Open Access

Synthesis, docking study and biological evaluation of some new thiourea derivatives bearing benzenesulfonamide moiety

Chemistry Central Journal201711:42

DOI: 10.1186/s13065-017-0271-7

Received: 17 February 2017

Accepted: 16 May 2017

Published: 19 May 2017

Abstract

Background

A series of novel N-(2, 6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3at was synthesized by the addition of N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 to the appropriate aromatic amine. The structures of the synthesized compounds were inspired from the second line antituberculosis pro-drugs.

Results

Most of the new compounds were screened for their activity against Mycobacterium tuberculosis. The results of the antimycobacterial assay showed that compound 3i exerted the highest activity (MIC = 3.13 µg/mL), followed by compound 3s (MIC = 6.25 µg/mL).

Conclusion

The structure–activity relationship (SAR) analysis revealed that the introduction of the benzo[1,3]dioxol moiety in 3i and the 4-morpholinyl-4-phenyl moiety in 3s has proven to give the most potent compounds in this study. Docking of the promising compounds inside the active site of M. tuberculosis enoyl reductase InhA was performed in order to emphasize the results. The compounds showed a similar orientation to that of GSK 625 inside the active site of 5JFO and bind to Met 98 in a way similar to that of the co-crystallized ligand.

Keywords

Thiourea Sulfonamides Structure–activity relationship Antimycobacterial

Background

Tuberculosis (TB), is a disease caused by the facultative intracellular bacterium called Mycobacterium tuberculosis (MTB). WHO declared TB as a global health crisis [1] and a main cause of death due to the lack of appropriate treatment against resistant strains [2]. In 2012, TB was responsible for the death of 1.3 million people worldwide, Over 95% of them were from developing countries, also, TB represents the third cause of death for women aged 15–44. In addition, about one-third of the world’s population harbors a dormant MTB infection, representing a significant incidence of the disease for the future [3]. TB treatment is tedious and time-consuming, that requires direct therapy and follow-up for not less than 6 months using these four drugs (isoniazid, rifampicin, pyrazinamide and ethambutol [1, 4]. In addition, the recurrences of latent tuberculosis, are particularly prevalent in individuals with compromised immune system [5]. However, the present treatment protocols have proven to be underwhelming due to drug–drug interactions, intolerance, drug toxicity and poor patient adherence due to the lengthy treatment protocols [1, 6]. That’s why more effective and shorter treatment regimens are required.

Thioureas act as precursors for the synthesis of different classes of acyclic and heterocyclic compounds, in addition to their high biological activity [710]. Second line antituberculosis pro-drugs as thioacetazone which is useful in preventing resistance to more powerful drugs such as isoniazid, isoxyl (thiocarlide) that is effective against multi-drug resistant strains, ethionamide (ETH) and prothionamide (Fig. 1) [1117], were used to inspire the structures of our new thiourea derivatives, together with their mode of action. On the other hand, sulfonamides were largely employed as preventive and chemotherapeutic agents against various diseases [18], recent studies have shown that sulfonamides also possess antimycobacterial activity [19].
Fig. 1

Second line antituberculosis pro-drugs

For the above-mentioned reasons and as a part of our interest in the synthesis and screening of potentially bioactive compounds [2024], we herein, report the synthesis of some novel N-(2,6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido)benzenesulfonamides 3at to be evaluated for their antimycobacterial activity. The promising compounds 3i and 3s were docked inside the active site of M. tuberculosis enoyl reductase InhA, to predict their possible mode of action. InhA enzyme was chosen as it contains a very hydrophobic site that favorably interacts with thioamide or thiourea moieties [25].

Results and discussion

Chemistry

Isothiocyanates are widely used building blocks in the synthesis of nitrogen, sulfur and oxygen heterocycles [26]. The high electrophilicity and nucleophilicity associated with the carbon and sulfur atoms, respectively, of the isothiocyanates and their extended π electron system make them unique precursors for a large variety of target molecules. The intermediate, N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 [27] used for the preparation of the target compounds have been synthesized via thiophosgenation of sulfadimethoxine 1 at room temperature in the presence of dilute hydrochloric acid, according to the reported procedure (Scheme 1).
Scheme 1

Synthesis of the thiourea derivatives 3at

A series of N-(2,6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3at was prepared by condensation of aromatic amines with N-(2,6-dimethoxypyrimidin-4-yl)-4-isothiocyanatobenzenesulfonamide 2 [27] in dioxane at reflux temperature in the presence of catalytic amounts of triethylamine, (Scheme 1). The structures of synthesized compounds 3at were confirmed by the absence of characteristic absorption band at 2000–2200/cm (N=C=S). Also, the IR of 3 is characterized by the presence of NH, thiocarbonyl (C=S) and SO2 absorption bands. For example, the 1H NMR spectrum of compound 3b showed two singlets at δ 3.81 and 3.84 ppm which were assigned for the two methoxy protons, a singlet at δ 6.1 ppm assigned to the pyrimidine-H, two downfield shifted singlets at δ 11.5 and 11.9 ppm which were readily assigned to the HN(1) and HN(2) protons, in addition to the presence of methyl, SO2NH and aromatic protons. The thiocarbonyl group of the thiourea moiety was also observed in the 13C-NMR spectrum. The formation of thioureas 3at can be explained through the previously reported mechanism [24].

