Startseite Naturwissenschaften Synthesis and biological evaluation of novel 4-oxo-5-cyano thiouracil derivatives as SecA inhibitors
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Synthesis and biological evaluation of novel 4-oxo-5-cyano thiouracil derivatives as SecA inhibitors

  • Fante Bamba , Jinshan Jin , Phang C. Tai und Binghe Wang EMAIL logo
Veröffentlicht/Copyright: 17. Mai 2020
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Heterocyclic Communications
Aus der Zeitschrift Heterocyclic Communications Band 26 Heft 1

Abstract

The continuous emergence of drug-resistant strains of bacteria poses an urgent risk to human health and dictates the need for new antimicrobials. Along this line, we have been working on developing inhibitors of SecA, a key component of the bacterial Sec-dependent secretion machinery. Herein, we describe the synthesis and antimicrobial evaluation of 6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives as potential SecA inhibitors.

Keywords: SecA inhibitor; small molecule; antimicrobial; target; drug-resistant

Introduction

Bacterial infection remains a serious threat to human health, largely because of the continuous emergence of drug-resistance strains of bacteria [1, 2]. To address this concern, both the World Health Organization (WHO) [3] and the US Center for Disease Control (CDC) [4] issued calls for urgent actions. Therefore, there has been much effort in search of new antimicrobials. Especially desirable are efforts toward identifying and inhibiting new targets and/ or new mechanisms of actions. Along this line, we have been working on developing SecA inhibitors as a way to achieve antimicrobial activities. SecA is a key component of the bacterial protein secretion (Sec) pathways. It is an ATPase-driven “motor,” which couples the hydrolysis of ATP to the stepwise translocation of preproteins across the bacterial cytoplasmic membrane [5, 6, 7, 8]. Because SecA is a conserved and essential protein in all bacteria and is absent in humans, it is considered as a promising antibacterial drug target. Various SecA inhibitors (Figure 1) have been described in the literature [9]. Prior to our recent efforts, sodium azide was known as a SecA inhibitor and was reported to possess antibacterial activity with IC50 of 1mM. The first natural product inhibitor of SecA, CJ-21058 [10] isolated from an unidentified fungus, showed antibacterial activity against Gram-positive bacteria by inhibiting the SecA translocation ATPase activity. Additional examples include pannomycin [11], thiazolo[4,5-d]pyrimidine derivatives [12], and others [13, 14]. During our studies on developing small molecule SecA inhibitors, we reported a structure-based virtual screening approach for the discovery of small-molecule inhibitors of the intrinsic ATPase activity of SecA [15]. Later on, we described optimization work [16] and inhibitors of different structural scaffolds [17, 18]. Among all the efforts, we reported 4-oxo-5-cyano thiouracil derivatives as SecA inhibitors [19]. Herein, we describe our efforts in optimizing a hit (Figure 1), a 4-oxo-5-cyano thiouracil, and evaluation of new analogs for antibacterial activities. The work is based on the general structural scaffold of the lead with the aim of searching for the surrounding chemical space [16]. Below, we describe the results and implications in guiding future work in this area.

Figure 1 Lead compound for the synthesis of novel SecA inhibitors.
Figure 1

Lead compound for the synthesis of novel SecA inhibitors.

Results and discussion

Chemistry

Based on our earlier work [19], the compound in Figure 1 was the lead compound for further exploration of the chemical space that could inhibit SecA. In this respect, we focused our attention on the para position of the phenyl group, para position of the benzylthio group and the linker between the biphenyl rings. Specifically, we designed compounds with various substituents such as F-, Me-, MeO- on the phenyl group at position 4; linkers such as -CH2O-, -O-, or -HN-CO- between the two phenyl rings, and substituents such as -N3, -COOMe, or -CF3 at the 4-position of the benzylthioether moiety. Such variations led to compounds 3a-w.

The synthetic route of the compounds 3a-w is outlined in Scheme 1. Compounds 1a-e were prepared by O-benzylation of 4-hydroxybenzaldehyde using the appropriate aryl halides under basic conditions [20]. The corresponding 4-formylbenzoic acid was coupled with the respective phenyl/aryl amines using isobutyl chloroformate in the presence of triethylamine to provide amide of type 1g-h by published procedure [21]. Following the methods for obtaining the core scaffold previously [16], compounds 2a-I were obtained by condensation of an appropriate aldehyde with ethyl cyanoacetate and thiourea in the presence of piperidine. This was followed by the S-benzylation in the presence of potassium carbonate in acetonitrile to obtain compounds 3a-w.

Scheme 1 Syntheses of compounds 3a-w.
Scheme 1

Syntheses of compounds 3a-w.

