Open Access

Utility of 2-thioxo-pyrido[2,3-d]pyrimidinone in synthesis of pyridopyrimido[2,1-b][1,3,5]-thiadiazinones and pyridopyrimido[2,1-b][1,3]thiazinones as antimicrobial agents

Chemistry Central Journal201711:57

https://doi.org/10.1186/s13065-017-0286-0

Received: 11 March 2017

Accepted: 15 June 2017

Published: 20 June 2017

Abstract

Background

Pyridopyrimidines are of current interest because of their extensive variety of biological and pharmacological activities.

Results

A series of pyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]thiadiazinones was obtained by aminomethylation of pyridopyrimidinethione with formaldehyde solution (37%) and different primary aromatic amines. Another series of pyrido[2′,3:4,5]pyrimido[2,1-b][1,3]thiazinones was prepared by Michael addition reaction of pyridopyrimidinethione to the activated double bond of a number of arylidene malononitrile and 2-(benzo[d][1,3]dioxol-5-ylmethylene)malononitrile. The mechanisms of formation of the synthesized compounds were discussed and the assigned structure was established via microanalysis and spectral data (IR, 1H NMR, and Ms.). A comparative study of the biological activity of the synthesized compounds with chloramphenicol and trimethoprim/sulphamethoxazole is shown in Table 1. Generally, all synthesized compounds showed adequate inhibitory effects on the growth of Gram-positive and Gram-negative bacteria.

Conclusions

In this study, we use a simple (synthetic) strategy for the synthesis of pyrimidothiadiazines, based on their aminomethylation through the Mannich reaction; they have also been synthesized by the application of the Michael addition to activated nitriles. Mechanisms and structures of the newly synthesized compounds were examined: the antimicrobial activity of some selected compounds was evaluated, which demonstrated adequate inhibitory effects.

Keywords

Pyridopyrimidinethione Michael Addition Hydrazone Bis-hydrazone Pyrazolines Antimicrobial agents

Background

Pyridopyrimidines and their intertwined heterocyclic ring frameworks are of current interest [14]. Pyrido[2,3-d]pyrimidines are annulated uracil which, have gotten significant consideration over the last years because of their extensive variety of biological and pharmacological activities, such as anticancer [59], antimicrobial [10, 11], antiviral [12, 13], anti-inflammatory agents [14] antifolate [15, 16], PDE IV inhibitors [17], and Inhibitors for hepatitis B virus [18]. Also, pyridopyrimidine moiety was considered as the best-known tyrosine kinase inhibitor for the treatment of endless myelogenous leukemia and medication resistance rises by enhancement of the improvement of a transformation [19]. In the perspective of every one of these actualities mentioned above and as a major aspect of our program to hunt down, possibly bioactive new specialists [2028], we report in this the union of novel pyridopyrimido[2,1-b][1,3,5]thiadizinone and pyridopyrimido[2,1-b][1,3]thiazinone derivatives. Moreover, the antimicrobial activities of the objective products were assessed.

Results and discussion

Chemistry

Treatment of 1,3-di(thiophen-2-yl)prop-2-en-1-one (1) [29] with 6-amino-2-thioxo-2,3-dihydropyrimidin-4(1H)-one (2) in presence of glacial acetic acid followed by acidifying with hydrochloric acid afforded 5,7-di(thiophen-2-yl)-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3) (see Scheme 1). The reaction of 4,6-di(thiophen-2-yl)-3,4-dihydropyrimidine-2(1H)-thione (3) with each of the substituted anilines (4ag) and excess aqueous formaldehyde solution (37%) in dioxane in the presence of a few drops of conc. hydrochloric acid afforded 3,7,9-triaryl-3,4-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]thiadiazin-6(2H)-ones (7ag) as a single product as evidenced by TLC analysis of the crude product. The elemental analysis and mass spectral data of the isolated products were consistent with the compound (7) (see Scheme 1). The chemical structure of the compounds (7ag) was confirmed based on elemental analysis and spectral information. The 1H NMR (DMSO-d 6) spectrum of compound (7a) showed signals at δ = 4.83 (s, 2H, CH2), 5.43 (s, 2H, CH2), 6.57–7.84 (m, 11H, Ar–H), and 8.03 (s, 1H, pyridine-H5). It’s IR spectrum revealed absorption bands at 1597 cm−1 (C=N), 1648 cm−1 (C=O), 2923, 3063 cm−1 (C–H) (Scheme 1).
Scheme 1

Synthesis of pyridopyrimidothiadiazinone derivatives (7ag)