In vitro antimycobacterial activity evaluation

Evaluation of the synthesized compounds against M. tuberculosis (RCMB 010126) was initially carried out using the microplate Alamar blue assay (MABA) at the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University (Cairo, Egypt) at a concentration of 200 µg/mL (Table 1). As seen in Table 1, compound 3i was the most potent analog exhibiting good antimycobacterial activity that produced growth inhibition of 74.9%.
Table 1

The inhibitory activities of the synthesized compounds against Mycobacterium tuberculosis

Sample code

% Inhibition

SD

3a

25.3

1.1

3b

0

0

3c

0

0

3d

8.9

0.3

3e

36.2

2.1

3f

11.3

0.8

3g

14.7

0.6

3i

74.9

4.3

3l

12.5

1.1

3n

0

0

3o

0

0

3p

23.9

1.4

3q

41.2

2.8

3r

53.8

2.6

3s

59.2

4.3

3t

10.3

0.8

Isoniazid

93.5

1.4

The results of the antimycobacterial activity as minimum inhibitory concentration (MIC) are presented in Table 2 and confirming that compound 3i exerted the highest antimycobacterial activity (MIC = 3.13 µg/mL), followed by compound 3s (MIC = 6.25 µg/mL) then compounds 3r, 3q, 3e, 3a, 3p, 3g, 3l, 3f, 3t and 3d, respectively. On the other hand, compounds 3b3c3n and 3o exhibited no antimycobacterial activity under these experimental conditions.
Table 2

The estimated minimum inhibitory concentrations (MICs) of the synthesized compounds against Mycobacterium tuberculosis

Tested compounds

MIC values (µg/mL)

MIC (µM)

3a

50

98.8

3b

NA

NA

3c

NA

NA

3d

200

373.8

3e

50

102.2

3f

200

435.7

3g

100

192.7

3i

3.13

6.4

3l

200

400.8

3n

NA

NA

3o

NA

NA

3p

100

173.9

3q

25

43.5

3r

12.5

21.7

3s

6.25

11.8

3t

200

397.6

Isoniazid

0.195

1.42

NA no anti-TB activity under the screening conditions

From the results in Table 2, it is apparent that the 4-position of the thiourea derivatives 3at, crucially affected the antimycobacterial activity. In which, incorporation of a Benzo[1,3]dioxol group in compound 3i led to good activity against M. tuberculosis (MIC = 3.13 µg/mL). The introduction of a methoxy group at 2-position of the spirodecane system increased the activity (except for 3b). The introduction of an electron-donating group at the 4-position, as methyl and methoxy groups, increased the activity. However, di- and trimethoxy substitutions (compounds 3c, 3d and 3g) led to decrease in the lipophilicity with a subsequent decrease in the antimycobacterial activity, indicating that the increased lipophilicity is crucial for the antitubercular activity.

It is well documented that increasing the lipophilicity, increases the diffusion through the lipid domain, thus, increasing the efficacy of the antimycobacterial agent [2831].

Molecular docking

Tuberculosis is characterized by a number of drug targets namely: InhA, RpoB, DNA Gyrase, ATP synthase, and DprE1, inhibitors of those targets were found to be promising leads [32]. Isoniazid is still the most potent treatment targeting InhA enzyme. Isoniazid was found to interfere with Nicotinamide adenine dinucleotide (NAD)-utilizing enzymes, primarily the enoyl-ACP reductase encoded by the InhA gene, leading to the arrest of mycolic acid synthesis, which is essential to M. tuberculosis [32, 33]. InhA enzyme was chosen based upon its hydrophobic properties that favorably interact with thioamide or thiourea moieties [25].

In our present study to determine the possible mode of action of the target compounds, molecular docking of compounds 3i and 3s was performed in the active site of Mycobacterium tuberculosis enoyl reductase InhA to explore their possible binding modes. The protein data bank file (PDB: 5JFO) was selected for this purpose. The file contains M. tuberculosis enoyl reductase InhA enzyme co-crystallized with N-[1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl]-5-[(1S)-1-(3-methyl-1H-pyrazol- 1-yl)ethyl]-1,3,4-thiadiazol-2-amine (GSK 625) [34]. All docking procedures were carried out using molecular operating environment (MOE) software 10.2008. Docking protocol was verified by re-docking of the co-crystallized ligand in the binding pocket of the enzyme with energy score (S) = −10.44 kcal/mol and root mean standard deviation (RMSD) = 0.39 (Fig. 2). The 2D ligand interaction of compound 3i (Fig. 3) demonstrates that the compound binds to the amino acid of the active site Met 98 through two hydrogen bonds (1.72, 2.44 Å). Regarding compound 3s, the 2D and 3D ligand interaction simulations (Figs. 4 and 5) showed that 3s binds in the same fashion to the co-crystallized ligand displaying two hydrogen bonds with the active pocket amino acid Met 98 leading to an overall binding energy of = −11.64 kcal/mol (Table 3).
Fig. 2

Superimposition of the co-crystallized ligand (red) and the re-docked ligand (blue) inside the active site of 5JFO

Fig. 3

2D interactions of compound 3i with the active site amino acids of 5JFO

Fig. 4

2D interactions of compound 3s with the active site amino acids of 5JFO

Fig. 5

3D docking of compound 3s (S = −11.64 kcal/mol) in the active site of 5JFO

Table 3

Docking results of the targeted compounds inside 5JFO active site

Compound

Energy score (S) (Kcal/mol)

Amino acids

Interacting groups

Length (Å)