Biological evaluation

The activities of the synthesized compounds were evaluated in a MIC assay using established procedures using a mutant of Escherichia. coli with a compromised outer membrane [19]. It was found that most of the compounds were not active at concentrations as high as 250 μM. Three compounds showed MIC at about 20 μM (3i, l, w), and one at about 8 μM (3m), which is comparable to some of our best compounds in this class [22]. In addition, select compounds were also tested against Gram-positive bacteria Bacillus anthracis (Sterne strain). With the limited data set, it seems that the potency against B. anthracis was comparable with or higher than that of E. coli. For example, the MIC of 3w was 25 μM against E. coli and 12.5 μM against B. anthracis. By examining the details, it seems that a CF3 group at the R2 position is beneficial, especially if the central linker is –CH2-O-. With a -O- linker, it seems that an ester group also offers a good outcome. Overall, the results are very useful information for those who might be interested in SecA inhibitor for both improved potencies and for avoiding chemical space that would not be productive.

Conclusion

We have described the design, syntheses and biological evaluation of a novel structural class of small-molecule SecA inhibitors with μM inhibition. A CF3 group at the R2 position and a diaryl ether linker seem to be beneficial for improved potency of the lead compound.

Experimental

All chemical reagents and solvents used were reagent grade or purified using standard methods. TLC analyses were conducted on silica gel plates (Sorbent Silica G UV254). Column chromatography was carried out on flash silica gel (Sorbent 230–400 mesh). NMR spectra were recorded at 1H (400 MHz) and 13C (100 MHz) on a Bruker instrument. Coupling constants (J) and chemical shifts (δ) are given in hertz and ppm respectively, using TMS (1H NMR) and solvents (13C NMR) as internal standards.

General procedure for the synthesis of (2a-i): Our previously published [24] procedure was followed. Briefly, to a solution of ethanol (25 mL) and appropriate aldehyde (RCHO, 5 mmol) was added ethyl cyanoacetate (0.5 mL, 5 mmol), thiourea (0.38 g, 5 mmol) and piperidine (1.0 mL, 10 mmol). The mixture was heated under reflux overnight and then cooled to room temperature. The precipitate was dissolved in 0.5 M NaOH (20 mL) and washed with ethyl acetate (15 ml ×3). Then the aqueous solution was acidified to pH ~ 2 by slow addition of 1 M HCl. This caused the product to precipitate, which was then filtered using vacuum filtration.

General procedure for the synthesis of (3a-w): To a solution of 4-(4-(benzyloxy)phenyl)-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile derivatives (1.36 mmol) in CH3CN (10 ml), K2CO3 (6.79 mmol) was added and the resulting mixture was stirred for 10-15 min. To this was added the appropriate (bromomethyl)phenyl derivatives (1.22 mmol) and the reaction was stirred at room temperature for 16-18h. Upon disappearance of the starting material, the solvent was removed in vacuo. The dried residue was washed by H2O (pH = 9-10, 20 mL × 2) and brine (15 ml × 2) followed by product extraction in ethyl acetate (20 ml). The solvent was evaporated in vacuo to obtain crude product, which was purified using silica gel column chromatography.

2-mercapto-4-(4-((4-methylbenzyl)oxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2b)

Yield 37%; white solid; 1H NMR (DMSO-d6): δ 13.16 (bs, 1H), 12.86 (s, 1 H), 7.66 (d, J = 8.8 Hz, 2H), 7.37 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 5.16 (s, 2H); 13C NMR (DMSO-d6): δ 177.5, 161.7, 159.7, 137.8, 133.9, 131.2, 129.5, 128.4, 122.8, 116.1, 115.1, 89.5, 69.9, 21.3. HRMS (ESI) (m/z): Calcd. for C19H14N3O2S, [M-H]+: 348.0803; found: 348.0803.

2-mercapto-4-(4-((4-methoxybenzyl)oxy)phenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2c)

Yield 42%; white solid; 1H NMR (DMSO-d6): δ 13.15 (bs, 1H), 12.85 (s, 1H), 7.66 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.12 (s, 2H), 3.76 (s, 3H); 13C NMR (DMSO-d6): δ 177.4, 161.7, 161.6, 159.6, 159.6, 131.2, 130.1, 128.7, 22.7, 116.1, 115.0, 114.3, 89.4, 69.7, 55.5. HRMS (ESI) (m/z): Calcd. for C19H14N3O3S, [M-H]+: 364.0750; found: 364.0753.