According to a survey of the literature [2934], the S-alkylated pyrimidines cyclization occurs at N-atom, adjoining to the C=O group instead of the other N-molecule, based on 13C NMR data. Thus, the 13C NMR spectral data of compound (7a) shows carbonyl carbon signals of the pyrimidinone at 162 ppm, indicating that the N-atom adjoining to C=O is sp3-hybridized, which is different from C=O adjoining a sp2-hybridized nitrogen that usually appears at 170–175 ppm. [29]. Therefore, the structure of compound (7b) is found in one form namely, (A), rather than (B). Fares et al. recently confirmed that the cyclization carried out at N-atom, adjoining to the C=O group based on single-crystal X-ray analysis [35]; so, the structures of the products (7ag) being formulated as linear isomers (A) rather than isomeric angular isomers (B) as represented in Fig. 1.
Fig. 1

The strategic structures of the products (7ag)

In light of the aforementioned results, the mechanism summarized in Scheme 1 represents the most appropriate pathway for the formation of (7ag) from the reaction of thione (3) with the appropriate amines (4ag), and formaldehyde solution. The reaction involves initial formation of intermediate compound (5), which undergoes addition of another formaldehyde molecule as soon as it is formed to give the S-alkylated pyrimidinones (6). The intermediate compound so formed (6) undergo in situ cyclization as soon as they are formed, via elimination of a water molecule to afford the targets compounds (7ag) (Scheme 1).

Another group of fused pyrimidothiazinones was designed by treatment of pyridopyrimidinethione (3) with each of the appropriate arylidene malononitrile (9ac) in refluxing ethanol in the presence of a catalytic amount of piperidine afforded the pyridopyrimidothiazinones (12ac) by application of Michael’s addition reaction. The structures of compounds (12ac) were confirmed by elemental analysis and spectral data. In each case the IR spectra of (12ac) revealed three absorption bands near ν = 1656, 2192, 3184 and 3427 cm−1 attributed to the carbonyl, nitrile and the amino groups. The 1H NMR spectrum of (12a) showed signals at δ = 4.80 (s, 1H, CH), 6.87–7.78 (m, 11H, Ar–H), 8.01 (s, 1H, pyridine-H5), and 9.30 (s, 2H, NH2, D2O exchangeable) (see “Experimental section”). The mass spectra of products (12) appeared in each case a molecular ion peak which was compatible with the molecular formula of the assigned structure. A plausible mechanism was summarized (see Scheme 2) to demonstrate the formation of products (12). It was proposed that the reaction of pyridopyrimidinethione (3) with arylidene malononitrile carried out by initial Michael’s addition reaction of the thiol group to the activated double bond of compound (10) to give the non-isolable intermediate (11), which undergo tandem intramolecular cyclization and tautomerism to afford the final products (12) (Scheme 2).
Scheme 2

Synthesis of pyridopyrimidothiazinone derivatives (12ac) and (14)

In the same way, treatment of 4,6-di(thiophen-2-yl)-3,4-dihydropyrimidine-2(1H)-thione (3) with 2-(benzo[d][1,3]dioxol-5-ylmethylene)malononitrile (13) afforded pyridopyrimidothiazinone derivative (14). The reaction takes place by the Michael’s addition reaction of thione (3) to (13) under the same reaction conditions (Scheme 2). The chemical structure of the compound (14) was confirmed based on elemental analysis, and spectral data. The 1H NMR (DMSO-d 6) spectrum of compound (14) showed signals at δ = 4.62 (s, 1H, CH), 5.99 (s, 2H, CH2), 6.75–7.82 (m, 9H, Ar–H), 8.05 (s, 1H, pyridine-H5), and 9.81 (s, 2H, NH2, D2O exchangeable). It’s IR spectrum revealed absorption bands at 1592 cm−1 (C=N), 1685 cm−1 (C=O), 2190 cm−1 (CN), 2938, 3074 cm−1 (C–H), 3188, 3432 cm−1 (NH2) (Scheme 2).

