Home Synthesis and antitubercular activity of new N-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-(nitroheteroaryl)carboxamides
Article Open Access

Synthesis and antitubercular activity of new N-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-(nitroheteroaryl)carboxamides

  • Roberto Martínez EMAIL logo , Gladys J. Nieves Zamudio , Gustavo Pretelin-Castillo , Rubén O. Torres-Ochoa , José L. Medina-Franco , Clara I. Espitia Pinzón , Mayra Silva Miranda , Eugenio Hernández and Blanca Alanís-Garza
Published/Copyright: April 19, 2019
Download Article (PDF)
Heterocyclic Communications
From the journal Heterocyclic Communications Volume 25 Issue 1

Abstract

Nitro-substituted heteroaromatic carboxamides 1a-e were synthesized and tested against three Mycobacterium tuberculosis cell lines. The activities can be explained in terms of the distribution of the electronic density across the nitro-substituted heteroaromatic ring attached to the amide group. 1,3,5-Oxadiazole derivatives 1c-e are candidates for the development of novel antitubercular agents. Ongoing studies are focused on exploring the mechanism by which these compounds inhibit M. tuberculosis cell growth.

Keywords: antitubercular agents; carboxamides; 1,3,4-oxadiazoles; synthesis

Introduction

Tuberculosis (TB) is a one of the top causes of death worldwide, and in 2017 the World Health Organization reported 10 million new cases of TB, 1.6 million deaths due to TB and 0.3 million deaths resulting from co-infections by HIV [1]. Although the rate of decline in TB was 3.9 % from 2015 to 2017, there were 457,560 new cases of multidrug-resistant TB (MDR-TB) and 558,000 people with rifampicin-resistant TB (RR-TB). Therefore, TB poses a challenge to researchers searching for potent drugs that can control the growth of the bacillus Mycobacterium tuberculosis while minimizing side effects or the development of drug resistance [2]. Excellent reviews have been published covering the literature between 2000 and 2015 about compounds with activity against M. tuberculosis [3, 4, 5]. Notably, Kumar and co-workers grouped anti-TB compounds into 62 different molecular frameworks. In their most recent compilation (2005-2015), they only included compounds exhibiting minimum inhibitory concentration (MIC) values similar to or higher than those of standard drugs used in bioassays [6], with 12 different oxadiazoles meeting this criterion. The 1,3,4-oxadiazole ring system indeed exerts a wide variety of pharmacological activities such as anti-inflammatory [7], antiviral [8], antineoplastic [9], FAK inhibitory [10], adulticidal [11] and anti-Alzheimer properties [12]. A review of the literature up to 2017 includes 440 citations of 1,3,4-oxadiazoles with biological activity but only 34 of these citations describe 1,3,4-oxadiazoles with anti-TB activity [13]. A 5-nitrofuranyl scaffold is present in many derivatives with diverse biological activities including anti-inflammatory [14, 15], antibacterial [16], antileishmanial [17] and anti-tubercular agents [18, 19, 20, 21]. It has been proposed that the presence of the nitro group increases the ability of a molecule to form hydrogen bonds with receptor [22].

We have recently reported the synthesis of caulerpin, a bis-indole alkaloid from the marine alga Caulerpa sp. that displays excellent biological activity [23]. Nevertheless, the conventional synthetic approach to medicinal chemistry is a time-consuming, complicated and expensive process that produces candidate compounds with low diversity. Although this approach is still valuable, it is unable to fulfill the increasing demand for new drugs. Therefore, experimental drug discovery is currently being aided with chemo-informatics approaches that are frequently used to identify active compounds, select candidates, and optimize leads. Chemo-informatic approaches has been promising over the past few years in finding pharmacologically active compounds across a broad range of therapeutic areas [24]. Katsuno and co-workers published a comprehensive summary of the criteria to consider when developing new drugs against infectious diseases such as TB [25], and in our work we consider criteria such as selectivity index (SI>10), MIC (lower than 10 μΜ) and activity against drug-resistant strains, to guide our screening of new compounds having potential use as anti-TB drugs. In the present study, we report a new compound active against M. tuberculosis, selected by carrying out a structural analysis of a major public database of compounds reported to have TB activity. We then used the bioisosterism concept [26] to generate a list of other possible compounds (Figure 1) which we subsequently synthesized and tested as inhibitors of the growth of M. tuberculosis.

Figure 1 Designed compounds based on isosteric modification of lead compound 1a.
Figure 1

Designed compounds based on isosteric modification of lead compound 1a.

Results and discussion

We conducted a chemotype analysis of compounds in PubChem [27] with reported activity against M. tuberculosis. To this end, the chemotype methodology developed by Johnson and Xu [28] to identify promising molecular scaffolds as starting points for optimization was used. In the approach of Johnson and Xu, each chemotype is assigned a unique alphanumeric identifier of four characters [29]. The same approach was previously published to identify promising scaffolds for anti-AIDS activity [30]. Based on the substructure search, the molecular scaffold of compound 1a (compound identifier, CID in PubChem 4225334) was selected (chemotype identifier BKQ4R). We also compared the newly designed compounds with the reference molecule 1a. The high structure similarity suggested that their biological activity would be also comparable (Figure 1). This assumption was made considering that here are no activity cliffs, specifically, no similar compounds with very different biological activity [31]. Physical and spectroscopic data for compound 1a have not yet been published.