4-(4-((4-fluorobenzyl)oxy)phenyl)-2-mercapto-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (2d)

Yield 40%; white solid; 1H NMR (DMSO-d6): δ 13.17 (bs, 1H), 12.84 (s, 1H), 7.68 (d, J = 8.0 Hz, 2H), 7.54 (m, 2H), 7.24 (t, J = 8.8 Hz, 2H), 7.18 (d, J = 8.8 Hz, 2H), 5.19 (s, 2H); 13C NMR (DMSO-d6): δ 177.4, 163.6, 161.4, 159.5, 133.2, 131.1, 130.6, 115.8, 115.6, 114.9, 89.1, 69.2. HRMS (ESI) (m/z): Calcd. for C18H12FN3O2S, [M-H]+: 352.0551; found: 352.0556.

2-mercapto-6-oxo-4-(4-((4-(trifluoromethyl)benzyl)oxy) phenyl)-1,6-dihydropyrimidine-5-carbonitrile (2e)

Yield 36%; white solid; 1H NMR (DMSO-d6): δ 13.18 (bs, 1H), 12.73 (s, 1H), 7.79 (d, J = 8.0 Hz, 4H), 7.70 (m, 4H), 7.19 (d, J = 8.8 Hz, 2H), 5.34 (s, 2H); 13C NMR (DMSO-d6): δ 177.8, 161.9, 161.2, 159.9, 141.9, 131.2, 129,1, 128.7, 128.6, 126.0, 125.8, 125.8, 123.6, 123.3, 116.3, 115.0, 89.2, 69.0. HRMS (ESI) (m/z): Calcd. for C19H11F3N3O2S, [M-H]+: 402.0519; found: 402.0522.

4-(5-cyano-2-mercapto-6-oxo-1,6-dihydropyrimidin-4-yl)-N-phenylbenzamide (2g)

Yield 42%; white solid; 1H NMR (DMSO-d6): δ 12.32 (s, 1H), 10.41 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.85 (d, J = 8.0 Hz, 2H), 7.80 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 8.0 Hz, 2H), 7.10 (t, J = 7.2 Hz, 2H); 13C NMR (DMSO-d6): δ 180.1, 167.6, 165.3, 163.9, 160.9, 141.1, 139.4, 137.5, 136.6, 129.5, 129.1, 129.0, 128.2, 128.0, 124.3, 120.9, 120.8, 118.6, 117.0, 88.8. HRMS (ESI) (m/z): Calcd. for C18H11N4O2S, [M-H]+: 347.0597; found: 347.0599.

N-(4-chlorophenyl)-4-(5-cyano-2-mercapto-6-oxo-1,6-dihydropyrimidin-4-yl)benzamide (2h)

Yield 38%; white solid; 1H NMR (DMSO-d6): δ 11.76 (s, 1H), 10.52 (s, 1H), 8.03 (d, J = 8.0 Hz, 2H), 7.86 (m, 4H), 7.42 (d, J = 8.8 Hz, 2H); 13C NMR (DMSO-d6): δ 183.1, 166.6, 165.5, 162.7, 140.3, 138.5, 136.3, 128.9, 128.7, 127.9, 122.4, 118.8, 86.2. HRMS (ESI) (m/z): Calcd. for C18H10ClN4O2S, [M-H]+: 381.0208; found: 381.0209.

4-(5-cyano-2-mercapto-6-oxo-1,6-dihydropyrimidin-4-yl)-N-(p-tolyl)benzamide (2i)

Yield 34%; white solid; 1H NMR (DMSO-d6): δ 11.68 (s, 1H), 10.29 (s, 1H), 8.02 (d, J = 8.4 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H), 7.68 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4Hz, 2H); 13C NMR (DMSO-d6): δ 183.6, 167.0, 165.2, 162.7, 140.8, 137.0, 136.6, 133.2, 129.4, 128.6, 127.7, 120.9, 119.1, 86.0, 20.9. HRMS (ESI) (m/z): Calcd. for C19H13N4O2S, [M-H]+: 361.0754; found: 361.0763.

4-(4-(benzyloxy)phenyl)-6-oxo-2-((4-(trifluoromethyl) benzyl)thio)-1,6-dihydropyrimidine-5-carbonitrile (3a)

Yield 54%; white solid; 1H NMR (DMSO-d6): δ 7.93 (d, J = 8.4 Hz, 2H), 7.66 (qd, J = 8.0 Hz, 4H), 7.48 (d, J = 7.2 Hz, 2H), 7.41 (t, J = 7.2 Hz, 1H), 7.37(m, 1H), 7.18 (d, J = 8.4 Hz, 2H), 5.22 (s, 2H), 4.61 (s, 2H); 13C NMR (DMSO-d6): δ 166.7, 165.5, 161.6, 142.5, 136.9, 131.2, 130.1, 128.9, 128.4, 128.3, 127.9, 126.0, 125.8, 125.7, 123.3, 116.9, 115.2, 91.9, 69.9, 33.8. HRMS (ESI) (m/z): Calcd. for C26H17F3N3O2S, [M-H]+: 492.0994; found: 492.0998.