Ligand

−10.44

Met 98

C=N

2.72

Met 98

NH

2.75

3a

−8.44

Met 98

SO2

3.01

Met 98

NH

2.14

3b

−8.30

Met 98

SO2

2.17

Met 98

NH

3.12

3c

−7.89

Met 98

SO2

2.63

Met 98

NH

2.35

3d

−9.02

Met 98

SO2

1.78

Met 98

NH

2.54

3e

−8.80

Met 98

SO2

1.90

Met 98

NH

2.31

Ser 19

CO

2.76

3f

−8.32

Met 98

SO2

3.13

Met 98

NH

2.85

3g

−7.92

Met 98

SO2

2.12

Met 98

NH

2.90

3i

−9.07

Met 98

SO2

1.72

Met 98

NH

2.44

3l

−7.91

Met 98

SO2

2.41

Met 98

NH

3.04

3n

−9.00

Met 98

SO2

2.31

Met 98

NH

2.82

Thr 17

N–CH3

3.08

3o

−8.42

Met 98

SO2

2.89

Met 98

NH

3.10

Ser 20

CO

1.99

3p

−8.98

Met 98

SO2

2.67

Met 98

NH

2.71

Ser 19

CO

3.05

3r

−8.14

Met 98

SO2

1.83

Met 98

NH

2.98

Ser 19

N (triazole)

3.02

Thr 17

N (triazole)

2.56

3s

−11.64

Met 98

SO2

2.15

Met 98

NH

2.65

Ser 20

CO

3.10

3t

−7.88

Met 98

SO2

2.73

Met 98

NH

2.84

SAR (structure activity relationship)

From the results revealed by the antimycobacterial activity and the docking study, it is apparent that the group attached to the thiourea is crucial for the activity. The benzo[1,3]dioxol derivative 3i (MIC = 6.4 µM) was the most potent, followed by the 4-morpholinyl-4-phenyl derivative 3s (MIC = 11.8 µM), the oxygen atom of morpholine binds to Ser 20 inside the active site. Also, 3i and 3s have shown similar binding to that of the co-crystallized ligand inside the active site of M. tuberculosis enoyl reductase InhA and the best binding score in this series. The dipyridinyl-[1,2,4]triazole 3r and the 2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindole derivative 3q also showed potent activity, with MIC = 21.7 and 43.5 µM, respectively. It is apparent that the nitrogens of the triazole ring in 3r tend to make additional binding interactions inside the active site of the enzyme as well as the carbonyl group in 3q, which may contribute to their antimycobacterial activity.

Experimental

Chemistry

All analyses were performed at King Saud University Research Center (Riyadh, Saudi Arabia). Melting points were determined in open capillaries on a Gallenkamp melting point apparatus (Sanyo Gallenkamp, Southborough, UK). Precoated silica gel plates (Kieselgel 0.25 mm, 60 F254, Merck, Darmstadt, Germany) were used for thin layer chromatography using a developing solvent system of 4:1 chloroform/methanol and the spots were detected by the ultraviolet lamp. IR spectra (KBr discs) were recorded using an FT-IR spectrometer (Perkin Elmer, Waltham, MA, USA). 1H-NMR spectra were scanned on NMR spectrometer (Bruker AXS Inc., Flawil, Switzerland), operating at 500 MHz for 1H and 125.76 MHz for 13C. Chemical shifts are expressed in δ values (ppm) relative to TMS as an internal standard, using DMSO-d6 as a solvent. Mass spectra were recorded on a 600 GC/MS (Clarus, Middletown, CT, USA) and TQ 320 GC/MS/MS mass spectrometers (Varian, West Sussex, UK). Elemental analyses were done on a model 2400 CHNSO analyzer (Perkin Elmer, Waltham, MA, USA). All reagents used were of the analytical grade.

General method for the synthesis N-(2,6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3at

A mixture of isothiocyanatobenzenesulfonamide 2 [27] (0.01 mol) with a heterocyclic amine (0.01 mol) was refluxed in dioxane (30 mL) containing triethylamine (0.1 mL) for 1 h. The solvent was evaporated, the solid obtained was washed with petroleum ether (bp 40–60 °C) and crystallized from ethanol to afford the thiourea derivatives.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(2-methyl-4-nitro-phenyl)thioureido)benzenesulfonamide (3a)

This compound was obtained as yellow powder from ethanol; yield 84%; m.p. 137.9 °C. IR: 3471, 3363, 3230 (NH), 3100 (arom.), 2983, 2817 (aliph.), 1633 (CN), 1396, 1151 (SO2), 1290 (CS). 1H-NMR: δ 2.1 [s, 3H, CH3], 3.79, 3.84 [2s, 6H, 2OCH3], 6.5 [s, 1H, H-pyrimidine], 6.8–7.9 [m, 7H, Ar–H], 9.8 [s, 1H, SO2NH], 11.4 [s, 2H, 2NH]; 13C-NMR: 17.4, 55.4 (2), 80.6, 112.7, 120.7, 124.5 (2), 126.6, 128.4 (2), 133.0, 139.8, 141.3, 143.8 (2), 154.4, 162.6, 169.0, 178.5. Anal. Calcd. for C20H22N6O6S2: C, 47.42%; H, 4.38%; N, 16.59%; S, 12.66%. Found: C, 47.40%; H, 4.30%; N, 16.50%; S, 12.60%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(2-methyl-6-nitro-phenyl)thioureido) benzenesulfonamide (3b)

This compound was obtained as yellow powder from ethanol; yield 82%; m.p. 199.3 °C. IR: 3458, 3371 (NH), 3100 (arom.), 2970, 2831 (aliph.), 1622 (CN), 1392, 1130 (SO2), 1251 (CS). 1H-NMR: δ 2.1 [s, 3H, CH3], 3.81, 3.84 [2s, 6H, 2OCH3], 6.1 [s, 1H, H-pyrimidine], 6.8–8.0 [m, 7H, Ar–H], 8.8 [s, 1H, SO2NH], 11.5, 11.9 [2s, 2H, 2NH]. 13C-NMR: 18.3, 53.4, 53.6, 83.6, 121.7, 123.8 (2), 126.2 (2), 131.2 (2), 136.5(2), 136.9, 141.2, 144.8, 155.6, 167.1, 172.8, 186.3. Anal. Calcd. for C20H22N6O6S2: C, 47.42%; H, 4.38%; N, 16.59%; S, 12.66%. Found: C, 47.40%; H, 4.30%; N, 16.50%; S, 12.60%.