The compound 4,6-di(thiophen-2-yl)-3,4-dihydropyrimidine-2(1H)-thione (3) was reacted with hydrazine hydrate in refluxing ethanol to afford 2-hydrazinyl-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (15). The chemical structure of the compound (15) was confirmed based on elemental analysis, spectral data and chemical transformation. The 1H NMR (DMSO-d 6) spectrum of compound (15) showed signals at δ = 2.88 (s, D2O exchangeable, 2H, NH2), 4.87 (s, D2O exchangeable, 1H, NH), 6.57–7.96 (m, 6H, Ar–H), 8.26 (s, 1H, pyridine-H5), and 9.23 (s, D2O exchangeable, 1H, NH). It’s IR spectrum revealed absorption bands at 1600 cm−1 (C=N), 1635 cm−1 (C=O), 2924, 3096 cm−1 (C–H), 3179–3423 cm−1 (NH2 and 2NH). Therefore, treatment of 2-hydrazinyl-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (15) with each of the appropriate aldehydes (16ac) and terephthaldehyde (18) in refluxing acetic acid in the presence of a few drops of concentrated hydrochloric acid afforded the corresponding hydrazones derivatives (17ac) and bis-hydrazone (19), respectively. The chemical structures of the compound (17ac) and (19) (Scheme 3) were confirmed based on elemental analysis and spectral data. For example, the 1H NMR (DMSO-d 6) spectrum of compound (17a) showed signals at δ = 7.11–7.96 (m, 11H, Ar–H), 8.01 (s, 1H, pyridine-H5), 8.10 (s, 1H, CH=N), and 11.39, 11.86 (2s, 2H, 2NH, D2O exchangeable). It’s IR spectrum revealed absorption bands at 1591 cm−1 (C=N), 1646 cm−1 (C=O), 2924, 3023 cm−1 (C–H), 3165, 3447 cm−1 (2NH).
Scheme 3

Synthesis of pyridopyrimidine derivatives (17ac), (19), (21) and (23)

Also, 2-hydrazinyl-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (15) reacted with ethyl acetoacetate (20) or acetyl acetone (22) in refluxing acetic acid to give pyrazolines (21) and (23), respectively. The chemical structures of the compounds (21) and (23) were confirmed based on elemental analysis and spectral data. For example, the 1H NMR (DMSO-d 6) spectrum of compound (23) showed signals at δ = 1.89 (s, 3H, CH3), 2.24 (s, 3H, CH3), 6.17 (s, 1H, pyrazole-H4), 6.90–7.82 (m, 6H, Ar–H), 8.03 (s, 1H, pyridine-H5), and 11.20 (s, 1H, NH, D2O exchangeable). It’s IR spectrum revealed absorption bands at 1601 cm−1 (C=N), 1634 cm−1 (C=O), 2924, 3096 cm−1 (C–H), 3343 cm−1 (NH).

Biological screening

Antimicrobial activity

In-vitro antimicrobial screening of compounds 7ag, 12ac, 14, 17ac, 19, 21 and 23 prepared for the study were carried out using cultures of two fungal strains, namely, Candida albicans (ATCC 10231) (CA) and Aspergillus niger (ATCC) (AN), as well as four bacterial species, namely, Gram-positive bacteria, Staphylococcus aureus (ATCC 29213) (SA), and Bacillus subtilus (ATCC 6051) (BS), Gram-negative bacteria, and Escherichia coli (ATCC 25922) (EC). Chloramphenicol and Miconazole are used as antibacterial and antifungal reference drugs to evaluate the potency of the tested compounds under the same conditions (Table 1).
Table 1

Antimicrobial activity expressed as inhibition diameter zones in a centimeter (cm) of tested compounds against the pathogenically stains based on disk diffusion as the assay

Compound no.

Fungi

G+ bacteria

G bacteria

AN

CA

SA

BS

EC

7a

NA

20

17

18

18

7b

NA

NA

18

20

15

7c

NA

8

21

18

12

7d

NA

8

18

14

13

7e

NA

NA

22

12

17

7f

NA

24

18

15

23

7g

NA

22

25

21

13

12a

NA

25

19

17

11

12b

NA

25

18

14

19

12c

NA

20

15

13

25

14

NA

21

20

16

19

17a

NA

11

15

14

16

17b

NA

13

14

21

20

17c

NA

14

16

9

11

19

NA

22

25

15

8

21

NA

11

12

9

10

23

NA

11

10

13

13

Chloramphenicol

30

24

29

Miconazole

28

26

DMSO

NA

NA

NA

NA

NA

Conclusions

In this study, we use a simple (synthetic) strategy for the synthesis of pyrimidothiadiazines, based on their aminomethylation through the Mannich reaction; they have also been synthesized by the application of the Michael addition to activated nitriles. Mechanisms and structures of the newly synthesized compounds were examined: the antimicrobial activity of some selected compounds was evaluated, which demonstrated adequate inhibitory effects.

Experimental section

General methods

Melting points were recorded on a Gallenkamp electrothermal apparatus, with infrared spectra (KBr) determined on a Pye Unicam SP-3000 (Cambridge, UK) infrared spectrophotometer. 1H NMR was assessed on a Varian Gemini 300 spectrometer (300 MHz) (Raleigh, NC, USA) in DMSO-d6 with TMS as an internal standard. Mass spectra were recorded on a GCMS-QP 1000 EX Shimadzu spectrometer. We conduct elemental analyses at the Microanalytical Center, University of Cairo, Giza, Egypt.