The preparation of compounds 1a-e started with esterification of 4-chlorobenzoic acid (2, Scheme 1), with MeOH in the presence of sulfuric acid to provide methyl 4-chlorobenzoate (3). Next, the 4-chlorophenylhydrazide 4 was prepared from 3 [32]. Treatment of 4 with cyanogen bromide (CNBr) in MeOH afforded 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (5) in 62% yield [33]. The coupling reaction between 5 and crude acyl chlorides 6a-e was achieved in the presence of sodium hydride in dry THF to afford the desired products 1a-e in 30-62% yield [34].

Scheme 1 Synthetic route to compounds 1a-e. Reagents and conditions: (i) MeOH, H2SO4, reflux; (ii) NH2NH2, MeOH; (iii) CNBr, MeOH; (iv) NaH, anhydrous THF, reflux.
Scheme 1

Synthetic route to compounds 1a-e. Reagents and conditions: (i) MeOH, H2SO4, reflux; (ii) NH2NH2, MeOH; (iii) CNBr, MeOH; (iv) NaH, anhydrous THF, reflux.

The activities of compounds 1a-e as inhibitors of the growth of the M. tuberculosis strains H37Rv and 209 were evaluated using 250 μg/mL-0.98 μg/mL serial two-fold dilutions. Rifampin (RIF) is usually used for the treatment of mycobacterial infections, including TB, and the anti-TB activities of the synthesized compounds 1a-e were compared with the activity of RIF. As shown in Table 1, RIF shows the MIC100 value of 0.06 μg/mL and is hence more active than compounds 1a-e. Of compounds 1a-e, 1a shows the most activity, with the MIC100 value of 7.8 μg/mL (23.45 μΜ), followed by 1b, 1d and 1e, each of them with MIC100 of 15.6 μg/mL, followed by 1c. According to the criteria for anti-TB hits and leads, the MIC100 value of 1a is not competent under replicating growth conditions (< 10 μM) but compounds 1b-e demonstrate a greater SI and, therefore, can be considered as anti-TB leads. Minimal microbicidal activity measurements showed 1a has the highest bactericidal activity, followed by 1d and 1b, and 1e, with 1c being the least active. The values of minimum bactericidal activity show that 1a also has the highest bactericidal activity followed by 1d and 1b, with compounds 1c and 1e being the least active [35].

Table 1

Anti-M. tuberculosis effects and cytotoxicity levels of compounds 1a-e.

CompoundRMIC100 (μg/mL)MBC (μg/mL)IC50, in Vero cells (μg/mL)Selectivity index (SI)
1a5-NO2C4H2O7.802.00106.013.59
1b5-NO2C4H2S15.6015.6036.04.61
1c5-NO2C4H3N31.2531.2568.32.18
1d3-NO2C6H415.603.9061.13.92
1e5-C6H515.6031.2544.12.83
Rifampin-0.06ND>1000>16,666

  1. M. tuberculosis H37Rv ATCC 27294 reference strain: M. tuberculosis. MIC: minimal inhibition concentration determined by using REMA. IC50: inhibitory concentration at 50% determined by carrying out an MTT assay in Vero cells. MBC: minimal bactericidal activity. SI = IC50/MIC100.

Another criterion used to determine whether a compound can be considered as an early lead for an anti-TB drug is in vitro activity against M. tuberculosis strains that are resistant to a single TB drug, such as isoniazid or RIF, indicating a new mechanism of action. We also evaluated the compounds with non-virulent bacteria M. tuberculosis H37Ra. Non-virulent bacteria are susceptible to lower concentrations of drugs than virulent strains. Specifically, the activities of the synthesized compounds 1a–1e as inhibitors of the growth of bacteria of the M. tuberculosis strains H37Ra and 209 (RIF resistant-strain) using 250 μg/mL- 0.98 μg/mL serial two-fold dilutions were evaluated (Table 2). Also listed in Table 2 are the MIC100 values of RIF. All compounds are active against M. tuberculosis H37Ra (non-pathogenic) and 209 (resistant strain) with compound 1a being the most active. This result shows that compound 1a is an anti-TB hit with a new mechanism of action that should be explored.

Table 2

REMA-determined MIC100 values of 1a-e against virulent, nonvirulent and RIF-resistant M. tuberculosis bacteria.

CompoundRMIC100 (μg/mL) in H37Rv ATCC 27294MIC100 ( μg/mL) in H37RaMIC100 (μg/mL) in Mtb-209 (resistant)
1a5-NO2C4H2O7.801-2.007.8
1b5-NO2C4H2S15.6015.6015.60
1c5-NO2C4H3N31.257.87.8
1d3-NO2C6H415.6031.3015.60
1e5-C6H515.6062.5031.25
Rifampin-0.060.008>64

  1. M. tuberculosis H37Rv ATCC 27294 reference strain: Mtb. M. tuberculosis H37Ra: non-virulent strain. Mtb-209: RIF-resistant clinical isolate of M. tuberculosis.

It can be seen that bioisosteric modifications of the 5-nitrofuran moiety of compound 1a to give compounds 1b-e preserves anti-TB activity, albeit with inhibitory activities less than that of the lead compound 1a. The data for compounds 1b-e suggest that the anti-TB effect depends on the aromaticity of the ring attached to the amide group, particularly if this ring has low aromaticity (phenyl > thiophene > pyrrole > furan) [36]. The relatively low anti-TB activity of the 5-nitropyrrole compound 1c, relative to the activities of 1b, 1d and 1e, may be due to the pyrrole-NH group of 1c forming a hydrogen bonding interaction with the active site.