2-((4-azidobenzyl)thio)-4-(4-((4-methylbenzyl)oxy) phenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (3b)

Yield 61%; white solid; 1H NMR (DMSO-d6): δ 8.00 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 7.20 (t, J = 8.8 Hz, 4H), 7.07 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 4.54 (s, 2H), 2.31 (s, 3H); 13C NMR (DMSO-d6): δ 166.8, 165.4, 161.8, 139.0, 137.7, 133.9, 133.9, 131.2, 131.1, 129.5, 128.3, 127.7, 119.6, 116.7, 115.3, 92.0, 69.9, 34.0, 21.2. HRMS (ESI) (m/z): Calcd. for C26H19N6O2S, [M-H]+: 479.1290; found: 479.1300.

methyl4-(((5-cyano-4-(4-((4-methylbenzyl)oxy)phenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)thio)methyl)benzoate (3c)

Yield 55%; white solid; 1H NMR (DMSO-d6): δ 7.94 (d, J = 8.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 7.6 Hz, 2H), 7.36 (d, J = 7.6 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.17 (s, 2H), 4.60 (s, 2H), 3.83 (s, 3H), 2.31 (s, 3H); 13C NMR (DMSO-d6): δ 166.8, 166.4, 165.5, 161.7, 137.7, 133.9, 131.2, 129.8, 129.7, 129.5, 129.0, 128.4, 127.8, 115.2, 91.8, 69.9, 52.5, 34.1, 21.2. HRMS (ESI) (m/z): Calcd. for C28H22N3O4S, [M-H]+: 496.1331; found: 496.1337.

2-((4-azidobenzyl)thio)-4-(4-((4-methoxybenzyl)oxy) phenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (3d)

Yield 50%; white solid; 1H NMR (DMSO-d6): δ 8.00 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.14 (s, 2H), 4.54 (s, 2H), 3.76 (s, 3H); 13C NMR (DMSO-d6): δ 168.1, 166.6, 165.3, 161.9, 161.7, 159.6, 139.0, 133.9, 131.2, 131.1, 130.1, 128.8, 127.7, 119.7, 116.7, 115.3, 115.0, 114.3, 92.0, 69.8, 55.5, 34.0. HRMS (ESI) (m/z): Calcd. for C26H19N6O3S, [M-H]+: 495.1239; found: 495.1249.

Methyl4-(((5-cyano-4-(4-((4-methoxybenzyl)oxy)phenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)thio)methyl)benzoate (3e)

Yield 49%; white solid; 1H NMR (DMSO-d6): δ 7.95 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.0 Hz, 4H), 7.57 (d, J = 8.0 Hz, 2H), 7.41 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 6.96 (d, J = 8.4 Hz, 2H), 5.13 (s, 2H), 4.60 (s, 2H), 3.83 (s, 3H), 3.76 (s, 3H); 13C NMR (DMSO-d6): δ 166.6, 166.3, 165.2, 161.8, 159.6, 142.9, 131.2, 130.1, 128.8, 129.7, 129.1, 128.8, 127.6, 115.1, 114.3, 92.0, 69.8, 55.5, 52.6, 34.1. HRMS (ESI) (m/z): Calcd. for C28H22N3O5S, [M-H]+: 512.1280; found: 522.1299.

4-(4-((4-methoxybenzyl)oxy)phenyl)-6-oxo-2-((4-(trifluoromethyl)benzyl)thio)-1,6-dihydropyrimidine-5-carbonitrile (3f)

Yield 54%; white solid; 1H NMR (DMSO-d6): δ 7.92 (d, J = 8.4 Hz, 2H), 7.66 (qd, J = 8.0 Hz, 4H), 7.41 (d, J = 8.4 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.8 Hz, 2H), 5.12 (s, 2H), 4.60 (s, 2H), 3.73 (s, 3H); 13C NMR (DMSO-d6): δ 166.6, 161.7, 159.6, 142.6, 131.3, 130.1, 128.8, 128.5, 128.2, 127.9, 126.0, 125.8, 125.7, 117.1, 115.2, 114.3, 91.7, 69.7, 55.5, 30.9. HRMS (ESI) (m/z): Calcd. for C27H19F3N3O3, [M-H]+: 522.1099; found: 522.1090.