Preparation of 5,7-di(thiophen-2-yl)-2-thioxo-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (3)

A mixture of chalcone (1) (2.20 g, 10 mmol) and 6-amino-2-thioxo-2,3,4-trihydro-1H-pyrimidin-4-one (2) (1.43 g, 10 mmol) in glacial acetic acid (30 mL) was heated under reflux for 6 h after cooling, the reaction mixture was then poured into an ice/HCl mixture, and the solid product was collected and recrystallized from acetic acid as yellow solid, yield 76%, mp 236–238 °C; IR (KBr, cm−1) ν = 3426, 3281 (2NH), 3038, 2916 (C–H), 1643 (C=O), 1602 (C=N); 1H NMR (DMSO-d 6) at δ = 6.67–8.33 (m, 6H, Ar–H), 8.37 (s, 1H, pyrimidine-H), 11.43, 12.11 (2s, 2H, 2NH, exchangeable with D2O); MS m/z (%) 343 (M+, 100), 310 (19), 228 (18), 171 (23), 111 (17), 40 (25). Calculated combustion elemental analysis (Anal. Calcd.) for C15H9N3OS3 (342.99): C, 52.46; H, 2.64; N, 12.23. Found: C, 52.33; H, 2.51; N, 12.04%.

Synthesis of 3,7,9-triaryl-3,4-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]-thiadiazin-6(2H)-ones (7ag)

General procedure A mixture of thione (3) (0.343 g, 1 mmol), 37% formaldehyde solution (2 mL) and the appropriate aniline derivative (4ag) (1 mmol) in dioxane (20 mL) in the presence of few drops of HCl was stirred at room temperature for 4–8 h (monitored by TLC). The solid that precipitated was filtered off, washed with water, dried and finally crystallized from dioxane or EtOH to give the respective products (7ag). The physical and spectral data of products (7ag) are depicted as follows.

3-Phenyl-7,9-di(thiophen-2-yl)-3,4-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]thiadiazin-6(2H)-one (7a)

Yellow solid; yield 72%; mp 186–190 °C (dioxane); IR (KBr): v max = 1597 (C=N), 1648 (C=O), 2923, 3063 (C–H) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 4.83 (s, 2H, CH2), 5.43 (s, 2H, CH2), 6.57–7.84 (m, 11H, Ar–H), 8.03 (s, 1H, pyridine-H5); MS (70 eV): m/z = 460 (M+, 12), 377 (55), 253 (82), 170 (69), 64 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C23H16N4OS3 (460.05): C, 59.98; H, 3.50; N, 12.16. Found: C, 59.90; H, 3.34; N, 12.03%.

7,9-Di(thiophen-2-yl)-3-(p-tolyl)-3,4-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]thiadiazin-6(2H)-one (7b)

Yellow solid; yield 75%; mp 153–155 °C (dioxane); IR (KBr): v max = 1596 (C=N),1644 (C=O), 2920, 3029 (C–H) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 2.23 (s, 3H, CH3), 5.42 (s, 2H, CH2), 5.79 (s, 2H, CH2), 6.66–7.99 (m, 10H, Ar–H), 8.11 (s, 1H, pyridine-H5); MS (70 eV): m/z = 474 (M+, 8), 342 (48), 221 (70), 77 (81), 59 (96), 40 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C24H18N4OS3 (474.06): C, 60.73; H, 3.82; N, 11.80. Found: C, 60.79; H, 3.69; N, 11.66%.

3-(4-Methoxyphenyl)-7,9-di(thiophen-2-yl)-3,4-dihydropyrido[2′,3′:4,5]pyrimido-[2,1-b][1,3,5]-thiadiazin-6(2H)-one (7c)

Pale green solid; yield 68%; mp 131–133 °C (EtOH); IR (KBr): v max = 1592 (C=N),1638 (C=O), 2923, 3043 (C–H) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 3.67 (s, 3H, OCH3), 5.38 (s, 2H, CH2), 5.74 (s, 2H, CH2), 6.64–7.83 (m, 10H, Ar–H), 8.00 (s, 1H, pyridine-H5); MS (70 eV): m/z = 490 (M+, 9), 469 (52), 342 (42), 171 (38), 111 (63), 44 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C24H18N4O2S3 (490.06): C, 58.75; H, 3.70; N, 11.42. Found: C, 58.53; H, 3.51; N, 11.58%.

