научная статья по теме SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW SUBSTITUTED PYRIDO[3,2:4,5]THIENO[3,2-D]-PYRIMIDINONE DERIVATIVES Химия

Текст научной статьи на тему «SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW SUBSTITUTED PYRIDO[3,2:4,5]THIENO[3,2-D]-PYRIMIDINONE DERIVATIVES»

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EHOOPrAHH^ECKAa XHMH3, 2014, moM 40, № 3, c. 335-340

SYNTHESIS AND ANTIMICROBIAL ACTIVITY OF SOME NEW SUBSTITUTED PYRIDO[3',2':4,5]TfflENO[3,2-tf]-

PYRIMIDINONE DERIVATIVES

© 2014 Ahmed A. Fayed*, **• #, Abd El-Galil E. Amr**, ***, Mohamed A. Al-Omar***, Elsayed E. Mostafa****

*Respiratory Department, Applied Organic & Biochemistry Division, College of Medical Rehabilitation Sciences, Taibah University, Al-Madinah Al-Munawara, 3893 Saudi Arabia **Applied Organic Chemistry Department, National Research Center, Cairo, Dokki, Egypt ***Pharmaceutical Chemistry Department, Drug Exploration & Development Chair (DEDC), College of Pharmacy,

King Saud University, Riyadh, 11451 Saudi Arabia ****Department of Microbial Chemistry, National Research Center, Cairo, Egypt Recevied November 21, 2013; in final form, December 11, 2013

A series of new 3-substituted-7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methylpyri-do[3',2':4,5]thieno[3,2-d]pyrimidin-4(3H)-one derivatives were synthesized as antimicrobial agents using 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,4-dichlorophenyl)-2-methyl-4H-pyrido[3',2':4,5]thieno[3,2-d]-[1,3]oxazin-4-one as a starting compound. Its condensation with substituted aniline derivatives or phenyl hydrazine gave the corresponding N-substituted derivatives. Treatment of the starting compound with hydrazine hydrate afforded the corresponding N-amino derivative, which was reacted with substituted phenylisocyanate and phenyl-isothiocyanate derivatives to give the corresponding semicarbazides and thiosemicarbazide derivatives. All the newly synthesized compounds were evaluated for their antimicrobial activities in comparison to streptomycin and fusidic acid as positive controls. The structure assignments of the new compounds are based on chemical and spectroscopic evidence.

Keywords: oxazinone, thienopyrimidine, semi- and thiosemicarbazides, antimicrobial agents DOI: 10.7868/S013234231403004X

INTRODUCTION

In our previous work, some of fused heterocyclic derivatives were studied as antimicrobial [1], 5a-re-ductase inhibitors, antiviral, anti-tumor, anti-parkin-sonism, hypoglycemic, anti-microbial, anti-inflammatory, analgesic, and antipyretic agents [2—9]. In addition, biological and antianalgesic activities of many heterocyclic compounds containing a sulfur atom have been reviewed [10—12]. On the other hand, thienopyrimidine and thioxopyrimidine derivatives have promising biological [13, 14] and anticancer activities [15, 16]. Recently, some new substituted thienopyrimidine derivatives were synthesized [17] and evaluated as anti-inflammatory [18], antiproliferative [19], and analgesic [20] agents. In view of these observations and as continuation of our previous works in heterocyclic chemistry, we have herein synthesized some new thienopy-rimidine derivatives and tested their anti-microbial activities.

# Corresponding author (e-mail: dr_ahmedfayed14@yahoo.com).

RESULTS AND DISCUSSION

In the present work, 2-chloro-6-ethoxy-4-[(2-me-thyl-4-oxo-9-(2,6-dichlorophenyl)pyrido[3',2':4,5]-thieno[3,2-d]oxazin-7-yl]pyridines (II) was used as starting material and it was prepared from the corresponding 1-(2-chloro-6-ethoxypyridin-4-yl)-3-(2,6-dichlorophenyl)prop-2-en-1-one (I) according to the reported methods [1] (Scheme 1).

Treatment ofoxazinone derivatives (IIa, b) with substituted aniline derivatives or phenylhydrazine in glacial acetic acid under reflux condition afforded the corresponding 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,6-dichlorophenyl)-2-methyl-3-[N-(substituted phe-nyl)pyrido[3',2':4,5]thieno[3,2-d]pyrimidine-4(3H)-one (IIIa—e) and 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,6-dichlorophenyl)-3-phenyl-2 - methylpyrido[3',2':4,5]-thieno[3,2-d]pyrimidine-4(3H)-one (IV), respectively. In addition, reacting of (II) with hydrazine hydrate in refluxing ethanol afforded the corresponding N-amino thienopyrimidine derivative (V), which was reacted with substituted phenylisothiocyanate to give the corresponding thiosemicarbazide derivatives (VIa—e), respectively (Scheme 2).