4-(3-(3,5-Dimethoxyphenyl)thioureido)-N-(2,6-dimethoxy-pyrimidin-4-yl)benzenesulfonamide (3c)

This compound was obtained as yellow powder from ethanol; yield 80%; m.p. 179.6 °C. IR: 3437, 3210 (NH), 3100 (arom.), 2920, 2848 (aliph.), 1622 (CN), 1354, 1153 (SO2), 1274 (CS). 1H-NMR: δ 3.81, 3.82 [2s, 6H, 2OCH3, pyrimidine], 3.84, 3.88 [2s, 6H, 2OCH3], 5.6 [2s, 3H, CH, dimethoxyphenyl], 6.2 [s, 1H, H-pyrimidine], 6.9–8.1 [m, 4H, Ar–H], 8.9 [s, 1H, SO2NH], 9.7 [s, 2H, 2NH]; 13C-NMR: 55.1, 55.4, 55.5 (2), 79.4, 98.7, 112.7 (2), 128.1 (2), 131.7 (2), 134.6, 140.7, 142.3, 158.7 (2), 159.1, 163.8, 174.6, 192.4. Anal. Calcd. For C21H23N5O6S2:C, 49.89%; H, 4.59%; N, 13.85%; S, 12.68%. Found: C, 49.80%; H, 4.50%; N, 13.80%; S, 12.60%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(3,4,5-trimethoxyphenyl)thioureido) benzenesulfonamide (3d)

This compound was obtained as Brown powder from ethanol; yield 87%; m.p. 275.5 °C. IR: 3433, 3356 (NH), 3053 (arom.), 2939, 2835 (aliph.), 1616 (CN), 1354, 1128 (SO2), 1276 (CS). 1H-NMR: δ 3.61, 3.67 [2s, 6H, 2O CH3], 3.81, 3.84 [2s, 9H, 3OCH3], 5.9 [s, 2H, Ar–H], 6.4 [s, 1H, H-pyrimidine], 6.9–8.3 [m, 4H, Ar–H], 9.7 [s, 1H, SO2NH], 11.8 [s, 2H, 2NH]. 13C-NMR: 55.2, 55.6, 55.9 (2), 63.7, 83.5, 98.0 (2), 121.6 (2), 128.3 (2), 132.1, 133.7, 135.2, 140.6, 156.0 (2), 158.8, 166.4, 170.3, 181.1. Anal. Calcd. for C22H25N5O7S2: C, 49.34%; H, 4.70%; N, 13.08%; S, 11.97%. Found: C, 49.34%; H, 4.70%; N, 13.08%; S, 11.97%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(4-ethoxyphenyl)thioureido) benzenesulfonamide (3e)

This compound was obtained as Grey powder from ethanol; yield 83%; m.p. 234.2 °C. IR: 3296, 3217 (NH), 3100 (arom.), 2978, 2929, 2873 (aliph.), 1639 (CN), 1390, 1168 (SO2), 1246 (CS). 1H-NMR: δ 1.2 [t, 3H, CH3, J = 8 Hz], 3.90, 3.92 [2s, 6H, 2OCH3], 4.0 [q, 2H, CH2], 6.8 [s, 1H, H-pyrimidine], 7.0–8.4 [m, 8H, Ar–H], 9.5 [s, 1H, SO2NH], 11.7 [s, 2H, 2NH]. 13C-NMR: 15.2, 53.2, 53.9, 63.5, 84.6, 115.0 (2), 120.3 (2), 127.9 (2), 128.3 (2), 133.3 (2), 142.1, 153.4, 154.0, 164.8, 172.6, 179.3. Anal. Calcd. for C21H23N5O5S2: C, 51.52%; H, 4.74%; N, 14.30%; S, 13.10%. Found: C, 51.50%; H, 4.70%; N, 14.30%; S, 13.10%.

4-(3-Benzyl-thioureido)-N-(2,6-dimethoxy-pyrimidin-4-yl)benzenesulfonamide (3f)

This compound was obtained as yellow powder from ethanol; yield 88%; m.p. > 360 °C. IR: 3365, 3188 (NH), 3034 (arom.), 2981, 2827 (aliph.), 1622 (CN), 1390, 1128 (SO2), 1251 (CS). 1H-NMR: δ 3.61, 3.64 [2s, 6H, 2OCH3], 4.3 [s, 2H, CH2], 6.4 [s, 1H, CH pyrimidine], 7.0–8.5 [m, 9H, Ar–H], 9.9 [s, 1H, SO2NH], 10.8, 11.7 [2s, 2H, 2NH]. 13C-NMR: 49.2, 53.4, 53.8, 85.6, 120.8 (2), 125.7, 127.3 (2), 127.7 (2), 128.8 (2), 139.4 (2), 139.6, 161.5, 167.9, 171.9, 178.8. Anal. Calcd. for C20H21N5O4S2: C, 52.27%; H, 4.61%; N, 15.24%; S, 13.95%. Found: C, 52.20%; H, 4.60%; N, 15.20%; S, 13.90%.