3-(4-Chlorophenyl)-7,9-di(thiophen-2-yl)-3,4-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]-thiadiazin-6(2H)-one (7d)

Brown solid; yield 78%; mp 192–194 °C (dioxane); IR (KBr): v max = 1592 (C=N),1646 (C=O), 2920, 2957, 3099 (C–H) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 5.42 (s, 2H, CH2), 5.79 (s, 2H, CH2), 6.61–7.92 (m, 10H, Ar–H), 8.03 (s, 1H, pyridine-H5); MS (70 eV): m/z = 496 (M++2, 3), 494 (M+, 10), 327 (52), 192 (48), 131 (100), 62 (70). Calculated combustion elemental analysis (Anal. Calcd.) for C23H15ClN4OS3 (494.01): C, 55.80; H, 3.05; N, 11.32. Found: C, 55.89; H, 3.02; N, 11.17%.

3-(4-Bromophenyl)-7,9-di(thiophen-2-yl)-3,4-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]-thiadiazin-6(2H)-one (7e)

Yellow solid; yield 77%; mp 173–175 °C (dioxane); IR (KBr): v max = 1590 (C=N),1650 (C=O), 2912, 2956, 3095 (C–H) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 5.40 (s, 2H, CH2), 5.81 (s, 2H, CH2), 6.84–7.92 (m, 10H, Ar–H), 8.04 (s, 1H, pyridine-H5); MS (70 eV): m/z = 540 (M++2, 7), 538 (M+, 8), 343 (53), 228 (50), 111 (100), 45 (95). Calculated combustion elemental analysis (Anal. Calcd.) for C23H15BrN4OS3 (537.96): C, 51.21; H, 2.80; N, 10.39. Found: C, 51.37; H, 2.64; N, 10.18%.

3-(4-Nitrophenyl)-7,9-di(thiophen-2-yl)-3,4-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3,5]-thiadiazin-6(2H)-one (7f)

Brown solid; yield 75%; mp 160–162 °C (dioxane); IR (KBr): v max = 1596 (C=N),1654 (C=O), 2911, 2957, 3094 (C–H) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 5.40 (s, 2H, CH2), 5.74 (s, 2H, CH2), 6.67–7.97 (m, 10H, Ar–H), 8.03 (s, 1H, pyridine-H5); MS (70 eV): m/z = 505 (M+, 14), 344 (37), 191 (51), 111 (86), 57 (100), 43 (84). Calculated combustion elemental analysis (Anal. Calcd.) for C23H15N5O3S3 (505.03): C, 54.64; H, 2.99; N, 13.85. Found: C, 54.48; H, 2.91; N, 13.69%.

3-(2,4-Dichlorophenyl)-7,9-di(thiophen-2-yl)-3,4-dihydropyrido[2′,3′:4,5]pyrimido-[2,1-b][1,3,5]-thiadiazin-6(2H)-one (7g)

Yellow solid; yield 77%; mp 135–137 °C (DMF); IR (KBr): v max = 1593 (C=N),1649 (C=O), 2911, 2959, 3095 (C–H) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 5.32 (s, 2H, CH2), 5.78 (s, 2H, CH2), 6.75–7.42 (m, 8H, Ar–H), 7.74 (s, 1H, Ar–H), 8.10 (s, 1H, pyridine-H5); MS (70 eV): m/z = 527 (M+, 8), 446 (27), 220 (100), 187 (52), 82 (89), 43 (58). Calculated combustion elemental analysis (Anal. Calcd.) for C23H14Cl2N4OS3 (527.97): C, C, 52.17; H, 2.67; N, 10.58. Found: C, 52.29; H, 2.48; N, 10.49%.

Synthesis of pyridopyrimidothiazinone derivatives (12ac) and (14)

General procedure To a solution of thione (3) (0.343 g, 1 mmol), an appropriate amount of arylidenemalononitrile (7ac), and (13) (1 mmol) 20 mL of ethanol (EtOH), 0.5 mL of piperidine was added. The mixture so obtained was refluxed for 8 h. The solid substance that precipitated after cooling was filtered off, washed with water, dried and finally crystallized from EtOH to give products (12ac) and (14), respectively.