Conclusions

Compounds 1a-e were synthesized using two convergent pathways with the hydrazide 2 as a common intermediate. The anti-TB activities of compounds 1a-e were evaluated using three Mycobacterium tuberculosis cell lines. The results suggest that the anti-TB activity of compounds 1a-e can be explained in terms of the distribution of electronic density across the ring attached to the amide group. Our ongoing studies are focused on exploring the mechanism by which these new compounds inhibit M. tuberculosis cell growth.

Experimental

Melting points were measured in open capillaries using a Mel-Temp apparatus. 1H-NMR spectra were recorded in DMSO-d6 on a Jeol Eclipse 300 spectrometer (300 MHz). 13C-NMR spectra were recorded at 75 MHz under otherwise similar conditions. IR spectra were obtained in KBr pellets using a Magna-IR spectrometer. Mass spectra were recorded on a Jeol JEM-AX505HA spectrometer with electronic impact (EI) ionization at 70 eV for low-resolution measurements and a Jeol AccuTOF DART and Jeol JMS700 (FAB+) instruments, for high-resolution measurements. Flash column chromatography was carried out on silica gel 60 (230–400 mesh ASTM) from Macherey-Nagel GmbH. Progress of the reactions was monitored by using TLC. The compounds were visualized using a dual short-wavelength/long-wavelength UV lamp or staining with an ethanol solution of potassium permanganate, vanillin or p-anisylaldehyde. All reagents were used as purchased from Aldrich.

Synthesis of methyl 4-chlorobenzoate (3)

A solution of 4-chlorobenzoic acid (2, 33.07 mmol) and H2SO4 (1 mL) in anhydrous methanol (20 mL) was heated under reflux for 20 h. After consumption of starting material (monitored using TLC), the mixture was neutralized with a saturated NaHCO3 solution (2 x 25 mL) and extracted with AcOEt (3 x 100 mL). The organic extracts were combined, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give 3 as a yellow oil (yield 80 %). The physical and spectral data of 3 were in accordance with previously reported data [37].

Synthesis of 4-chlorobenzohydrazide (4)

A solution of ester 3 (26.36 mmol) and hydrazine (61.85 mmol) in anhydrous methanol (20 mL) was heated under reflux for 12 h. After consumption of the starting material (as monitored using TLC), the reaction mixture was cooled, and the resulting solid was filtered using suction. The crude product was crystallized from hexane to give 4 as a white crystalline solid; yield 82%; mp 162-164°C. The physical and spectral data of 4 were in accordance with previously reported data [37].

Synthesis of 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (5)

A solution of 4 (5.86 mmol) and CNBr (10.65 mmol) in anhydrous methanol was heated under reflux for 5 h. After consumption of the starting material (as monitored using TLC), the mixture was neutralized with a saturated NaHCO3 solution (2 x 25 mL) and the resulting solid was filtered using suction. The crude product was crystallized from methanol to give 5 as a white solid; yield 62%; mp 242-244°C. The physical and spectral data of 5 were in accordance with previously reported data [37].

General procedure for synthesis of compounds 1a-e

A solution of 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-amine (5, 0.51 mmol) in anhydrous THF (15 mL) was treated with NaH (1.53 mmol), and the resulting mixture was cooled to 0°C under a nitrogen atmosphere before addition of acyl chloride 6a-e (0.51 mmol). The mixture was stirred at room temperature for 15 h, quenched with a saturated NaHCO3 solution (30 mL) and extracted with AcOEt (3 x 50 mL). The organic extracts were combined, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified using flash column chromatography on silica gel eluting with hexanes/EtOAc (6:4) to furnish the 1,3,4-oxadiazole 1a-e.

N-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-5-nitrofuran-2-carboxamide (1a)

Yield 30% of a yellow solid; mp 250-252°C; IR: 3139, 1607 cm-1; 1H NMR (DMF-d7): δ 7.40 (1H, d, J = 4 Hz), 7.64 (2H, d, J = 8 Hz), 7.74 (1H, d, J = 4 Hz), 7.94 (2H, d, J = 8 Hz); 13C NMR (DMF-d7): δ 113.8, 116.5, 123.6, 127.1, 127.8, 129.8, 136.5, 152.2, 157.8, 162.6, 168.3. HRMS (DART). Calcd for C13H8ClN4O5, [M+1]+: m/z 335.0183. Found: m/z 335.0186.

N-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-5-nitrothiophene-2-carboxamide (1b)

Yield 38% of a yellow solid; mp 260-262°C; IR: 3103, 1714 cm-1; 1H NMR (DMSO-d6) δ: 7.68 (2H, d, J = 8 Hz), 7.95 (3H, m), 8.15 (1H, d, J = 4 Hz). 13C NMR (DMSO-d6): δ 124.5, 128.9, 129.4, 130.0, 130.8, 131.4, 137.6, 143.9, 154.2, 159.8, 165.4. HRMS (DART). Calcd for C13H7ClN4O4S, [M]+: m/z 350.9954. Found: m/z 350.9957.

