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Communication

1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer

by
Anton Shetnev
1,
Sergey Baykov
2,*,
Stanislav Kalinin
2,
Alexandra Belova
1,
Vladimir Sharoyko
2,
Anton Rozhkov
2,
Lev Zelenkov
2,
Marina Tarasenko
3,
Evgeny Sadykov
4,
Mikhail Korsakov
1 and
Mikhail Krasavin
2
1
Pharmaceutical Technology Transfer Center, Ushinsky Yaroslavl State Pedagogical University, 108 Respublikanskaya St., Yaroslavl 150000, Russia
2
Institute of Chemistry, Saint Petersburg State University, 26 Universitetskii Pr, Peterhof, Saint Petersburg 198504, Russia
3
Yaroslavl State Technical University, 88 Moscowsky Pr, Yaroslavl 150023, Russia
4
A.E. Favorsky Irkutsk Institute of Chemistry, Siberian Branch Russian Academy of Science, 1 Favorsky Str, Irkutsk 664033, Russian
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(7), 1699; https://doi.org/10.3390/ijms20071699
Submission received: 28 February 2019 / Revised: 31 March 2019 / Accepted: 3 April 2019 / Published: 5 April 2019
(This article belongs to the Special Issue Bioactive Oxadiazoles)
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Versions Notes

Abstract

:
Replacement of amide moiety with the 1,2,4-oxadiazole core in the scaffold of recently reported efflux pump inhibitors afforded a novel series of oxadiazole/2-imidazoline hybrids. The latter compounds exhibited promising antibacterial activity on both Gram-positive (Staphylococcus aureus, Bacillus subtilis) and Gram-negative (Escherichia coli, Pseudomonas fluorescens) strains. Furthermore, selected compounds markedly inhibited the growth of certain drug-resistant bacteria. Additionally, the study revealed the antiproliferative activity of several antibacterial frontrunners against pancreas ductal adenocarcinoma (PANC-1) cell line, as well as their type-selective monoamine oxidase (MAO) inhibitory profile.

1. Introduction

The drug resistance of microbial pathogens is one of the greatest challenges to human health these days [1]. It is, therefore, of utmost importance to discover novel antibacterial scaffolds, as well as improve our knowledge of how we can employ already studied compounds and their analogs for the treatment of bacterial diseases.
There are few known mechanisms of bacterial drug resistance, each of which makes a pathogen invincible for commonly used agents [2]. Particularly, in some cases, deactivation of the antibiotic occurs through enzymatic degradation or modification of the antibiotic molecule rendering it inactive. Some bacteria employ protection, alteration or overexpression of the antibiotic target. Meanwhile, decreasing the expression of the porin or expressing more selective porin variant helps to prevent antibiotics from penetrating the cell membrane or cell wall. Finally, some pathogens efficiently use efflux systems, maintaining the intracellular concentration of the antibiotic lower than the minimum inhibitory levels.
Considering this, intensive efforts have been made to find the possibility to specifically block the efflux function in prokaryotic cells. The latter effect, if achieved, causes the loss of the ability of bacteria to counter the effects of antibiotics, and thus restores the pathogens drug sensitivity [3,4]. A recent study based on this idea is the one reported by Heynes et al. who discovered a new class of efflux pump inhibitors in prokaryotic cells based on 2-imidazolines derivatives (Scheme 1) [5]. Although these compounds alone did not show pronounced antibacterial properties, they markedly potentiated the effect of Novobiocin on several E. coli strains, inhibiting the efflux pump expressed by these bacteria. Despite the intriguing activity exhibited by these compounds, the presence of amide moiety as the central “core” of the molecule can be considered a disadvantage of the newly discovered chemotype of inhibitors as they are expected to be rapidly hydrolyzed in vivo [6]. Thus, we came up with an idea to examine 1,2,4-oxadiazole ring as an alternative core for the promising 2-imidazoline-containing periphery, as it could provide novel two-heterocycles-hybrid based series of compounds for further diverse biological evaluation. These expectations were supported by several successful series of variously biologically active oxadiazoles synthesized and evaluated in our group [7,8,9,10], as well as by recent example of anti-MRSA (Methicillin-Resistant Staphylococcus aureus) and anti-VRE (Vancomycin-Resistant Enterococcus) active antibiotics incorporating 3-phenoxyphenyl-substituted 1,2,4-oxadiazoles, that have been recently reported [11,12,13,14,15,16,17].