4-Amino-6-oxo-2-phenyl-7,9-di(thiophen-2-yl)-2,6-dihydropyrido[2′,3′:4,5]pyrimido-[2,1-b][1,3]-thiazine-3-carbonitrile (12a)

Brown solid; yield 68%; mp 163–165 °C; IR (KBr): v max = 1591 (C=N),1626 (C=O), 2185 (CN), 2937, 3067 (C–H), 3193, 3413 (NH2) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 4.80 (s, 1H, CH), 6.87–7.78 (m, 11H, Ar–H), 8.01 (s, 1H, pyridine-H5), 9.30 (s, 2H, NH2, D2O exchangeable); MS (70 eV): m/z = 497 (M+, 17), 314 (38), 211 (71), 172 (52), 77 (82), 43 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C25H15N5OS3 (497.04): C, 60.34; H, 3.04; N, 14.07. Found: C, 60.39; H, 3.15; N, 13.94%.

4-Amino-2-(4-methoxyphenyl)-6-oxo-7,9-di(thiophen-2-yl)-2,6-dihydropyrido-[2′,3′:4,5]pyrimido-[2,1-b][1,3]thiazine-3-carbonitrile (12b)

Brown solid; yield 66%; mp 167–169 °C; IR (KBr): v max = 1590 (C=N),1630 (C=O), 2200 (CN), 2930, 3052 (C–H), 3193, 3427 (NH2) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 3.81 (s, 3H, OCH3), 4.63 (s, 1H, CH), 6.83–7.75 (m, 10H, Ar–H), 7.98 (s, 1H, pyridine-H5), 9.43 (s, 2H, NH2, D2O exchangeable); MS (70 eV): m/z = 527 (M+, 6), 305 (36), 211 (39), 153 (64), 80 (93), 64 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C26H17N5O2S3 (527.05): C, 59.18; H, 3.25; N, 13.27. Found: C, 59.04; H, 3.16; N, 13.03%.

4-Amino-2-(4-chlorophenyl)-6-oxo-7,9-di(thiophen-2-yl)-2,6-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3]thiazine-3-carbonitrile (12c)

Brown solid; yield 69%; mp 204–206 °C; IR (KBr): v max = 1593 (C=N),1684 (C=O), 2194 (CN), 2942, 3073 (C–H), 3165, 3437 (NH2) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 4.84 (s, 1H, CH), 6.85–7.83 (m, 10H, Ar–H), 8.06 (s, 1H, pyridine-H5), 9.79 (s, 2H, NH2, D2O exchangeable); MS (70 eV): m/z = 533 (M++2, 1), 531 (M+, 4), 330 (64), 211 (54), 158 (66), 80 (53), 64 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C25H14ClN5OS3 (531.00): C, 56.43; H, 2.65; N, 13.16. Found: C, 56.62; H, 2.63; N, 13.10%.

4-Amino-2-(benzo[d][1,3]dioxol-5-yl)-6-oxo-7,9-di(thiophen-2-yl)-2,6-dihydropyrido[2′,3′:4,5]pyrimido[2,1-b][1,3]thiazine-3-carbonitrile (14)

Brown solid; yield 72%; mp 213–215 °C; IR (KBr): v max = 1592 (C=N), 1685 (C=O), 2190 (CN), 2938, 3074 (C–H), 3188, 3432 (NH2) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 4.62 (s, 1H, CH), 5.99 (s, 2H, CH2), 6.75–7.82 (m, 9H, Ar–H), 8.05 (s, 1H, pyridine-H5), 9.81 (s, 2H, NH2, D2O exchangeable); MS (70 eV): m/z = 541 (M+, 12), 402 (51), 309 (63), 211 (64), 80 (100), 57 (84). Calculated combustion elemental analysis (Anal. Calcd.) for C26H15N5O3S3 (541.62): C, 57.66; H, 2.79; N, 12.93. Found: C, 57.42; H, 2.70; N, 12.62%.

Synthesis of 2-hydrazinyl-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (15)

Hydrazine hydrate (80%, 20 mL) was added to thione (3) (3.43 g, 10 mmol) in the presence of dry EtOH (40 mL), and the reaction mixture was kept under reflux for 30 h and then cooled. The precipitated solid was filtered off and crystallized from dimethylformamide (DMF) to give (4) as a white solid, mp 325–327 °C; 70% yield; IR (KBr): v max = 1600 (C=N), 1635 (C=O), 2924, 3096 (C–H), 3179–3423 (NH2 and 2NH), cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 2.88 (s, D2O exchangeable, 2H, NH2), 4.87 (s, D2O exchangeable, 1H, NH), 6.57–7.96 (m, 6H, Ar–H), 8.26 (s, 1H, pyridine-H5), 9.23 (s, D2O exchangeable, 1H, NH); MS (70 eV): m/z = 341 (M+, 28), 232 (64), 203 (47), 111 (100), 97 (54), 58 (68). Calculated combustion elemental analysis (Anal. Calcd.) for C15H11N5OS2 (341.04): C, 52.77; H, 3.25; N, 20.51%. Found: C, 52.64; H, 3.14; N, 20.35%.