N-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-5-nitro-1H-pyrrole-2-carboxamide (1c)

Yield 30% of a yellow solid; mp 278-280°C; IR: 3176, 1635 cm-1; 1H NMR (DMSO-d6) δ: 6.98 (1H, d, J = 4 Hz), 7.07 (1H, d, J = 4 Hz), 7.67 (2H, d, J = 8.5 Hz), 7.95 (2H, d, J = 8.5 Hz); 13C NMR (DMSO-d6): δ 111.5, 114.6, 122.9, 128.2, 130.1, 132.2, 136.7, 143.4, 158.8, 159.5, 160.0. HRMS (DART). Calcd for C13H9ClN5O4, [M+1]+: m/z 334.0343. Found: m/z 334.0347.

N-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)-3-nitrobenzamide (1d)

Yield 59% of a white solid; mp 264-266°C; IR: 3176, 1635 cm-1; 1H NMR (DMSO-d6): δ 8.88 (1H, s), 8.49 (1H, d, J = 7.5 Hz), 8.39 (1H, d, J = 7.5 Hz), 7.95 (2H, d, J = 8 Hz), 7.78 (1H, m), 7.65 (2H, d, J = 8 Hz); 13C NMR (DMSO-d6): δ 122.1, 123.2, 123.7, 127.4, 128.0, 129.7, 130.5, 130.6, 134.8, 135.4, 136.7, 147.9, 165.6. HRMS (DART). Calcd for C15H10ClN4O4, [M+1]+: m/z 345.0390. Found: m/z 345.0394.

N-(5-(4-Chlorophenyl)-1,3,4-oxadiazol-2-yl)benzamide (1e)

Yield 78% of a white solid; mp 224-226°C; IR: 3050, 1712 cm-1; 1H NMR (DMSO-d6) δ: 7.65 – 7.51 (3H, m), 7.69 (2H, d, J = 8.5 Hz), 7.98 (2H, d, J = 8.5 Hz), 8.04 (2H, d, J = 7 Hz), 12.2 (1H, br); 13C NMR (DMSO-d6): δ 122.2, 127.8, 128.3, 128.6, 129.6, 132.2, 133.0, 136.4, 158.0, 160.4, 164.9. HRMS (DART). Calcd for C15H11ClN3O2, [M+1]+: m/z 300.0540. Found: m/z 300.0540.

In vitro antimycobacterial assay

Stock solutions of all compounds were prepared in 100% dimethyl sulfoxide (DMSO) at 10 μg/mL. For the REMA assay, compounds were diluted in 7H9 medium without tyloxapol. For reference drugs, stocks of 64 μg/mL were prepared and filtered through a membrane with pore diameters of 0.22 mm (Millipore; Darmstadt, Germany). All working solutions were kept refrigerated at -200 C until they were evaluated.

The cytotoxicity assay

The assay was carried out using Vero cell lines (kidney of African green monkey) from ATCC. The cells were cultured in RPMI 1640 medium supplemented with 10% FBS and nonessential amino acids.

Cytotoxicity assay

Ten-thousand Vero cells were placed in a 96 well-plate and incubated for 24 h in 100 μL of RPMI medium. After incubation, the plate was washed and new fresh medium with the compound at a various concentration was added. Each tested compound was incubated for 48h at 37°C in a 5% CO2 atmosphere. Then, a volume of 10 μL of MTT (5 μg/mL in sterile PBS) was added to each well and incubation was continued for another 4 h. The medium was removed and a volume of 100 μL of DMSO was added to solubilize the formazan. Absorbance was determined at a wavelength of 570 nm and cytotoxicity was calculated as % toxicity = (1-(ABS problem/ABS control))*100. Controls were cells without treatment [38].

M. tuberculosis culture conditions

M. tuberculosis, H37Rv, H37Ra and 209 strains were cultivated in a 7H9-glycerol-10% ADC-0.01% tyloxapol medium at 37°C until an O.D. of 0.4 at a wavelength of 600 nm was reached. Working bacteria-solutions were obtained by dilution 1:25 in 7H9-ADC 10%.

Antimicrobial susceptibility test using the resazurin microtiter assay (REMA)

The assay used here was previously described by Collins and Franzablau [39]. Briefly, the outer wells of a 96-well plate were each filled with 200 μL of sterile PBS to prevent dehydration from occurring during the long-duration (8-day) incubation. RIF was used as a reference drug (16 -0.001 μg/mL serial two-fold dilutions) in each plate, and controls of DMSO, DMSO+Mtb, medium, media+Mtb, and compound only to validate the plate were also included. Compounds were evaluated at various concentrations from 0.98 μg/mL to 250 μg/mL, and in triplicate in independent assay experiments. Plates were incubated for six days; then, 30 μL of 0.01% resazurin (weight/volume) (Sigma Aldrich) were added to each well and the plates were incubated for two more days. Visual inspection was used to determine the colors of the contents of each well, with blue interpreted as no growth, pink as growth, and MIC as the last concentration in which blue color were observed. The minimum inhibitory concentration (MIC) is defined as the minimum concentration of tested compound to which there was not higher shift from resazurin (blue) to resorufin (pink) than that generated by control of a 1:100 dilution of the bacterial inoculum [36].

Minimal bactericidal concentration

The MBC values were determined for the well (s)+compound that did produce a shift in color and were then re-incubated in fresh medium. A volume of 5 μL of this well (s) was added to 195 μL of fresh medium and incubated for carrying out the REMA assay as described above. MBC corresponds to the minimum concentration of tested compound that does not produce a shift in cultures reincubated in fresh medium [36].

Selectivity indexes

The SI values were obtained using the formula SI = IC50 in Vero cells and the MIC100 values were determined using REMA.