2. Result and Discussion

2.1. Chemistry

The original approach to the synthesis of 1,2,4-oxadiazoles 3a-g and 5a-q has been previously described by our group (for more information see Supplementary Material) [9,18,19,20,21], and the four newly prepared compounds 3h and 5r-t were obtained in the similar manner (Scheme 2).

2.2. Antibacterial Activity

A screening of the antibacterial activity was carried out on compounds 3a-h and 5a-t against a number of both Gram-positive and Gram-negative nonpathogenic bacteria (Staphylococcus aureus, Escherichia coli, Bacillus subtilis, Pseudomonas fluorescens), as well as three pathogenic strains, including E. coli and Enterobacter spp.
Antimicrobial activities were determined by the microbroth dilution method using the Clinical Laboratory Standards Institute (CLSI) recommendations and are summarized in Table 1 (See Experimental) [22].
Evaluated compounds exhibited medium, weak or no antibacterial activity. The most potent antimicrobial agents turned out to have some degree of structural similarity, representing two motifs: halogenated aromatic ring (R2) and methyl substituted imidazoline (R1 = Me). The values of minimal inhibition concentrations (MICs) for the listed compounds were in the region between 8 and 32 µg/mL.
Obviously, the introduction of alkyl into the R2 position (3a, 3c, and 5b) dramatically decreased the antibacterial activity of compounds, resulting in the MIC values higher than 256 µg/mL; while the activity dropped even more upon substitution of alkyl group for the large aromatic moieties (3g, 5a, 5m, 5c). Furthermore, no activity was observed for the rest of heteroaryl-substituted derivatives, that is, for those incorporating triazole, imidazole, and thiophene (3f, 5f, 5l, 5o, 5q) rings. Finally, the derivatives bearing alkyl substituted phenyl ring in R2 position (3 and 5) displayed no or poor activity (≥32 μg/mL) (3b, 3h, 5d, 5e, 5j, 5k, 5n, 5t) with the exception of compound 5r.
Most potent antimicrobial agents 3d, 3e, 5g, 5k, 5r, and 5s identified in the screening were additionally tested against ampicillin and rifampicin resistant strains of E. coli, as well as against clinically isolated poly-resistant strain of Enterobacter spp. The observed MIC values (µg/mL) are represented in Table 2.
Except for 5k, studied compounds showed activity against all tested strains, and 3d displayed MIC values in the range of 8–16 µg/mL, thus being a promising candidate for further development as an antibacterial agent.

2.3. MAO Inhibition Studies

It is well known that the use of antibiotics is often accompanied by some undesired effects. In particular, some antibiotics, such as linezolid [23] and furazolidone [24], are able to block the function of, monoamine oxidase (MAO) enzyme, increasing the risk of certain adverse effects, such as the “cheese reaction”, serotonin syndrome [25], etc. Among others, some 2-imidazolines are also known to inhibit MAOs [26]. Recently, we investigated the properties of MAO inhibition for the compounds 3a-g and 5a-q (Table 3) [9]. Selected results are listed in Table 3, demonstrating that some of the prepared 2-imidazolines are high potency inhibitors of human MAO-B, while comparatively lower potencies have been recorded for human MAO-A inhibition.
These compounds are thus specific inhibitors of MAO-B. Since adverse reactions, such as the “cheese reaction” or serotonin syndrome, are associated with the inhibition of MAO-A, the lower potency inhibition of MAO-A displayed by these compounds greatly reduces the risk for these undesired effects. We conclude that MAO inhibition exhibited by these compounds should not be a limitation for further development as antimicrobial agents.

2.4. Cytotoxicity Assay

The ability of several antibacterial frontrunner compounds (with MIC ≤ 64 µg/mL) 3d, 3e, 5g, 5k, 5r, and 5s to affect the viability of pancreas ductal adenocarcinoma (PANC-1) cell line at 10, 50, and 100 µM concentrations was evaluated using the MTT assay (Figure 1) [27,28]. Interestingly, the experiment revealed no or mild cytotoxic effect of all the compounds shown at 10 µM concentration. However, at higher concentrations (50 and 100 µM), most compounds displayed pronounced effect on the survival of cancer cell, decreasing cell viability to the level of less than 35% in comparison to 0 µM inhibitor control. Meanwhile, increasing concentration of compound 5s did not lead to substantial changes in the survival of PANC-1 culture cells. Thus, some of the prepared compounds exhibit antiproliferative and cytotoxic activity at a low micromolar range of concentrations. In combination with the antimicrobial activity displayed at the same level of concentrations, this data may gain the attention of medicinal chemists as the anticancer potential of some antibiotics has been thoroughly studied during the last years [29,30].