II

Scheme 1. Synthetic pathway for starting material (II).

Antimicrobial activities of the newly synthesized compounds (III—VI)

Fungi Yeast Bacteria

Comp. no. Gram-ve Gram+ve

A.n. Pen. sp. C.a. R.i. B.s. S.l. Str. sp. E.c. P. sp.

(IIIa) 10 13 10 11 20 21 21 23 23

(IIIb) 7 5 8 9 12 13 6 13 12

(IIIc) 13 12 12 13 13 12 11 10 9

(IIId) 10 12 11 11 11 10 13 12 11

(IIIe) 19 20 19 19 13 12 11 10 9

(IIIf) 12 10 11 11 20 21 20 19 20

(IV) 19 20 19 19 13 12 11 10 9

(V) 10 12 11 11 11 10 13 12 11

(VIa) 17 16 16 17 23 24 22 23 21

(VIb) 13 12 12 13 13 12 11 10 9

(VIc) 17 16 16 17 23 24 22 23 21

(VId) 15 16 13 14 11 12 11 12 13

(VIe) 23 22 22 20 23 22 11 24 23

(VIf) 12 10 11 11 20 21 20 19 20

Streptomycin - - - - 22 21 21 22 21

Fusidic acid 17 17 18 18 - - - - -

A.n., Aspergillus niger; Pen. sp., Penicillium sp.; C.a., Candida albican; Str. sp., Streptomyces sp., R.i., Rhodotorula ingeniosa; B.s., Bacillus subtilis; S.l, Streptococcus lactis; E.c., Escherichia coli; P. sp., Pseudomonas sp.

Cl

Cl

OEt

II

OEt

Illa—e

X

nh2nh2

a, X = H; b, X = Cl; c, X = OMe; d, X = CH3; e, X = F

Cl

Cl

Cl

R

a, X = O, R = H; b, X = O, R = Cl; c, X = O, R = CH3; d, X = O; R = H; e, X = O, R = Cl; f, X = O, R = CH3

Scheme 2. Synthetic pathway for starting material (III—VI).

Biological Activity

The zone of inhibition (in mm) was compared with the inhibition zones obtained using streptomycin and fusidic as positive controls for antibacterial and antifungal activities, respectively. From the obtained results in the table, antibacterial screening revealed that compounds (IIIf), (VIa), (VIc), (VIe) and (VIf) showed the highest inhibition against all bacterial organisms. Also, antifungal activity assay revealed that the compounds (IIIe), (IV), and (VIe) exhibited highest inhibition against fungi and yeast organisms. The results of antibacterial activity assessment are summarized in the following table.

EXPERIMENTAL

Melting points were measured using Electrothermal 9100 digital melting point apparatus (Buchi, Switzerland) and are uncorrected. IR spectra (v, cm-1) were recorded on a Perkin-Elmer 1600 FTIR equipment (Perkin-Elmer) in KBr discs. NMR spectra were registered on a Jeol 5000 MHz spectrometer (Jeol, Japan) in DMSO-af6 (1H-NMR at 500 MHz, 13C-NMR at 125 MHz), and chemical shifts are reported as 5, ppm, relative to the internal standard Me4Si. The mass spectra were registered at 70 eV with a Finnigan SSQ 7000 spectrometer (Madison, WI, USA) using EI and the values of m/z are indicated in Dalton. Elemental analyses were performed on a Perkin-Elmer 2400 analyz-

er (Perkin-Elmer, USA) and were found within ±0.4% of the theoretical values. All reactions were followed by TLC (Silica gel, Aluminum Sheets 60 F254, Merck). Starting material (II) was prepared from the corresponding cinnamoyl derivatives (I) according to the reported procedures [1].

General procedure for compounds (IIIa—e) and (IV). A mixture of 7-(2-chloro-6-ethoxypyridin-4-yl)-9-(2,6-dichlorophenyl)-2-methyl-4H-pyrido-[3',2':4,5]-thieno[3,2-d][1,3]oxazin-4-one (II) [1] (1 mmol) and substituted aniline derivatives, namely, aniline, p-chloro-, p-methoxy-, p-methyl-, p-flouro-aniline, or phenylhydrazine (1 mmol) in glacial acetic acid (25 mL) was heated under reflux for 6 h. The reaction mixture was concentrated under reduced pressure, poured into ice—water, and the formed solid was filtered, washed with water, dried, and crystallized from the proper solvent to afford the corresponding 3-sub-stituted pyrido[3',2':4,5]-thieno[3,2-d]pyrimidine derivatives (IIIa—e) and (IV), respectively.