Acknowledgements

Financial support from the DGAPA and UNAM (projects PAPIIT IN208015 and NUATEI-IIB-UNAM) is gratefully acknowledged. We also thank R. Patiño, A. Peña, E. Huerta, B. Quiroz, L. Velasco, J. Pérez, and E. Segura Salinas for technical support. Gladys J. Nieves Zamudio (273584) and Gustavo Pretelín Castillo (308250) are recipients of CONACYT Graduate Scholarships.

References

[1] <http://www.who.int/en/news-room/fact-sheets/detail/tuberculosis> cited 16 February, 2018Search in Google Scholar

[2] Wong, E.; Cohen, K.; Bishai, W. Rising to the challenge: new therapies for tuberculosis. Trends Microbiol 2013, 21, 493-501.10.1016/j.tim.2013.05.002Search in Google Scholar PubMed PubMed Central

[3] Nayyar, A.; Jain, R. Recent advances in new structural classes of anti-tuberculosis agents. Curr. Med. Chem. 2005, 12, 1873–1886.10.2174/978160805207310904010506Search in Google Scholar

[4] Rawat, B.; Rawat, D.S. Antituberculosis drug research: a critical overview. Med. Res. Rev 2013, 33, 693–764.10.1002/med.21262Search in Google Scholar PubMed

[5] Negi, A. S.; Kumar, J. K.; Luqman, S.; Saikia, D.; Khanuja, S. P. S. Antitubercular potential of plants: A brief account of some important molecules. Med. Res. Rev. 2010, 30, 603-645.10.1002/med.20170Search in Google Scholar PubMed

[6] Kumar, V.; Patel, S.; Jain, R. New structural classes of antituberculosis agents. Med. Res. Rev 2018, 38, 684-740.10.1002/med.21454Search in Google Scholar PubMed

[7] Akhter, M.; Husain, A.; Azad, B.; Ajmal, M. Aroylpropionic acid based 2,5-disubstituted-1,3,4-oxadiazoles: synthesis and their anti-inflammatory and analgesic activities. Eur. J. Med. Chem 2009, 44, 2372–2378.10.1016/j.ejmech.2008.09.005Search in Google Scholar PubMed

[8] Calcagno, A.; D’Avolio, A.; Bonora, S. Pharmacokinetic and pharmacodynamic evaluation of Raltegravir and experience from clinical trials in HIV-positive patients. Expert Opin. Drug Metab. Toxicol 2015, 11, 1167-1176.10.1517/17425255.2015.1056732Search in Google Scholar PubMed

[9] Nieddu, V.; Pinna, G.; Marchesi, I.; Sanna, L.; Asproni, B.; Pinna, G. A.; Bagella, L.; Murineddu, G. Synthesis and antineoplastic evaluation of novel unsymmetrical 1,3,4-oxadiazoles. J. Med. Chem 2016, 59, 10451−10469.10.1021/acs.jmedchem.6b00468Search in Google Scholar PubMed

[10] Sun, J.; Ren, S. Z.; Lu, X. Y.; Li, J. J.; Shen, F. Q.; Xu, C.; Zhu, H. L. Discovery of a series of 1,3,4-oxadiazole-2(3H-thione derivatives containing piperazine skeleton as potential FAK inhibitors. Bioorg. Med. Chem. 2017, 25, 2593–2600.10.1016/j.bmc.2017.03.038Search in Google Scholar PubMed

[11] Tok, F.; Kocyigit-Kaymakcioglu, B.; Tabanca, N.; Estep, A. S.; Gross, A. D.; Geldenhuys, W. J.; Becnel, J. J.; Bloomquist, J. R. Synthesis and structure–activity relationships of carbohydrazides and 1,3,4‐oxadiazole derivatives bearing an imidazolidine moiety against the yellow fever and dengue vector. Aedes aegypti. Pest. Manag. Sci. 2017, 74, 413-421.10.1002/ps.4722Search in Google Scholar

[12] Mei, W.; Ji, S.; Xiao, W.; Wang, X.; Jiang, C.; Ma, W.; Zhang, H.; Gong, J.; Guo, Y. Synthesis and biological evaluation of benzothiazol-based 1,3,4-oxadiazole derivatives as amyloid β-targeted compounds against Alzheimer’s disease Monatsh. Chem. 2017, 148, 1807-1815.10.1007/s00706-017-1993-xSearch in Google Scholar

[13] Search in the SciFinder database with the entry “biological activity of 1,3,4-oxadiazoles”, October 10, 2017.Search in Google Scholar

[14] Kipandula, W.; Young, S.A.; MacNeill, S. A.; Smith, T. K. Screening of the MMV and GSK open access chemical boxes using a viability assay developed against the kinetoplastid Crithidia fasciculata. Mol. Biochem. Parasitol 2018, 222, 61-6910.1016/j.molbiopara.2018.05.001Search in Google Scholar PubMed

[15] Kumar Reddy, A. L.V.; Kathale, N. E. Synthesis, Characterization and antiinflammatory activity of chalcone derivatives linked with Apocynin and 5-nitrofuran moiety. Asian J. Chem 2018, 30, 312-316.10.14233/ajchem.2018.20950Search in Google Scholar

[16] Xu, B., Ding, X., Wu, Y.; Cui, L.; Qian, P.; Wang, D.; Zhao, Y. Synthesis and antibacterial activity of oxazolidinone derivatives containing nitro heteroaromatic moiety. Chem. Res. Chin. Univ 2018 34, 51-56.10.1007/s40242-018-7302-3Search in Google Scholar