3. Materials and Methods

3.1. General Methods

All reagents and solvents were obtained from commercial sources and were used without purification. DMSO was dried over molecular sieves (4 Å). Reactions were monitored by analytical thin layer chromatography (Merck KGaA, Darmstadt, Germany) using Macherey-Nagel TLC sheets (Silufol UV-254), and the developed sheets were visualized under UV light. NMR spectra were recorded on Bruker AVANCE DPX 400 (RUKER Corporation, Billerica, MA, USA) at 400 MHz and 101 MHz for 1H and 13C, respectively. Chemical shifts are reported as parts per million (δ, ppm) and were referenced to the residual solvent peaks at 7.26 and 2.50 ppm for 1H in CDCl3 and DMSO-d6, respectively, and 77.16 and 39.52 ppm for 13C in CDCl3 and DMSO-d6, respectively. Multiplicities are abbreviated as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; br, broad. Coupling constant, J, is reported in Hertz (Hz). Melting points were determined in open capillary tubes with an Electrothermal IA 9300 series Digital Melting Point Apparatus (Electrothermal, Standfoshire, UK). High-resolution mass spectra (HRMS) were recorded with a Bruker maXis HRMS-ESI-QTOF (RUKER Corporation, Billerica, MA, USA) equipped with electrospray ionization source and MeOH was used as the solvents.

3.2. General Procedure for the Synthesis of 3,5-Disubstituted-1,2,4-oxadiazoles (3a-h and 5a-t)

To a solution of the amidoxime (2 mmol) and the appropriate carboxylic ester (2 mmol) in DMSO (1 mL), 120 mg (3 mmol) powdered NaOH was rapidly added. The reaction mixture was stirred at room temperature for the required time (TLC or precipitation of the product). The reaction mixture was diluted with cold water (30–50 mL), and the resulting precipitate was collected by filtration, washed with water (30 mL), dried and purified by column chromatography (eluent: 5% methanol/95% chloroform).
3-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)-5-(4-ethylphenyl)-1,2,4-oxadiazole (3h)
White powder, 34% (216 mg) yield, m.p. 196–198 °C. 1H NMR (400 MHz, DMSO) δ 8.14 (m, 4H), 8.04 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.2 Hz, 2H), 7.07 (br s, 1H), 3.66 (s, 4H), 2.75 (q, J = 7.6 Hz, 2H), 1.25 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 176.1, 168.3, 163.4, 150.4, 133.9, 129.5, 128.5, 128.4, 128.1, 127.4, 121.3, 28.7, 15.5. HRMS (ESI) calcd for C19H18N4O [M+H]+ 319.1553, found 319.1573.
5-(4-(5-Methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-3-(p-tolyl)-1,2,4-oxadiazole (5r)
Pale powder, 59% (330 mg) yield, m.p. 89–90 °C. 1H NMR (400 MHz, DMSO) δ 8.23 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H), 7.99 (d, J = 8.1 Hz, 2H), 7.41 (d, J = 8.0 Hz, 2H), 7.22 (br s, 1H), 4.09–3.98 (m, 1H), 3.81 (t, J = 11.1 Hz, 1H), 3.24 (dd, J = 11.8, 7.9 Hz, 1H), 1.20 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 175.3, 168.8, 161.7, 142.1, 135.3, 130.3, 128.5, 128.3, 127.5, 125.0, 123.8, 22.4, 21.6. HRMS (ESI) calcd for C19H18N4O [M+H]+ 319.1553, found 319.1555.
3-(3-Chlorophenyl)-5-(4-(5-methyl-4,5-dihydro-1H-imidazol-2-yl)phenyl)-1,2,4-oxadiazole (5s)
White powder, 36% (243 mg) yield, m.p. 139–141 °C. 1H NMR (400 MHz, DMSO) δ 8.16 (m, 4H), 8.03 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.1 Hz, 1H), 7.71 (t, J = 7.9 Hz, 1H), 7.18 (br s, 1H), 4.09–3.96 (m, 1H), 3.81 (t, J = 11.0 Hz, 1H), 3.23 (dd, J = 11.8, 7.9 Hz, 1H), 1.20 (d, J = 6.3 Hz, 3H). 13C NMR (101 MHz, DMSO) δ 174.8, 168.4, 161.9, 134.7, 134.1, 133.7, 132.1, 128.4, 127.9, 127.7, 127.4, 127.1, 125.7, 57.6, 56.9, 22.4. HRMS (ESI) calcd for C18H15ClN4O [M+H]+ 339.1007, found 339.1028.
5-(4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl)-3-(p-tolyl)-1,2,4-oxadiazole (5t).
White powder, 39% (240 mg) yield, m.p. 246–247 °C. 1H NMR (400 MHz, DMSO) δ 8.25 (d, J = 8.3 Hz, 2H), 8.09 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.1 Hz, 2H), 7.43 (d, J = 8.0 Hz, 2H), 7.12 (s, 1H), 3.88 (br s, 2H), 3.47 (br s, 2H), 2.42 (s, 3H). 13C NMR (126 MHz, DMSO) δ 175.5, 169.0, 163.3, 142.1, 135.6, 130.2, 128.6 128.2, 127.6, 125.3, 124.1, 21.5, 21.4. HRMS (ESI) calcd for C16H18N4O [M+H]+ 305.1397, found 305.1386.