2-((4-azidobenzyl)thio)-4-(4-((4-fluorobenzyl)oxy) phenyl)-6-oxo-1,6-dihydropyrimidine-5-carbonitrile (3g)

Yield 47%; white solid; 1H NMR (DMSO-d6): δ 8.00 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.2 Hz, 4H), 7.46 (d, J = 7.6 Hz, 2H), 7.25 (d, J = 8.4 Hz, 2H), 7.20 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 7.6 Hz, 2H), 5.21 (s, 2H), 4.54 (s, 2H); 13C NMR (DMSO-d6): δ 166.6, 165.5, 163.5, 161.8, 161.6, 161.1, 139.1, 133.9, 133.2, 133.1, 131.3, 131.1, 130.6, 130.5, 127.9, 119.6, 116.7, 115.9, 115.6, 115.3, 115.1, 92.0, 69.3, 34.0. HRMS (ESI) (m/z): Calcd. for C25H16FN6O2S, [M-H]+: 483.1039; found: 483.1031.

Methyl 4-(((5-cyano-4-(4-((4-fluorobenzyl)oxy)phenyl)-6-oxo-1,6-dihydropyrimidin-2-yl)thio)methyl)benzoate (3h)

Yield 63%; white solid; 1H NMR (DMSO-d6): δ 7.94 (d, J = 8.8 Hz, 2H), 7.89 (d, J = 8.0 Hz, 4H), 7.52 - 7.58 (m, 4H), 7.25 (t, J = 8.8 Hz, 2H), 7.17 (d, J = 8.8 Hz, 2H), 5.20 (s, 2H), 4.58 (s, 2H), 3.84 (s, 3H); 13C NMR (DMSO-d6): δ 166.6, 166.4, 163.5, 161.4, 143.4, 133.2, 131.1, 130.6, 130.5, 129.7, 129.7, 129.0, 128.2, 117.3, 115.8, 115.6, 115.1, 90.6, 69.2, 52.5, 34.1. HRMS (ESI) (m/z): Calcd. for C27H19FN3O4S, [M-H]+: 500.1080; found:500.1093.

4-(4-((4-fluorobenzyl)oxy)phenyl)-6-oxo-2-((4-(trifluoromethyl)benzyl)thio)-1,6-dihydropyrimidine-5-carbonitrile (3i)

Yield 66%; white solid; 1H NMR (DMSO-d6): δ 7.92 (d, J = 8.0 Hz, 2H), 7.94 (qd, J = 8.0 Hz, 4H), 7.53 (t, J = 6.4 Hz, 2H), 7.23 (t, J = 8.4 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 5.19 (s, 2H), 4.58 (s, 2H); 13C NMR (DMSO-d6): δ 166.7, 166.2, 163.5, 161.4, 161.1, 142.8, 133.2, 132.5, 131.1, 130.6, 130.5, 130.1, 128.2, 125.7, 117.3, 115.8, 115.6, 115.1, 90.6, 69.2, 33.8. HRMS (ESI) (m/z): Calcd. for C26H16F4N3O2S, [M-H]+: 510.0899; found: 510.0896.

2-((4-azidobenzyl)thio)-6-oxo-4-(4-((4-(trifluoromethyl) benzyl)oxy)phenyl)-1,6-dihydropyrimidine-5-carbonitrile (3j)

Yield 71%; white solid; 1H NMR (DMSO-d6): δ 8.01 (d, J = 8.8 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.06 (d, J = 8.4 Hz, 2H), 5.36 (s, 2H), 4.53 (s, 2H); 13C NMR (DMSO-d6): δ 161.4, 141.8, 139.0, 133.9, 131.3, 131.1, 129.1, 128.6, 128.1, 125.8, 119.6, 116.7, 115.3, 115.1, 92.1, 69.0, 34.0. HRMS (ESI) (m/z): Calcd. for C26H16F3N6O2S, [M-H]+: 533.1008; found: 533.1001.

Methyl 4-(((5-cyano-6-oxo-4-(4-((4-(trifluoromethyl) benzyl)oxy)phenyl)-1,6-dihydropyrimidin-2-yl)thio) methyl)benzoate (3k)

Yield 52%; white solid; 1H NMR (DMSO-d6): δ 7.96 (d, J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 7.6 Hz, 2H), 7.70 (d, J = 7.6 Hz, 2H), 7.56 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 5.76 (s, 2H), 4.60 (s, 2H), 3.83 (s, 3H); 13C NMR (DMSO-d6): δ 166.4, 161.4, 142.9, 141.9, 131.3, 129.7, 129.7, 129.1, 128.6, 125.8, 125.8, 115.3, 92.1, 69.0, 55.3, 52.5, 34.1. HRMS (ESI) (m/z): Calcd. for C28H19F3N3O4S, [M-H]+: 550.1048; found: 550.1039.