[17] Romero, A. H.; Medina, R.; Alcala, A.; Garcia-Marchan, Y.; Nunez-Duran, J.; Leanez, Jacques; Mijoba, Ali; Ciangherotti, Carlos; Serrano-Martin, Xenon; Lopez, Simon E. Design, synthesis, structure-activity relationship and mechanism of action studies of a series of 4-chloro-1-phthalazinyl hydrazones as a potent agent against Leishmania braziliensis. Eur. J. Med. Chem 2017, 127, 606-620.10.1016/j.ejmech.2017.01.022Search in Google Scholar PubMed

[18] Asadipour, A.; Edraki, N.; Nakhjiri, M.; Yahya-Meymandi, A.; Alipour, E.; Saniee, P.; Siavoshi, F.; Shafiee, A.; Foroumadi, A. Anti-Helicobacter pylori activity and structure-activity relationship study of 2-alkylthio-5-(nitroaryl)-1,3,4-thiadiazole derivatives. IJPR. 2013, 12, 281-287.Search in Google Scholar

[19] Krasavin, M.; Lukin, A.; Vedekhina, T.; Manicheva, O.; Dogonadze, M.; Vinogradova, T.; Zabolotnykh, N.; Rogacheva, E.; Kraeva, L.; Yablonsky, P. Conjugation of a 5-nitrofuran-2-oyl moiety to aminoalkylimidazoles produces non-toxic nitrofurans that are efficacious in vitro and in vivo against multidrug-resistant Mycobacterium tuberculosis. Eur. J. Med. Chem 2018, 157, 1115-1126.10.1016/j.ejmech.2018.08.068Search in Google Scholar PubMed

[20] Chiarelli, l. R.; Mori, M.; Barlocco, D.; Beretta, G.; Gelain, A.; Pini, E.; Porcino, M.; Mori, G.; Stelitano, G.; Costantino, L.; Lapillo, M.; Bonanni, D.; Poli, G.; Tuccinardi, T.; Villa, S.; Meneghetti, F. Discovery and development of novel salicylate synthase (MbtI) furanic inhibitors as antitubercular agents. Eur. J. Med. Chem 2018, 155, 754-763,10.1016/j.ejmech.2018.06.033Search in Google Scholar PubMed

[21] Yempalla, K. R.; Munagala, Y. G.; Singh, S.; Magotra, A.; Kumar, S.; Rajput, V. S.; Bharate, S. S.; Tikoo, M.; Singh, G. D.; Khan, I. A.; Vishwakarma, R. A.; Singh, P.P. Nitrofuranyl methyl piperazines as new anti-TB agents: identification, validation, medicinal chemistry, and pk studies. ACS Med. Chem. Lett 2015, 6, 1041-1046.10.1021/acsmedchemlett.5b00141Search in Google Scholar PubMed PubMed Central

[22] Szatylowicz H.; Stasyuk O. A.; Fonseca Guerra C.; Krygowski, T. M. Effect of intra- and intermolecular interactions on the properties of para-substituted nitrobenzene derivatives. Crystals 2016, 6, 29.10.3390/cryst6030029Search in Google Scholar

[23] Canché-Chay, C.; Gómez-Cansino, R.; Espitia-Pinzón, C.; Torres-Ochoa, R. O.; Martínez, R. Synthesis and anti-tuberculosis activity of the marine natural product caulerpin and its analogues. Mar. Drugs 2014, 12, 1757-1772.10.3390/md12041757Search in Google Scholar PubMed PubMed Central

[24] Gasteiger, J. Chemoinformatics: achievements and challenges, a personal view. Molecules 2016, 21, 151-165.10.3390/molecules21020151Search in Google Scholar PubMed PubMed Central

[25] Katsuno, K.; Burrows, J. N.; Duncan, K.; van Huijsduijnen, R. H.; Kaneko, T.; Kita, K.; Mowbray, C.E.; Schmatz, D.; Warner, P.; Slingsby, B.T. Hit and lead criteria in drug discovery for infectious diseases of the developing world. Nat. Rev. Drug Discov. 2015, 14, 751-758.10.1038/nrd4683Search in Google Scholar PubMed

[26] Moreira Lima, L.; Barreiro, E. Bioisosterism: a useful strategy for molecular modification and drug design. Curr. Med. Chem. 2005, 12, 23-49.10.2174/0929867053363540Search in Google Scholar PubMed

[27] Kim S.; Thiessen, P. A.; Bolton, E. E.; Chen, J.; Fu, G.; Gindulyte, A.; Han, L.; He, J.; He, S.; Shoemaker, B. A.; Wang, J.; Yu, B.; Zhang, J.; Bryant, S. H. PubChem substance and compound databases. Nucleic Acids Res. 2016, 44, D1202-13.10.1093/nar/gkv951Search in Google Scholar PubMed PubMed Central

[28] Xu Y. J.; Johnson M. Using molecular equivalence numbers to visually explore structural features that distinguish chemical libraries. J. Chem. Inf. Comput. Sci 2002, 42, 912–926.10.1021/ci025535lSearch in Google Scholar PubMed

[29] Xu Y. J.; Johnson M.A. Algorithm for naming molecular equivalence classes represented by labeled pseudographs. J. Chem. Inf. Comput. Sci 2001, 41,181–185.10.1021/ci0003911Search in Google Scholar PubMed