3.3. Biological Evaluation

3.3.1. In Vitro Antibacterial Activity

All the synthesized compounds 3a-h and 5a-t were evaluated for their in vitro antimicrobial activity against Staphylococcus aureus (ATCC 25923) and Bacillus subtilis (VCМ V3142D) as examples of Gram-positive bacteria, and Escherichia coli (ATCC 25922) and Pseudomonas fluorescence (Р218) as examples of Gram-negative bacteria. The most potent antibacterial agents of this study (3d, 3e, 5g, 5k, 5r, and 5s) were further evaluated for activity against antibiotic-resistant strains Escherichia coli DH52 REF, Escherichia coli K802 Rif and clinical isolates of an antibiotic-resistant strain of Enterobacter spp. Overnight cultures were grown at 37 °C in Lysogeny broth (LB) and diluted to obtain an opacity equivalent to 0.5 on the McFarland scale. Screening vials were filled with solutions of the test compounds in 0.5% DMSO as prepared above with three replications for each treatment. Active pharmaceutical ingredient (API) pefloxacin (0.5–256 µg/mL) and 0.5% DMSO served as positive and negative controls, respectively. The entire vial was incubated at 35 ± 2 °C for 18 h. After incubation, the antibacterial activity of the test compounds was determined by measuring the absorption of the solution with a spectrophotometer at 500 nm.

3.3.2. MIC Measurement

The MICs of the most active compounds were measured using the twofold serial broth dilution method. The test organisms were grown in suitable broth for 18 h at 37 °C. Twofold serial dilutions of solutions of the test compounds were prepared at 256, 128, 64, 32, 16, 8, 4, 2, 1, and 0.5 µg/mL. The tubes were then inoculated with the test microbe; each 5 mL received 0.1 mL of the above inoculums and were incubated at 37 °C. The vials were subsequently observed for the presence or absence of microbial growth. The MIC values of the prepared compounds are listed in Table 1.

3.4. Cell Viability Assay

Human cell lines were maintained at 37 °C in a humidified atmosphere containing air and 5% CO2 as previously described [31]. Pancreas ductal adenocarcinoma cells PANC-1 were obtained from Russian collection cell cultures at the RAS Institute of Cytology (Saint Petersburg, Russian). The cell line was grown in Dulbecco’s Modified Eagle’s Medium-F12 (BioloT) containing 10% (v/v) heat-inactivated fetal calf serum (FCS, HyClone Laboratories, UT, USA), 1% l-glutamine, 1% sodium pyruvate, 50 U/mL penicillin, and 50 μg/mL streptomycin (BioloT). The cytotoxicity of oxadiazoles and the prepared imidazolines was evaluated using a routine Colorimetric method with tetrazolium dye—3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The cell lines were incubated for 48 h with medium containing different concentrations of investigated compounds. Following treatment, Dulbecco’s Modified Eagle’s Medium-F12 (100 μL/ well) and 20 μL of a 2.5 mg/mL MTT solution were added, and cells were incubated for 1 h at 37 °C. The used cell density was 5 × 103 cells/200 μL/well in 96-well microtiter plates. After aspiration of the supernatants, the MTT-formazan crystals formed by metabolically active cells were dissolved in dimethyl sulfoxide (100 μL/well), and the absorbance was measured at 540 nm and 690 nm in Varioskan LUX™ Multimode Microplate Reader (Thermo Scientific, Waltham, MA, USA). Values measured at 540 nm were subtracted for background correction at 690 nm, and the data were plotted as a percent of control DMSO-treated samples.