4-(3-(2,3-Dimethoxybenzyl)thioureido)-N-(2,6-dimethoxy-pyrimidin-4-yl) benzenesulfonamide (3g)

This compound was obtained as yellow powder from ethanol; yield 88%; m.p. 151.1 °C. IR: 3292, 3181 (NH), 3047 (arom.), 2986, 2866, 2831 (aliph.), 1587 (CN), 1388, 1172 (SO2), 1228 (CS). 1H-NMR: δ 3.75, 3.77, 3.80 [3s, 12H, 4OCH3], 4.3 [s, 2H, CH2],6.8 [s, 1H, H-pyrimidine], 6.9–8.0 [m, 7H, Ar–H], 8.1, 8.3 [2s, 3H, SO2NH + 2NH];13C-NMR: 40.4, 56.1 (2), 56.7, 60.5, 83.4, 112.3, 120.7 (2), 124.3 (2), 127.0, 128.1 (2), 133.1, 140.2, 146.6, 146.7, 161.4, 165.4, 169.5, 184.6. Anal. Calcd. for C22H25N5O6S2: C, 50.86%; H, 4.85%; N, 13.48%; S, 12.34%. Found: C, 50.80%; H, 4.80%; N, 13.40%; S, 12.30%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-phenethyl-thioureido)benzenesulfonamide (3h)

This compound was obtained as yellow powder from ethanol; yield 85%; m.p. 189.7 °C. IR: 3367, 3238 (NH), 3100 (arom.), 2981, 2811 (aliph.), 1635 (CN), 1394, 1130 (SO2), 1274 (CS). 1H-NMR: δ 2.7, 3.5 [2t, 4H, 2CH2, J = 8 Hz], 3.63, 3.65 [2s, 6H, 2OCH3], 6.6 [s, 1H, H-pyrimidine], 7.1–8.1 [m, 9H, Ar–H], 9.7 [s, 1H, SO2NH], 11.0 [s, 2H, 2NH]. 13C-NMR: 35.4, 40.4, 55.6, 55.9, 85.0, 124.1 (2), 126.6, 128.8 (2), 129.0 (2), 129.7 (2), 132.7, 140.1, 142.3, 161.5, 165.4, 170.2, 181.8. Anal. Calcd. for C21H23N5O4S2: C, 53.26%; H, 4.90%; N, 14.79%; S, 13.54%. Found: C, 53.26%; H, 4.90%; N, 14.79%; S, 13.54%.

4-(3-Benzo[1,3]dioxol-5-yl-thioureido)-N-(2,6-dimethoxy-pyrimidin-4-yl)benzenesulfonamide (3i)

This compound was obtained as yellow powder from ethanol; yield 85%; m.p. 247.1 °C. IR: 3385, 3169 (NH), 3064 (arom.), 2910, 2895 (aliph.), 1618 (CN), 1381, 1124 (SO2), 1240 (CS). 1H-NMR: δ 3.82, 3.84 [2s, 6H, 2OCH3], 5.9 [s, 1H, H-pyrimidine], 6.0 [s, 2H, O–CH2–O], 6.7–8.4 [m, 7H, Ar–H], 9.8 [s, 1H, SO2NH], 10.7, 11.4 [2s, 2H, 2NH]. 13C-NMR: 55.4, 56.5, 83.7, 101.2, 109.3, 113.6, 118.2, 120.9 (2), 128.8 (2), 129.1, 136.7, 142.6, 146.8, 148.2, 152.9, 167.5, 172.4, 182.0. Anal. Calcd. for C20H19N5O6S2: C, 49.07%; H, 3.91%; N, 14.31%; S, 13.10%. Found: C, 49.00%; H, 3.90%; N, 14.30%; S, 13.10%.

4-(3-Benzo[1,3]dioxol-4-yl-methyl-thioureido)-N-(2,6-dimethoxy-pyrimidin-4-yl)benzenesulfonamide (3j)

This compound was obtained as yellow powder from ethanol; yield 89%; m.p. > 360 °C. IR: 3410, 3371 (NH), 3100 (arom.), 2966, 2889 (aliph.), 1553 (CN), 1376, 1128 (SO2), 1251 (CS). 1H-NMR: δ 3.61, 3.64 [2s, 6H, 2OCH3], 4.2 [s, 2H, CH2NH], 6.0 [s, 2H, O–CH2–O], 6.6 [s, 1H, H-pyrimidine], 7.0–8.5 [m, 7H, Ar–H], 9.9 [s, 1H, SO2NH], 10.3, 12.6 [2s, 2H, 2NH]; 13C-NMR: 52.4, 54.3, 54.6, 82.4, 101.3, 108.5, 108.9, 120.6, 124.6 (2), 128.9 (2), 129.7, 133.2, 141.0, 143.9, 146.7, 160.5, 161.7, 163.6, 173.0. Anal. Calcd. for C21H21N5O6S2: C, 50.09%; H, 4.20%; N, 13.91%; S, 12.73%. Found: C, 50.09%; H, 4.20%; N, 13.90%; S, 12.70%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-naphthalen-1-yl-thioureido)benzenesulfonamide (3k)