[30] Medina-Franco, J. L.; Petit, J.; Maggiora, G. M. Hierarchical strategy for identifying active chemotype classes in compound databases. Chem. Biol. Drug Des. 2006, 67, 395-408.10.1111/j.1747-0285.2006.00397.xSearch in Google Scholar PubMed

[31] Medina-Franco, J. L. Activity cliffs: facts or artifacts? Chem. Biol. Drug Des. 2013, 81, 553–556.10.1111/cbdd.12115Search in Google Scholar PubMed

[32] Jorge, S.D.; Palace-Berl, F.; Masunari, A.; Cechinel, C. A.; Ishii, M.; Pasqualoto, K. F. M; Tavares, L.C. Novel benzofuroxan derivatives against multidrug-resistant Staphylococcus aureus strains: design using Topliss’ decision tree, synthesis and biological assay. Bioorg. Med. Chem 2011, 19, 5031-5038.10.1016/j.bmc.2011.06.034Search in Google Scholar PubMed

[33] Patel, N. B.; Patel, J. C. Synthesis and antimicrobial activity of 3-(1,3,4-oxadiazol-2-yl) quinazolin-4(3H-ones. Sci. Pharm. 2010, 78, 171–193.10.3797/scipharm.0912-16Search in Google Scholar PubMed PubMed Central

[34] Hou, Z.; Nakanishi, I.; Kinoshita, T.; Takei, Y.; Yasue, M.; Misu, R.; Suzuki, Y.; Nakamura, S.; Kure, T.; Ohno, H.; Murata, K.; Kitaura, K.; Hirasawa, A.; Tsujimoto, G.; Oishi, S.; Fujii, N. Structure-based design of novel potent protein kinase CK2 (CK2) inhibitors with phenyl-azole scaffolds. J. Med. Chem. 2012, 55, 2899–2903.10.1021/jm2015167Search in Google Scholar PubMed

[35] Coronado-Aceves, E. W.; Sánchez-Escalante, J. J.; López-Cervantes, J.; Robles-Zepeda, R. E.; Velázquez, C.; Sánchez-Machado, D. I.; Garibay-Escobar, A. Antimycobacterial activity of medicinal plants used by the Mayo people of Sonora, Mexico. J. Ethnopharmacol 2016, 190, 106-115.10.1016/j.jep.2016.05.064Search in Google Scholar

[36] Balaban, A. T.; Oniciu, D. C.; Katritzky, A. R. Aromaticity as a cornerstone of heterocyclic chemistry. Chem. Rev. 2004, 104, 2777-2812.10.1021/cr0306790Search in Google Scholar

[37] Khan, S. A.; Ahuja, P.; Husain, A. Oxidative cyclization of isoniazid with fluoroquinolones: synthesis, antibacterial and antitubercular activity of new 2,5‐disubstituted 1,3,4‐ oxadiazoles. J. Chin. Chem. Soc 2017, 64, 918–924.].10.1002/jccs.201600199Search in Google Scholar

[38] Mossman, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods 1983, 65, 55-63.10.1016/0022-1759(83)90303-4Search in Google Scholar

[39] Collins, L. A.; Franzblau, S. G. Microplate Alamar Blue assay versus BACTEC 460 system for high-throughput screening of compounds against Mycobacterium tuberculosis and Mycobacterium avium. Antimicrob. Agents Chemother 1997, 41,1004-1009.10.1128/AAC.41.5.1004Search in Google Scholar PubMed PubMed Central

Received: 2018-10-30
Accepted: 2018-11-19
Published Online: 2019-04-19

© 2019 Roberto Martínez et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 Public License.