4. Conclusion

To sum up, herein we report antibacterial, anticancer, and MAO-inhibitory activity of newly synthesized, as well as earlier obtained in our group, 1,2,4-oxadiazole/2-imidazoline hybrids. Some of the investigated compounds exhibited attractive antibacterial profile reaching MIC values between 8 and 32 µg/mL which makes them undoubtedly promising for further evaluation. Several frontrunners (3d, 3e, 5g, 5k, 5r, and 5s) have been studied in more details and showed pronounced bacteriostatic properties against drug-resistant strains, as well as substantial antiproliferative activity against pancreas ductal adenocarcinoma (PANC-1) cell line. In the meantime, type-selective MAO inhibitory profile revealed for the most active compounds is favorable for them to demonstrate good side-effect characteristics in further development. Finally, we strongly believe that this scaffold may gain the attention of medicinal chemists as easily accessible privileged structure serving as a starting point for novel libraries of biologically active compounds.

Supplementary Materials

Supplementary materials can be found at https://www.mdpi.com/1422-0067/20/7/1699/s1.

Author Contributions

A.S. and M.K. conceived, designed the experiments and wrote the manuscript. S.B., A.B., S.K., V.S., A.R., M.T., L.Z., and E.S. performed the experiments, analyzed the data, and wrote the experimental part. All authors were involved in the final writing of the work.

Funding

This work was financially supported by the Russian Foundation for Basic Research (RFBR) grant No. 18-33-01108. L.Z. is also grateful to Saint Petersburg State University for a postdoctoral fellowship.

Acknowledgments

The authors gratefully acknowledge the expert assistance as well as the kind help of Jacobus P Petzer for the manuscript preparation. The authors also appreciate the technical assistance for providing antimicrobial activities from I. Y. Filatova (Skryabin Institute of biochemistry and physiology of microorganisms RAS). Physicochemical studies were performed at the Magnetic Resonance Research Centre and Chemical Analysis and Materials Research Centre (both belong to Saint Petersburg State University).

Conflicts of Interest

The authors declare no conflict of interest.

Abbreviations

MICMinimal Inhibition Concentrations
MAOMonoamine Oxidase
MRSAMethicillin-Resistant Staphylococcus aureus
VREVancomycin-Resistant Enterococcus
APIActive Pharmaceutical Ingredient