6-oxo-4-(4-((4-(trifluoromethyl)benzyl)oxy)phenyl)-2-((4-(trifluoromethyl)benzyl)thio)-1,6-dihydropyrimidine-5-carbonitrile (3l)

Yield 68%; white solid; 1H NMR (DMSO-d6): δ7.94 (d, J = 8.0 Hz, 2H), 7.78 (d, J = 8.0 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.66 (qd, J = 8.4 Hz, 4H), 7.20 (d, J = 8.8 Hz, 2H), 5.35 (s, 2H), 4.61 (s, 2H); 13C NMR (DMSO-d6): δ 166.7, 165.3, 161.4, 142.4, 141.8, 131.3, 130.1, 129.1, 128.7, 128.2, 128.0, 125.8, 125.8, 125.7, 123.3, 116.7, 115.2, 92.2, 69.0, 33.9. HRMS (ESI) (m/z): Calcd. for C27H17F6N3O2S, [M-H]+: 560.0867; found: 560.0870.

6-oxo-4-(4-phenoxyphenyl)-2-((4-(trifluoromethyl) benzyl)thio)-1,6-dihydropyrimidine-5-carbonitrile (3m)

Yield 84%; white solid; 1H NMR (DMSO-d6): δ 7.93 (d, J = 8.0 Hz, 2H), 7.66 (qd, J = 8.0 Hz, 4H), 7.47 (t, J = 7.2 Hz, 2H), 7.24 (t, J = 7.2 Hz, 1H), 7.14 (d, J = 7.6 Hz, 2H), 7.10 (d, J = 7.6 Hz, 2H), 4.58 (s, 2H); 13C NMR (DMSO-d6): δ 166.6, 166.3, 162.8, 160.4, 155.6, 142.7, 131.4, 130.7, 130.2, 130.1, 128.4, 128.1, 126.0, 125.8, 125.7, 125.1, 123.3, 120.3, 117.7, 117.0, 90.3, 33.8. HRMS (ESI) (m/z): Calcd. for C25H15F3N3O2S, [M-H]+: 478.0837; found: 478.0828.

4-(2-((4-azidobenzyl)thio)-5-cyano-6-oxo-1,6-dihydropyrimidin-4-yl)-N-phenylbenzamide (3n)

Yield 65%; white solid; 1H NMR (DMSO-d6): δ 10.41 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.01 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 7.07 (d, J = 8.0 Hz, 2H), 4.48 (s, 2H); 13C NMR (DMSO-d6): δ 167.8, 167.1, 165.5, 163.0, 139.4, 138.8, 137.8, 134.6, 131.1, 129.1, 128.2, 124.6, 120.8, 119.6, 117.0, 93.4, 43.0. HRMS (ESI) (m/z): Calcd. for C25H16N7O2S, [M-H]+: 478.1086; found: 478.1099.

Methyl4-(((5-cyano-6-oxo-4-(4-(phenylcarbamoyl) phenyl)-1,6-dihydropyrimidin-2-yl)thio)methyl)benzoate (3o)

Yield 54%; white solid; 1H NMR (DMSO-d6): δ 10.41 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 4.57 (s, 2H), 3.83 (s, 3 H); 13C NMR (DMSO-d6): δ 167.7, 167.0, 166.4, 163.6, 143.4, 139.4, 138.8, 137.7, 129.7, 129.1, 129.0, 128.9, 128.2, 124.4, 120.8, 117.0, 93.4, 52.5, 34.1. HRMS (ESI) (m/z): Calcd. for C27H19N4O4S, [M-H]+: 495.1127; found: 495.1132.

4-(5-cyano-6-oxo-2-((4-(trifluoromethyl)benzyl)thio)-1,6-dihydropyrimidin-4-yl)-N-phenylbenzamide (3p)

Yield 48%; white solid; 1H NMR (DMSO-d6): δ 10.41 (s, 1H), 8.08 (d, J = 8.0 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.79 (d, J = 8.0 Hz, 2H), 7.67 (qd, J = 8.0 Hz, 4H), 7.37 (t, J = 8.0 Hz, 2H), 7.12 (t, J = 7.6 Hz, 1H), 4.56 (s, 2H); 13C NMR (DMSO-d6): δ 167.7, 167.0, 165.3, 164.1, 143.0, 139.4, 138.9, 137.6, 130.1, 129.1, 129.0, 128.2, 125.7, 124.3, 123.3, 120.8, 117.1, 93.4, 33.9. HRMS (ESI) (m/z): Calcd. for C26H16F3N4O2S, [M-H]+: 505.0946; found: 505.0941.