Synthesis of hydrazones (17ac)

A mixture of hydrazine derivative (15) (0.341 g, 1 mmol) and an appropriate amount of aldehyde (16ac) (1 mmol) in acetic acid (20 mL), and a few drops of concentrated hydrochloric acid (≈1 mL) were heated under reflux for 5 h. The resultant mixture obtained was then cooled and diluted with water. The formed solid product was then collected by filtration, dried and recrystallized from DMF to afford the corresponding hydrazones (17ac).

2-(2-Benzylidenehydrazinyl)-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (17a)

Yellow solid; yield 73%; mp 187–189 °C; IR (KBr): v max = 1591 (C=N),1646 (C=O), 2924, 3023 (C–H), 3165, 3447 (2NH) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 7.11–7.96 (m, 11H, Ar–H), 8.01 (s, 1H, pyridine-H5), 8.10 (s, 1H, CH=N), 11.39, 11.86 (2s, 2H, 2NH, D2O exchangeable); MS (70 eV): m/z = 429 (M+, 85), 352 (100), 310 (41), 171 (38), 90 (29). Calculated combustion elemental analysis (Anal. Calcd.) for C22H15N5OS2 (429.07): C, 61.52; H, 3.52; N, 16.31. Found: C, 61.59; H, 3.37; N, 16.18%.

2-(2-(4-Methylbenzylidene)hydrazinyl)-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (17b)

Yellow solid; yield 69%; mp 181–183 °C; IR (KBr): v max = 1591 (C=N),1685 (C=O), 2922, 3090 (C–H), 3169, 3416 (2NH) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 2.38 (s, 3H, CH3), 7.09–8.05 (m, 10H, Ar–H), 8.19 (s, 1H, pyridine-H5), 8.63 (s, 1H, CH=N), 11.39, 11.90 (2s, 2H, 2NH, D2O exchangeable); MS (70 eV): m/z = 443 (M+, 9), 352 (63), 220 (39), 117 (37), 91 (72), 64 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C23H17N5OS2 (443.09): C, 62.28; H, 3.86; N, 15.79. Found: C, 62.35; H, 3.64; N, 15.58%.

2-(2-(4-Chlorobenzylidene)hydrazinyl)-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (17c)

Yellow solid; yield 67%; mp 230–232 °C; IR (KBr): v max = 1590 (C=N),1683 (C=O), 2924, 3074 (C–H), 3193, 3417 (2NH) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 7.11–8.02 (m, 10H, Ar–H), 8.08 (s, 1H, pyridine-H5), 8.69 (s, 1H, CH=N), 11.53, 11.90 (2s, 2H, 2NH, D2O exchangeable); MS (70 eV): m/z = 465 (M++2, 5), 463 (M+, 12), 352 (37), 137 (83), 64 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C22H14ClN5OS2 (463.03): C, 56.95; H, 3.04; N, 15.09. Found: C, 56.77; H, 3.08; N, 14.86%.

Synthesis of bis-hydrazone (19)

A mixture of hydrazine derivative (15) (0.682 g, 2 mmol) and terephthaldehyde (18) (0.134 g, 1 mmol) in acetic acid (20 mL) and a few drops of concentrated hydrochloric acid (≈1 mL) were heated under reflux for 6 h. The reaction mixture was then cooled and diluted with water. The formed solid product was then collected by filtration, dried and recrystallized from DMF to obtain bis-hydrazone (19) as a brown residue with 65% yield. mp 307–309 °C; IR (KBr): v max = 1594 (C=N), 1675 (C=O), 2925, 3023 (C–H), 3188, 3433 (2NH) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 6.96–8.09 (m, 16H, Ar–H), 8.14 (s, 2H, 2pyridine-H5), 8.70 (s, 2H, 2CH=N), 11.47 (s, 2H, 2NH, D2O exchangeable), 11.82 (s, 2H, 2NH, D2O exchangeable); MS (70 eV): m/z = 780 (M+, 16), 480 (35), 362 (40), 130 (19), 64 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C38H24N10O2S4 (780.10): C, 58.44; H, 3.10; N, 17.94. Found: C, 58.59; H, 3.03; N, 17.75%.

Synthesis of pyrazolines (21) and (23)

A mixture of hydrazine derivative (15) (0.341 g, 1 mmol) and ethyl acetoacetate (20) or acetylacetone (22) (1 mmol) in acetic acid (20 mL) were heated under reflux for 5 h. The product started to separate out during the course of the reaction. The solid product was filtered, washed with water, dried and recrystallized from ethanol to give the corresponding pyrazoline derivatives (21) and (23).

