Synthesis and antifungal activity of novel oxazolidin-2-one linked-1,2,3-triazole derivatives

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Synthesis and antifungal activity of novel oxazolidin-2-one linked-1,2,3-triazole derivatives

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