4-(2-((4-azidobenzyl)thio)-5-cyano-6-oxo-1,6-dihydropyrimidin-4-yl)-N-(4-chlorophenyl)benzamide (3q)

Yield 18%; white solid; 1H NMR (DMSO-d6): δ 10.56 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.8 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 7.07 (d, J = 8.4 Hz, 2H), 4.44 (s, 2H); 13C NMR (DMSO-d6): δ 168.5, 166.9, 165.4, 164.7, 139.3, 138.7, 138.5, 137.1, 134.9, 133.6, 131.0, 129.0, 128.2, 127.8, 127.1, 125.5, 123.9, 122.3, 119.7, 119.5, 117.5, 113.8, 111.7, 92.7, 33.9. HRMS (ESI) (m/z): Calcd. for C25H15ClN7O2S, [M-H]+: 512.0696; found: 512.0698.

Methyl4-(((4-(4-((4-chlorophenyl)carbamoyl)phenyl)-5-cyano-6-oxo-1,6-dihydropyrimidin-2-yl)thio)methyl) benzoate (3r)

Yield 31%; white solid; 1H NMR (DMSO-d6): δ 10.55 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H), 7.90 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.57 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.8 Hz, 2H), 4.57 (s, 2H), 3.84 (s, 3H); 13C NMR (DMSO-d6): δ 167.6, 166.9, 166.4, 165.4, 163.7, 143.5, 139.0, 138.4, 137.3, 129.7, 129.3, 129.2, 129.1, 129.0, 128.9, 128.2, 127.9, 122.3, 117.0, 93.3, 52.58, 34.1. HRMS (ESI) (m/z): Calcd. for C27H18ClN4O4S, [M-H]+: 529.0737; found: 529.0734.

N-(4-chlorophenyl)-4-(5-cyano-6-oxo-2-((4-(trifluoromethyl)benzyl)thio)-1,6-dihydropyrimidin-4-yl) benzamide (3s)

Yield 17%; white solid; 1H NMR (DMSO-d6): δ 10.55 (s, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.94 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.8 Hz, 2H), 7.67 (qd, J = 8.0 Hz, 4H), 7.57 (d, J = 8.0 Hz, 2H), 7.43 (d, J = 8.8Hz, 2H), 4.52 (s, 2H); 13C NMR (DMSO-d6): δ 168.2, 166.9, 165.4, 143.1, 139.1, 138.4, 137.30, 130.1, 129.0,128.2, 127.9, 127.1, 126.0, 125.8, 125.7, 122.3, 117.2, 93.1, 33.8. HRMS (ESI) (m/z): Calcd. for C26H15ClF3N4O2S, [M-H]+: 539.0556; found: 539.0541.

4-(2-((4-azidobenzyl)thio)-5-cyano-6-oxo-1,6-dihydropyrimidin-4-yl)-N-(p-tolyl)benzamide (3t)

Yield 51%; white solid; 1H NMR (DMSO-d6): δ 10.34 (s, 1H), 8.08 (d, J = 8.4 Hz, 2H), 8.03 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.46 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.4 Hz, 2H), 7.07 (d, J = 8.0 Hz, 2H), 4.51 (s, 2H); 13C NMR (DMSO-d6): δ 167.1, 165.2, 138.9, 137.8, 136.7, 134.6, 133.5, 129.5, 129.0, 128.2, 120.8, 120.0, 119.6, 116.7, 93.4, 34.0, 20.9. HRMS (ESI) (m/z): Calcd. for C26H18N7O2S, [M-H]+: 492.1243; found: 492.1250.

Methyl-4-(((5-cyano-6-oxo-4-(4-(p-tolylcarbamoyl) phenyl)-1,6-dihydropyrimidin-2-yl)thio)methyl)benzoate (3u)

Yield 62%; white solid; 1H NMR (DMSO-d6): δ 10.34 (s, 1H), 8.07 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.0 Hz, 2H), 7.91 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 8.0 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.58 (s, 2H), 3.83 (s, 3H); 13C NMR (DMSO-d6): δ 167.5, 167.0, 166.4, 165.1, 143.5, 138.7, 137.7, 136.9, 133.3, 132.1, 129.9, 129.7, 129.5, 129.0, 128.9, 128.1, 117.0, 93.3, 52.5, 34.1, 20.9. HRMS (ESI) (m/z): Calcd. for C28H21N4O4S, [M-H]+: 509.1278; found: 509.1277.