7-(2-Chloro-6-ethoxypyridin-4-yl)-9-(2,6-dichlo-rophenyl)-2-methyl-3-phenylpyrido[3',2':4,5]thieno-[3,2-d]pyrimidine-4(3H)-one (IIIa). Yield 82%, mp 118— 120°C (AcOH); IR: v, 1671 (C=O); 1H NMR: 1.14 (t, 3H, CH3), 2.32 (s, 3H, CH3), 3.76 (q, 2H, CH2), 7.06-7.72 (m, 10H, 8 Ph-H + 2 pyr-H), 8.34 (s, 1H, pyr-5'-H); 13C NMR: 14.15, 25.18, 64.12, 100.00,

101.21, 116.20, 120.32, 121.60, 124.32, 126.40, 128.84, 129.60, 132.75, 132.83, 133.32, 134.43, 136.54, 145.65,

146.22, 149.80, 151.75, 154.12, 154.70, 157.44, 159.66, 163.78, 164.27 (29 C); MS, m/z(%): 594 (8) [M+]; Calc. for C29H19Cl3N4O2S (593.91): C, 58.65; H, 3.22; Cl, 17.91; N, 9.43; S, 5.40. Found: C, 58.60; H, 3.18; Cl, 17.86; N, 9.38; S, 5.34.

7-(2-Chloro-6-ethoxypyridin-4-yl)-9-(2,6-dichlo-rophenyl)-2-methyl-3-(4-chlorophenyl)pyrido-[3',2':4,5] thieno[3,2-d]pyrimidine-4(3H)-one (IIIb). Yield 66%, mp 232-234°C (AcOH/H2O); IR: 1676 (C=O); 1H NMR: 1.16 (t, 3H, CH3), 2.18 (s, 3H, CH3), 3.80 (q, 2H, CH2), 7.18-7.78 (m, 9H, 7 Ph-H + 2 pyr-H), 8.56 (s, 1H, pyr-5'-H); 13C NMR: 13.98, 24.88, 64.18, 99.95, 101.08, 116.24, 120.35, 123.56, 126.55, 128.86, 129.46, 129.76, 130.68, 132.80, 133.35, 134.45, 136.55, 145.68, 146.26, 149.81, 151.71, 154.15, 154.71, 157.45, 159.65, 163.76, 164.28 (29 C); MS, m/z (%): 628 (18) [M+]; Calc. for C29H18Cl4N4O2S (628.36): C, 55.43; H, 2.89; Cl, 22.57; N, 8.92; S, 5.10. Found: C, 55.35; H, 2.82; Cl, 22.51; N, 8.86; S, 5.04.

7-(2-Chloro-6-ethoxypyridin-4-yl)-9-(2,6-dichlo-rophenyl)-2 -methyl-3 - (4-methoxyphenyl)pyrido -[3',2':4,5]thieno[3,2-d]pyrimidine-4(3H)-one (IIIc). Yield 74%, mp 186-188°C (EtOH); IR: 1674 (C=O); 1H NMR: 1.16 (t, 3 H, CH3), 2.24 (s, 3H, CH3), 3.65 (s, 3H, OCH3), 3.76 (q, 2H, CH2), 6.68-7.65 (m, 9H, 7 Ph-H + 2 pyr-H), 8.45 (s, 1H, pyr-5'-H); 13C NMR: 14.16, 25.12, 55.85, 64.16, 100.01, 101.22, 114.56,

116.23, 120.33, 122.36, 125.12, 126.41, 128.83, 132.73, 133.37, 134.43, 136.52, 145.65, 146.21, 149.81, 151.73,

154.13, 154.72, 156.18, 157.45, 159.64, 163.75, 164.30 (30 C); MS, m/z (%): 624 (24) [M+]. Calc. for C30H21Cl3N4O3S (623.94): C, 57.75; H, 3.39; Cl, 17.05; N, 8.98; S, 5.14. Found: C, 57.70; H, 3.33; Cl, 17.00; N,8.94; S, 5.10.

7-(2-Chloro-6-ethoxypyridin-4-yl)-9-(2,6-dichlo-rophenyl)-2-methyl-3-(4-methylphenyl)pyrido-[3',2':4,5]-thieno- [3,2-rf]pyrimidi

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