This compound was obtained as yellow powder from ethanol; yield 81%; m.p. 152.0 °C. IR: 3354, 3232 (NH), 3051 (arom.), 2951, 2836 (aliph.), 1620 (CN), 1394, 1184 (SO2), 1247 (CS). 1H-NMR: δ 3.83, 3.86 [2s, 6H, 2OCH3], 5.9 [s, 1H, H-pyrimidine], 6.9–8.4 [m, 11H, Ar–H], 9.8 [s, 1H, SO2NH], 11.8 [s, 2H, 2NH]. 13C-NMR: 55.3, 56.5, 86.0, 107.9, 115.8, 122.7, 123.2 (2), 124.1, 125.9, 126.3, 127.1, 127.9, 128.2 (2), 130.0, 134.6, 143.1 (2), 163.7, 165.5, 173.6, 181.0. Anal. Calcd. for C23H21N5O4S2: C, 55.74%; H, 4.27%; N, 14.13%; S, 12.94%. Found: C, 55.70%; H, 4.20%; N, 14.10%; S, 12.90%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(5,6,7,8-tetrahydro-naphthalen-1-yl)thioureido)benzenesulfonamide (3l)

This compound was obtained as brown powder from ethanol; yield 83%; m.p. 257.9 °C. IR: 3400, 3309 (NH), 3082 (arom.), 2931, 2835 (aliph.), 1616 (CN), 1377, 1136 (SO2), 1280 (CS). 1H-NMR: δ 1.6–2.8 [m, 8H, 4CH2 cyclo], 3.81, 3.84 [2s, 6H, 2OCH3], 6.2 [s, 1H, H-pyrimidine], 6.6-8.0 [m, 7H, Ar–H], 8.8 [s, 1H, SO2NH], 11.7, 11.9 [2s, 2H, 2NH]. 13C-NMR: 22.6 (2), 23.3, 29.8, 55.1, 55.6, 82.7, 117.4, 119.5 (2), 120.8, 124.0, 127.4 (2), 137.1, 137.5, 137.6 (2), 146.5, 161.1, 161.8, 170.9, 179.8. Anal. Calcd. for C23H25N5O4S2: C, 55.29%; H, 5.04%; N, 14.02%; S, 12.84%. Found: C, 55.20%; H, 5.00%; N, 14.00%; S, 12.80%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-indan-5-yl-thioureido)benzenesulfonamide (3m)

This compound was obtained as yellow powder from ethanol; yield 80%; m.p. 119.1 °C. IR: 3458, 3253 (NH), 3061 (arom.), 2945, 2889, 2839 (aliph.), 1627 (CN), 1396, 1130 (SO2), 1273 (CS). 1H-NMR: δ 1.9–2.0 [m, 2H, CH2 cyclo], 2.7–2.8 [m, 4H, 2CH2 cyclo], 3.79, 3.80 [2s, 6H, 2OCH3], 5.8 [s, 1H, H-pyrimidine], 6.6–8.4 [m, 7H, Ar–H], 9.9 [s, 1H, SO2NH], 11.4, 12.3 [2s, 2H, 2NH]. 13C-NMR: 25.6, 32.2 (2), 55.4, 56.5, 79.8, 116.8 (2), 124.6 (2), 124.9, 128.3 (2), 137.2, 138.4, 144.6 (2), 145.7, 154.8, 170.0, 172.4, 183.0. Anal. Calcd. for C22H23N5O4S2: C, 54.42%; H, 4.77%; N, 14.42%; S, 13.21%. Found: C, 54.40%; H, 4.70%; N, 14.40%; S, 13.20%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(2-(1-methyl-1H-pyrrol-2-yl)ethyl)thioureido)benzenesulfonamide (3n)

This compound was obtained as brown powder from ethanol; yield 86%; m.p. > 360 °C. IR: 3410, 3216 (NH), 3100 (arom.), 2943, 2839 (aliph.), 1595 (CN), 1386, 1126 (SO2), 1262 (CS). 1H-NMR: δ 2.8 [t, 2H, CH2, J = 8 Hz], 3.5 [s, 3H, N–CH3], 3.70, 3.72 [2s, 6H, 2OCH3], 3.9 [t, 2H, CH2–NH, J = 8 Hz], 5.9–6.7 [m, 3H, 3H-pyrrole], 6.8 [s, 1H, H-pyrimidine], 7.0–8.2 [m, 4H, Ar–H], 9.9 [s, 1H, SO2NH], 11.2, 12.3 [2s, 2H, 2NH]. 13C-NMR: 25.4, 35.6, 44.2, 52.9, 53.8, 83.6, 105.1, 107.3, 123.8, 123.9 (2), 125.5, 128.0 (2), 134.2, 143.1, 162.6, 163.9, 173.4, 182.3. Anal. Calcd. for C20H24N6O4S2: C, 50.41%; H, 5.08%; N, 17.63%; S, 13.46% Found: C, 50.40%; H, 5.00%; N, 17.60%; S, 13.46%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(2-pyrrolidin-1-yl-ethyl)thioureido) benzenesulfonamide (3o)

This compound was obtained as brown powder from ethanol; yield 86%; m.p. 280.0 °C. IR: 3342, 3323 (NH), 3045 (arom.), 2972, 2856 (aliph.), 1622 (CN), 1386, 1180 (SO2), 1274 (CS). 1H-NMR (DMSO-d 6 ): δ 1.6–1.8 [m, 4H, CH2–CH2–pyrrolidine], 2.51–2.56 [m, 4H, CH2–N–CH2pyrrolidine], 2.62–2.68 [m, 2H, N–CH2], 3.4 [t, 2H, CH 2 –NH, J = 8 Hz], 3.82, 3.85 [2s, 6H, 2OCH3], 6.5 [s, 1H, H-pyrimidine], 6.9–7.9 [m, 4H, Ar–H], 9.8 [s, 1H, SO2NH], 11.4 [s, 2H, 2NH]; 13C-NMR: 23.3 (2), 40.4, 51.6, 52.9 (2), 53.5, 54.1, 81.7, 120.7 (2), 127.7 (2), 136.4, 140.2, 161.0, 166.3, 170.6, 180.5. Anal. Calcd. for C19H26N6O4S2: C, 48.91%; H, 5.62%; N, 18.01%; S, 13.74%. Found: C, 48.90%; H, 5.60%; N, 18.00%; S, 13.70%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(9,10-dioxo-9,10-dihydro-anthracen-2-yl)thioureido)benzenesulfonamide (3p)