Articles in the same Issue

  1. Research Article
  2. Magnesium porphyrazine with peripheral methyl (3,5-dibromophenylmethyl)amino groups – synthesis and optical properties
  3. Synthesis and fungicidal activity of novel imidazo[4, 5-b]pyridine derivatives
  4. Synthesis of indazolo[5,4-b][1,6]naphthyridine and indazolo[6,7-b][1,6]naphthyridine derivatives
  5. Zinc Chloride Catalyzed Amino Claisen Rearrangement of 1-N-Allylindolines: An Expedient Protocol for the Synthesis of Functionalized 7-Allylindolines
  6. Synthesis and Biological Evaluation of (E)-N’-Benzylidene-7-methyl-2-propyl-1H-benzo[d] imidazole-5-carbohydrazides as Antioxidant, Anti-inflammatory and Analgesic agents
  7. Efficient synthesis, reactions and spectral characterization of pyrazolo[4’,3’:4,5]thieno[3,2-d] pyrimidines and related heterocycles
  8. Asymmetric Mannich Reaction: Synthesis of Novel Chiral 5-(substituted aryl)-1,3,4-Thiadiazole Derivatives with Anti-Plant-Virus Potency
  9. Synthesis and antitubercular activity of new N-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-(nitroheteroaryl)carboxamides
  10. Remarkable electronic effect on the total stereoselectivity of the cycloaddition reaction of arylnitrile oxides with pyrrol-2-one derivatives
  11. Preliminary Communications
  12. Crystal structure and molecular docking studies of new pyrazole-4-carboxamides
  13. Research Article
  14. Synthesis of polycyclic phosphonates via an intramolecular Diels-Alder reaction of 2-benzoylbenzalaldehyde and alkenyl phosphites
  15. Asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol and zeaenol
  16. The first in situ synthesis of 1,3-dioxan-5-one derivatives and their direct use in Claisen-Schmidt reactions
  17. Synthesis and fungicidal activities of perfluoropropan-2-yl-based novel quinoline derivatives
  18. Combined XRD-paramagnetic 13C NMR spectroscopy of 1,2,3-triazoles for revealing copper traces in a Huisgen click-chemistry cycloaddition. A model case
  19. Cytotoxic and antimicrobial activities of some novel heterocycles employing 6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
  20. Substrate-controlled Diastereoselective Michael Addition of Alkylidene Malonates by Grignard Reagents
  21. Synthesis of 1,2,3 triazole-linked benzimidazole through a copper-catalyzed click reaction
  22. Synthesis and spectral characteristics of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides
  23. Facile One-pot Protocol of Derivatization Nitropyridines: Access to 3-Acetamidopyridin-2-yl 4-methylbenzenesulfonate Derivatives
  24. Naphthalene substituted benzo[c]coumarins: Synthesis, characterization and evaluation of antibacterial activity and cytotoxicity
  25. A Green Synthesis and Antibacterial Activity of N-Arylsulfonylhydrazone Compounds
  26. Preliminary Communications
  27. Facile Synthesis of Spiro[cyclohexane-1,3’-indoline]-2,2’-diones
  28. Research Article
  29. Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives
  30. [DMImd-DMP]: A highly efficient and reusable catalyst for the synthesis of 4H-benzo[b]pyran derivatives
https://doi.org/10.1515/hc-2019-0007
Keywords for this article
antitubercular agents; carboxamides; 1,3,4-oxadiazoles; synthesis
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Article
  2. Magnesium porphyrazine with peripheral methyl (3,5-dibromophenylmethyl)amino groups – synthesis and optical properties
  3. Synthesis and fungicidal activity of novel imidazo[4, 5-b]pyridine derivatives
  4. Synthesis of indazolo[5,4-b][1,6]naphthyridine and indazolo[6,7-b][1,6]naphthyridine derivatives
  5. Zinc Chloride Catalyzed Amino Claisen Rearrangement of 1-N-Allylindolines: An Expedient Protocol for the Synthesis of Functionalized 7-Allylindolines
  6. Synthesis and Biological Evaluation of (E)-N’-Benzylidene-7-methyl-2-propyl-1H-benzo[d] imidazole-5-carbohydrazides as Antioxidant, Anti-inflammatory and Analgesic agents
  7. Efficient synthesis, reactions and spectral characterization of pyrazolo[4’,3’:4,5]thieno[3,2-d] pyrimidines and related heterocycles
  8. Asymmetric Mannich Reaction: Synthesis of Novel Chiral 5-(substituted aryl)-1,3,4-Thiadiazole Derivatives with Anti-Plant-Virus Potency
  9. Synthesis and antitubercular activity of new N-[5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl]-(nitroheteroaryl)carboxamides
  10. Remarkable electronic effect on the total stereoselectivity of the cycloaddition reaction of arylnitrile oxides with pyrrol-2-one derivatives
  11. Preliminary Communications
  12. Crystal structure and molecular docking studies of new pyrazole-4-carboxamides
  13. Research Article
  14. Synthesis of polycyclic phosphonates via an intramolecular Diels-Alder reaction of 2-benzoylbenzalaldehyde and alkenyl phosphites
  15. Asymmetric total synthesis of filamentous fungi related resorcylic acid lactones 7-epi-zeaenol and zeaenol
  16. The first in situ synthesis of 1,3-dioxan-5-one derivatives and their direct use in Claisen-Schmidt reactions
  17. Synthesis and fungicidal activities of perfluoropropan-2-yl-based novel quinoline derivatives
  18. Combined XRD-paramagnetic 13C NMR spectroscopy of 1,2,3-triazoles for revealing copper traces in a Huisgen click-chemistry cycloaddition. A model case
  19. Cytotoxic and antimicrobial activities of some novel heterocycles employing 6-(1,3-diphenyl-1H-pyrazol-4-yl)-4-oxo-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile
  20. Substrate-controlled Diastereoselective Michael Addition of Alkylidene Malonates by Grignard Reagents
  21. Synthesis of 1,2,3 triazole-linked benzimidazole through a copper-catalyzed click reaction
  22. Synthesis and spectral characteristics of N-(1-([1,2,4]triazolo[3,4-b][1,3,4]thiadiazol-6-ylamino)-2,2,2-trichloroethyl)carboxamides
  23. Facile One-pot Protocol of Derivatization Nitropyridines: Access to 3-Acetamidopyridin-2-yl 4-methylbenzenesulfonate Derivatives
  24. Naphthalene substituted benzo[c]coumarins: Synthesis, characterization and evaluation of antibacterial activity and cytotoxicity
  25. A Green Synthesis and Antibacterial Activity of N-Arylsulfonylhydrazone Compounds
  26. Preliminary Communications
  27. Facile Synthesis of Spiro[cyclohexane-1,3’-indoline]-2,2’-diones
  28. Research Article
  29. Synthesis and AChE inhibitory activity of N-glycosyl benzofuran derivatives
  30. [DMImd-DMP]: A highly efficient and reusable catalyst for the synthesis of 4H-benzo[b]pyran derivatives
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 8.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hc-2019-0007/html
Scroll to top button