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Ijms 20 01699 sch001 550
Scheme 1. The design of a new series of antibacterial agents [5].
Scheme 1. The design of a new series of antibacterial agents [5].
Ijms 20 01699 sch001
Ijms 20 01699 sch002 550
Scheme 2. Synthesis of 1,2,4-oxadiazoles 3a-h and 5a-t.
Scheme 2. Synthesis of 1,2,4-oxadiazoles 3a-h and 5a-t.
Ijms 20 01699 sch002
Ijms 20 01699 g001 550
Figure 1. Cell viability MTT assay results for compounds 3d, 3e, 5g, 5k, 5r, and 5s at 10, 50, 100 µM concentrations against pancreas ductal adenocarcinoma (PANC-1) cell line (values are shown as the mean ± SEM of three experiments: (*) p < 0.05 and (**) p < 0.01 in comparison to control (0 µM)).
Figure 1. Cell viability MTT assay results for compounds 3d, 3e, 5g, 5k, 5r, and 5s at 10, 50, 100 µM concentrations against pancreas ductal adenocarcinoma (PANC-1) cell line (values are shown as the mean ± SEM of three experiments: (*) p < 0.05 and (**) p < 0.01 in comparison to control (0 µM)).
Ijms 20 01699 g001
Table
Table 1. Antibacterial activity compounds 3a-h and 5a-t.
Table 1. Antibacterial activity compounds 3a-h and 5a-t.
Ijms 20 01699 i001
ID Ijms 20 01699 i002R1R2MIC, µg/mL
Gram-positiveGram-negative
S.aureus(ATCC 25923)B. Subtillis (VCM V3142D)E. Coli (ATCC 25922)P. fluorescens(P218)
3ap-phenyleneH Ijms 20 01699 i003>256>256>256>256
3bp-phenyleneH4-MeC6H4>256>256>256>256
3cp-phenyleneHMe>256>256>256>256
3dp-phenyleneMe3,4-diClC6H388816
3em-phenyleneH3-ClC6H41283212864
3fm-phenyleneH Ijms 20 01699 i004>256>256>256>256
3gm-phenyleneH Ijms 20 01699 i005>256>256>256>256
3hp-phenyleneH4-EtC6H4256>256256256
5ap-phenyleneH Ijms 20 01699 i006256>256256>256
5bp-phenyleneH Ijms 20 01699 i007>256>256>256>256
5cp-phenyleneHPhOCH2256>256256>256
5dp-phenyleneH4-t-BuC6H4256>256256>256
5ep-phenyleneH4-PhOC6H4256256256>256
5fp-phenyleneH Ijms 20 01699 i004>256>256>256>256
5gp-phenyleneH3-ClC6H41681632
5hp-phenyleneH2-ClC6H4256128128128
5ip-phenyleneH Ijms 20 01699 i008>256>256>256>256
5jp-phenyleneH3,4-diMeOC6H3>256>256>256>256
5kp-phenyleneH3-MeOC6H41286432128
5lp-phenyleneH Ijms 20 01699 i009128256256>256
5mp-phenyleneH4-MeC6H4CH2>256>256>256>256
5np-phenyleneH4-PhC6H4256>256256>256
5o Ijms 20 01699 i010>256>256>256>256
5pp-phenyleneMe3,4-diClC6H3>256>256>256>256
5qp-phenyleneMe Ijms 20 01699 i011256>256256>256
5rp-phenyleneMe4-MeC6H41632832
5sp-phenyleneMe3-ClC6H432326464
5tp-phenyleneH4-MeC6H4>256>256>256>256
RefPefloxacine0.008<0.50.008<0.5
* Measurements performed in triplicates. MIC: Minimal Inhibition Concentration; API: Active Pharmaceutical Ingredient.
Table
Table 2. Antibacterial activity of compounds 3d, 3e, 5g, 5k, 5r, and 5s.
Table 2. Antibacterial activity of compounds 3d, 3e, 5g, 5k, 5r, and 5s.
IDMIC, µg/mL
E. coli (dhs2)E. coli (k802)Enterobacter spp.
3d16168
3e646432
5g321632
5k>64>64>64
5r326464
5s326464
Pefloxacin<0.5<0.5<0.5
* Measurements performed in triplicates. MIC: Minimal Inhibition Concentrations.
Table
Table 3. The human monoamine oxidase (MAO) inhibition potencies of oxadiazole derivatives (3d, 3e, 5g, 5k) and known antibiotics.
Table 3. The human monoamine oxidase (MAO) inhibition potencies of oxadiazole derivatives (3d, 3e, 5g, 5k) and known antibiotics.
IDIC50 (µM)
MAO-AMAO-B
3d14.7 ± 1.850.160 ± 0.0096
3e1.39 ± 0.0670.030 ± 0.0025
5g5.47 ± 0.5180.064 ± 0.0054
5k12.0 ± 0.2050.216 ± 0.019
Linezolid462.1
Tedizolid8.75.7

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Shetnev, A.; Baykov, S.; Kalinin, S.; Belova, A.; Sharoyko, V.; Rozhkov, A.; Zelenkov, L.; Tarasenko, M.; Sadykov, E.; Korsakov, M.; et al. 1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer. Int. J. Mol. Sci. 2019, 20, 1699. https://doi.org/10.3390/ijms20071699

AMA Style

Shetnev A, Baykov S, Kalinin S, Belova A, Sharoyko V, Rozhkov A, Zelenkov L, Tarasenko M, Sadykov E, Korsakov M, et al. 1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer. International Journal of Molecular Sciences. 2019; 20(7):1699. https://doi.org/10.3390/ijms20071699

Chicago/Turabian Style

Shetnev, Anton, Sergey Baykov, Stanislav Kalinin, Alexandra Belova, Vladimir Sharoyko, Anton Rozhkov, Lev Zelenkov, Marina Tarasenko, Evgeny Sadykov, Mikhail Korsakov, and et al. 2019. "1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer" International Journal of Molecular Sciences 20, no. 7: 1699. https://doi.org/10.3390/ijms20071699

APA Style

Shetnev, A., Baykov, S., Kalinin, S., Belova, A., Sharoyko, V., Rozhkov, A., Zelenkov, L., Tarasenko, M., Sadykov, E., Korsakov, M., & Krasavin, M. (2019). 1,2,4-Oxadiazole/2-Imidazoline Hybrids: Multi-target-directed Compounds for the Treatment of Infectious Diseases and Cancer. International Journal of Molecular Sciences, 20(7), 1699. https://doi.org/10.3390/ijms20071699

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