2-(3-Methyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl)-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (21)

Brown solid; yield 67%; mp 188–190 °C; IR (KBr): v max = 1601 (C=N),1631, 1694 (2C=O), 2920, 2964, 3099 (C–H), 3173 (NH) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 1.90 (s, 3H, CH3), 2.21 (s, 2H, CH2), 6.87–7.98 (m, 6H, Ar–H), 8.05 (s, 1H, pyridine-H5),11.21 (s, 1H, NH, D2O exchangeable); MS (70 eV): m/z = 407 (M+, 8), 319 (63), 230 (41), 179 (83), 64 (100). Calculated combustion elemental analysis (Anal. Calcd.) for C19H13N5O2S2 (407.05): C, 56.01; H, 3.22; N, 17.19. Found: C, 55.90; H, 3.42; N, 17.05%.

2-(3,5-Dimethyl-1H-pyrazol-1-yl)-5,7-di(thiophen-2-yl)pyrido[2,3-d]pyrimidin-4(3H)-one (23)

Brown solid; yield 69%; mp 212–214 °C; IR (KBr): v max = 1601 (C=N),1634 (C=O), 2924, 3096 (C–H), 3343 (NH) cm−1; 1H NMR (300 MHz, DMSO-d 6 ): δ = 1.89 (s, 3H, CH3), 2.24 (s, 3H, CH3), 6.17 (s, 1H, pyrazole-H4), 6.90–7.82 (m, 6H, Ar–H), 8.03 (s, 1H, pyridine-H5),11.20 (s, 1H, NH, D2O exchangeable); MS (70 eV): m/z = 405 (M+, 15), 318 (42), 210 (59), 111 (100), 64 (92). Calculated combustion elemental analysis (Anal. Calcd.) for C20H15N5OS2 (405.07): C, 59.24; H, 3.73; N, 17.27. Found: C, 59.33; H, 3.57; N, 17.05%.

Antimicrobial activity

Antimicrobial activity was determined using the agar disc diffusion assay method as described by Hossain et al. [36]. The tested organisms were sub-cultured on Trypticase soya agar medium (Oxoid Laboratories, UK) for bacteria and Sabouraud dextrose agar (Oxoid Laboratories, UK) for fungi. Chloramphenicol and Trimethoprim/sulphamethoxazole were used as a positive control and DMSO solvent as a negative control. The plates were done in duplicate and average zone of inhibition was calculated. Bacterial cultures were incubated at 37 °C for 24 h while the other fungal cultures were incubated at (25–30 °C) for 3–5 days. Antimicrobial activity was determined by measurement zone of inhibition.

Media used

Sabouraud dextrose agar the medium used for isolation of pathogenic yeasts has the following composition (g L−1): glucose, 20; peptone, 10; agar, 25 and distilled water, 1 L, pH was adjusted at 5.4. The medium was autoclaved at 121 °C for 15 min.

Trypticase soya agar (TSA) the medium was used to cultivate tested bacteria. It contains (g L−1) Tryptone (Pancreatic Digest of Casein) 15.0 g, Soytone (Papaic Digest of Soybean Meal) 5.0 g, Sodium Chloride 5.0 g, Agar 15.0 g and distilled water 1 L. The medium was autoclaved at 121 °C for 15 min.

Abbreviations

TSA: 

trypticase soya agar

(ATCC 10231) (CA): 

Candida albicans

(ATCC) (ASP): 

Aspergillus niger

(ATCC 29213) (SA): 

Staphylococcus aureus

(ATCC 6051) (BS): 

Bacillus subtilis

(ATCC 700603) (KP): 

Klebsiella pneumoniae

(ATCC 25922) (EC): 

Escherichia coli

MW: 

molecular weight

TLC: 

thin layer chromatography

Declarations

Authors’ contributions

YHZ and SMG have carried the literature study, designing part, designing of synthetic schemes, AMGM contributed in the synthesis as well as purification of compounds. YHZ did the final sequence alignment in the manuscript and drafted the manuscript. All authors read and approved the final manuscript.

Competing interests

The authors declare that they have no competing interests.

Consent for publication

All authors consent to the publication.

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Authors’ Affiliations

(1)
Department of Chemistry, Faculty of Science, Beni-Suef University
(2)
Department of Chemistry, Faculty of Science and Humanity Studies at Al-Quwayiyah, Shaqra University
(3)
Department of Chemistry, Faculty of Science, Cairo University

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© The Author(s) 2017