This compound was obtained as yellow powder from ethanol; yield 84%; m.p. 299.6 °C. IR: 3433, 3348, 3219 (NH), 3064 (arom.), 2921, 2871 (aliph.), 1705, 1672 (2CO), 1625 (CN), 1338, 1178 (SO2), 1280 (CS). 1H-NMR: δ 3.70, 3.73 [2s, 6H, 2OCH3], 6.6 [s, 1H, H-pyrimidine], 6.9–8.4 [m, 11H, Ar–H], 10.8 [s, 1H, SO2NH], 11.6, 11.9 [2s, 2H, 2NH]. 13C-NMR: 57.2, 57.8, 83.7, 118.5, 121.6 (2), 126.7 (2), 130.0, 133.4 (2), 133.7 (2), 134.1 (2), 134.7 (2), 135.3 (2), 141.0 (2), 155.1, 162.7, 172.4, 180.5, 183.7 (2). Anal. Calcd. for C27H21N5O6S2: C, 56.34%; H, 3.68%; N, 12.17%; S, 11.14%. Found: C, 56.30%; H, 3.60%; N, 12.10%; S, 11.10%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(2-methyl-1,3-dioxo-2,3-dihydro-1H-isoindol-5-yl)thioureido)benzenesulfonamide (3q)

This compound was obtained as yellow powder from ethanol; yield 85%; m.p. 194.7 °C. IR: 3475, 3363, 3219 (NH), 3055 (arom.), 2951, 2809 (aliph.), 1755, 1689 (2CO), 1622 (CN), 1382, 1157 (SO2), 1271 (CS). 1H-NMR: δ 3.0 [s, 3H, N-CH3], 3.70, 3.72 [2s, 6H, 2OCH3], 6.4 [s, 1H, H-pyrimidine], 6.8- 8.0 [m, 7H, Ar–H], 9.0 [s, 1H, SO2NH], 10.9 [s, 2H, 2NH]; 13C-NMR: 23.7, 55.4, 55.6, 81.2, 117.3, 125.0 (2), 127.9 (2), 128.0 (2), 130.7, 135.0 (2), 142.1 (2), 162.7, 168.5 (2), 168.8, 174.0, 185.2. Anal. Calcd. for C22H20N6O6S2: Anal. Calcd. for C27H21N5O6S2 C, 49.99%; H, 3.81%; N, 15.90%; S, 12.13%. Found: C, 49.90%; H, 3.80%; N, 15.90%; S, 12.10%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(3,5-dipyridin-2-yl- [1,2,4]triazol-4-yl)thioureido)benzenesulfonamide (3r)

This compound was obtained as brown powder from ethanol; yield 83%; m.p. 286.0 °C. IR: 3411, 3188 (NH), 3100 (arom.), 2960, 2829 (aliph.), 1622 (CN), 1377, 1138 (SO2), 1249 (CS). 1H-NMR: δ 3.70, 3.74 [2s, 6H, 2OCH3], 6.6 [s, 1H, H-pyrimidine], 7.1–8.6 [m, 12H, Ar–H], 9.8 [s, 1H, SO2NH], 10.9, 11.9 [s, 2H, 2NH]. 13C-NMR: 56.7, 56.9, 85.6, 121.9 (2), 125.0 (2), 126.1 (2), 128.8 (2), 137.9, 138.2 (2), 140.6, 143.1 (2), 150.0 (2), 151.6 (2), 162.8, 164.0, 174.3, 187.1. Anal. Calcd. for C25H22N10O4S2: Anal. Calcd. for C27H21N5O6S2 C, 50.84%; H, 3.75%; N, 23.71%; S, 10.86%. Found: C, 50.80%; H, 3.7 0%; N, 23.70%; S, 10.86%.

N-(2,6-Dimethoxy-pyrimidin-4-yl)-4-(3-(4-morpholin-4-yl-phenyl)thioureido)benzenesulfonamide (3s)

This compound was obtained as brown powder from ethanol; yield 81%; m.p. 184.0 °C. IR: 3377, 3304 (NH), 3069 (arom.), 2962, 2852 (aliph.), 1635 (CN), 1379, 1151 (SO2), 1263 (CS). 1H-NMR: δ 3.1–3.2 [m, 4H, CH2–N–CH2], 3.60–3.68 [m, 4H, CH2–O–CH2], 3.79, 3.85 [2s, 6H, 2OCH3], 5.9 [s, 1H, H-pyrimidine], 6.5–8.3 [m, 8H, Ar–H], 9.9 [s, 1H, SO2NH], 10.6, 11.0 [2s, 2H, 2NH]. 13C-NMR: 49.7 (2), 55.4, 55.6, 66.6 (2), 84.0, 112.9 (2), 119.8 (2), 124.9 (2), 127.6, 129.8 (2), 133.7, 140.0, 146.8, 155.9, 167.0, 173.4, 179.7. Anal. Calcd. for C23H26N6O5S2: C, 52.06%; H, 4.94%; N, 15.84%; S, 12.09%. Found: C, 52.00%; H, 4.90%; N, 15.80%; S, 12.00%.