4-(5-cyano-6-oxo-2-((4-(trifluoromethyl)benzyl)thio)-1,6-dihydropyrimidin-4-yl)-N-(p-tolyl)benzamide (3v)

Yield 45%; white solid; 1H NMR (DMSO-d6): δ 10.34 (s, 1H), 8.07 (d, J = 8.4 Hz, 2H), 7.97 (d, J = 8.4 Hz, 2H), 7.64 – 7.71 (m, 6H), 7.16 (d, J = 8.4 Hz, 2H), 4.59 (s, 2H); 13C NMR (DMSO-d6): δ 167.1, 167.0, 165.1, 162.8, 142.7, 138.5, 137.8, 136.9, 133.3, 130.2, 129.4, 129,0, 128.5, 128.2, 125.7, 123.5, 120.8, 116.7, 93.7, 33.9, 20.9. HRMS (ESI) (m/z): Calcd. for C27H18F3N4O2S, [M-H]+: 519.1108; found: 519.1094.

Acknowledgments

FB was a visiting scholar at GSU when conducting the lab research with partial financial support from the Islamic Development Bank (IDB) under a merit scholarship programme. Part of the research was conducted with the partial financial support of the National Institute of Health awarded to PCT and BW (AI104168).

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Received: 2019-11-06
Accepted: 2020-03-11
Published Online: 2020-05-17

© 2020 Bamba et al., published by De Gruyter

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

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https://doi.org/10.1515/hc-2020-0100
Schlagwörter für diesen Artikel
SecA inhibitor; small molecule; antimicrobial; target; drug-resistant
Creative Commons
BY 4.0

Artikel in diesem Heft

  1. Research Article
  2. Synthesis of 2-aryl-benzothiazoles via Ni-catalyzed coupling of benzothiazoles and aryl sulfamates
  3. Synthesis and characterization of a new series of thiadiazole derivatives as potential anticancer agents
  4. Isatin as a simple, highly selective and sensitive colorimetric sensor for fluoride anion
  5. The oxidative coupling between benzaldehyde derivatives and phenylacetylene catalyzed by rhodium complexes via C-H bond activation
  6. A Facile and Catalyst-free Synthesis of Hexahydroacridine-1,8(2H,5H )-dione and Octahydroacridin-10(1H )-yl)thiourea Derivatives: Inter- and Intramolecular Aza-Michael addition
  7. Reactivity of 1-allylsilatrane in ruthenium-catalyzed silylative coupling with olefins – mechanistic considerations
  8. Ball-Type Dioxy-o-Carborane Bridged Cobaltphthalocyanine: Synthesis, Characterization and DFT Studies For Dye-Sensitized Solar Cells as Photosensitizer
  9. Coumarin sulfonamide derivatives: An emerging class of therapeutic agents
  10. Synthesis and characterization of novel biological tetracoumarin derivatives bearing ether moieties
  11. Synthesis and antiproliferative activities of polymethoxyflavones aminoalkyl and amino acid derivatives
  12. Synthesis and biological evaluation of novel 4-oxo-5-cyano thiouracil derivatives as SecA inhibitors
  13. Synthesis, antibacterial activities, and sustained perfume release properties of optically active5-hydroxy- and 5-acetoxyalkanethioamide analogues
  14. Some topological indices of dendrimers determined by their Banhatti polynomials
  15. Synthesis, Characterization, and Antioxidant Activity of Some 2-Methoxyphenols derivatives
  16. Isatin-3-thiosemicarbazone as Chromogenic Sensor for the Selective Detection of Fluoride Anion
  17. Fluorescence properties in different solvents and synthesis of axially substituted silicon phthalocyanine bearing bis-4-tritylphenoxy units
  18. Design, Synthesis and Study of Antibacterial and Antitubercular Activity of Quinoline Hydrazone Hybrids
  19. Synthesis and optical characterization of bipod carbazole derivatives
  20. Synthesis and Biological Evaluation of Benzodioxole Derivatives as Potential Anticancer and Antioxidant agents
  21. Communication
  22. Visible light mediated aerobic oxidative hydroxylation of 2-oxindole-3-carboxylate esters: an alternative approach to 3-hydroxy-2-oxindoles
  23. Research Article
  24. Synthesis and Activity of New Schiff Bases of Furocoumarin
  25. Design, Synthesis and Biological Evaluation of N-((2-phenyloxazol-4-yl)methyl) Pyrimidine Carboxamide Derivatives as Potential Fungicidal Agents
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