4-(3-Adamantan-1-yl-thioureido)-N-(2,6-dimethoxy-pyrimidin-4-yl) benzenesulfonamide (3t)

This compound was obtained as white crystals from ethanol; yield 81%; m.p. 164.6 °C. IR: 3346, 3176 (NH), 3100 (arom.), 2910, 2852 (aliph.), 1625 (CN), 1375, 1186 (SO2), 1236 (CS). 1H-NMR: δ 1.6–1.7 [m, 3H, 3CH-adamantyl], 1.8-2.1 [m, 12H, 6CH2-adamantyl], 3.80, 3.83 [2s, 6H, 2OCH3], 5.9 [s, 1H, H-pyrimidine], 7.1–8.4 [m, 4H, Ar–H], 9.8 [s, 1H, SO2NH], 11.4, 12.6 [2s, 2H, 2NH]. 13C-NMR: 29.4 (3), 35.2 (3), 42.5 (3), 43.4, 59.2, 63.4, 85.3, 120.6 (2), 130.7 (2), 136.8, 142.1, 153.9, 169.5, 172.8, 182.1. Anal. Calcd. for C23H29N5O4S2: C, 54.85%; H, 5.80%; N, 13.91%; S, 12.73%. Found: C, 54.80%; H, 5.80%; N, 13.90%; S, 12.70%.

Antimycobacterial activity

The M. tuberculosis (RCMB 010126) strain was provided from the culture collection of the Regional Center for Mycology and Biotechnology (RCMB), Al-Azhar University (Cairo, Egypt). The antimycobacterial activity of the synthesized compounds was performed using the microplate Alamar blue assay technique [35] with minor modifications which were performed in sterile 96 well microplates. To prevent dehydration in experimental wells, the outer perimeter wells of the plate were filled with sterile water. 100 µL of 105 CFU/mL M. tuberculosis inoculum was added to the wells. For detecting the antimycobacterial activity of the synthesized compounds, 100 µL (at 200 µg/mL) dissolved in dimethyl sulfoxide was then added to the wells. Isoniazid was used as a positive control. Also, additional control wells consisted of bacteria only was performed. Five replicates were tested for each treatment along with the controls. The plates were then incubated for at least 4 days at 37 °C. After the end of incubation period, 20 µL of Alamar blue solution (Alamar Biosciences/Accumed, Westlake, OH, USA) and 12.5 µL of 20% Tween 80 (Merck, Darmstadt, Germany) were added to all the wells of the plate. The plates were then incubated again at 37 °C for 24 h in the dark. The results were recorded at 24 h post-reagent addition at 590 nm. The percent of inhibition was defined as: \(1 - \left( {{\text{mean of the test well}}/{\text{mean of B wells}}} \right) \; \times 100\). For the determination of the minimum inhibitory concentrations, stock solutions of the tested compounds were prepared in dimethyl sulfoxide and subsequent twofold dilutions were performed in the 96 well microplates to achieve concentrations ranged from 200 to 0.1 µg/mL. These concentrations were tested for their activity with estimation of the inhibition % as described before. The lowest drug concentration causing inhibition of M. tuberculosis was considered as the MIC.

Molecular docking

The molecular model of the new thiourea derivatives was done using MOE software suite 10.2008. Following geometry optimization, a systematic conformational search was carried out to RMS gradient of 0.05 Å with energy minimization of the resultant conformations employing the ConfSearch module implemented in MOE. All molecular mechanics computations were performed with the Merck Force Field (MMFF94s). The crystallographic structure of M. tuberculosis enoyl reductase InhA in complex with N-{1-[(2-chloro-6-fluorophenyl)methyl]-1H-pyrazol-3-yl]-5-[(1S)-1-(3-methyl-1H-pyrazol-1-yl)ethyl]-1,3,4-thiadiazol-2-amine (GSK 625) was obtained from the Protein Data Bank (PDB ID: 5JFO). Water molecules were ignored and hydrogen atoms were added to the enzyme and partial charges were calculated. Validation followed by docking of the compounds into the active site were carried out, after removing the co-crystallized ligand. The target protein was kept rigid, while the ligands adopt 50 separate docking simulations using default parameters. The conformations were chosen based on their S score, and appropriate fitting with the relevant amino acids in the binding pocket.

Conclusion

A new series of N-(2,6-dimethoxypyrimidin-4-yl)-4-(3-(aryl)thioureido) benzenesulfonamides 3at was synthesized. The target compounds were designed and synthesized as potential antitubercular agents. Compounds 3i and 3s were found to be the most potent in this study, the reference drug used in this study was isoniazid. Compound 3i (MIC = 3.13 µg/mL), was the most potent followed by compound 3s (MIC = 6.25 µg/mL). Also, the docking study showed that all the docked compounds exhibited similar binding interaction as those previously reported by the co-crystallized ligand when docked into the active site of M. tuberculosis enoyl reductase InhA.

Declarations

Authors’ contributions

MMG, MSAG, MSA were responsible for the organic synthesis, and characterization experiments. AMS was responsible for the docking study. MMA and MME carried out the antimycobacterial activity. All authors read and approved the final manuscript.

Acknowledgements

The authors would like to extend their sincere appreciation to the Deanship of Scientific Research at King Saud University for its funding of this research through the Research Group Project no. RGP-302.

Competing interests

The authors declare that they have no competing interests.

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Authors’ Affiliations

(1)
Department of Pharmacognosy, College of Pharmacy, King Saud University
(2)
Department of Drug Radiation Research, National Center for Radiation Research and Technology, Atomic Energy Authority
(3)
Department of Chemistry, Faculty of Science, Al-Azhar University
(4)
The Regional Center for Mycology and Biotechnology, Al-Azhar University

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