European chemical bulletin - vol. 2. no. 9. (2013.)

Synthesis and antimicrobial activities of novel -amino acids and heterocycles SYNTHESIS OF NOVEL ANTIBACTERIAL AND ANTIFUNGAL
-AMINO ACIDS AND HETEROCYCLIC COMPOUNDS
Maher A. El-Hashash[a], Sameh A. Rizk[a]*
Keywords: (E)-4-aryl-4-oxo-2-butenoic acid , furanones, thiadiazoles, pyridazinones, imidazolo[2,3-b]1,3,4-thiadiazoles,
thiadiazolopyrimidines, bezoxazinones, fused quinoxalinylquinazolinones
Utility of (E)-4-(acetylamino)phenyl-4-oxo-2-butenoic acid with new sulfur reagents e.g. 2-amino-5-aryl-thiadiazoles 2 to afford the
corresponding adducts (3, 4, 5, 6). Reaction of the latter compounds with different electrophilic and nucleophilic reagents affords some
important heterocycle such as various furanones, thiadiazoles, pyridazinones, imidazolo[2,3-b]1,3,4-thiadiazoles, thiadiazolopyrimidines,
bezoxazinones, fused quinoxalinylquinazolinones
*Corresponding Authors
publication for research, Cairo, Egypt. By Elementar Viro El Microanalysis IR spectra (KBr) were recorded on IR [a] Chemistry department , Science Faculty , Ain-Shams spectrometer ST-IR DOMEM Hartman Braun, Model: MBB 157, Canada and 1H-NMR spectra recorded on a varian 300 MHz (Germany 1999) using TMS as internal standard. The mass spectra were recorded on Shimadzu GCMS-QP-1000 INTRODUCTION
EX mass spectrometer at 70e.v. homogeneity of all compounds synthesized was checked by TLC. Amino acids are the smallest units of proteins and are useful components in a variety of metabolic activities. There are numerous advantages of taking amino acids as dietary Compounds 3-6
supplements, also provide many useful biological activities In vitro data [1] about amino acids include muscle protein maintenance, potentiation of immune function, affecting A solution of 4-(4-Acetylaminophenyl)-4-oxo-2-butenoic neuronal activities in the brain, tissue repair acceleration, acid (0.01 mol) and 5-aryl-2-amino-1,3,4-thiadiazole (0.016 protecting liver from toxic agents, pain relief effect, mol) in 30 ml ethanol was refluxed for 3 h. The crude lowering blood pressure, modulating cholesterol metabolism, product was washed by petroleum ether (b.p 40- 60oC), and stimulating insulin of growth hormone secretion and so on. then crystallized from ethanol to give the following It is important to be note that they are part of complex compounds . pathway and biological systems. Amino acids have proven to play a significant role in the synthesis of novel drug 4-(4-Acetylaminophenyl)-4-oxo-2-(5-phenyl-2-thiadi-
candidate with the use of non-proteinogenic and unnatural amino acids 2-7. Over the last decade the synthesis of non- azolylamino)butanoic acid (3)
proteinogenic unnatural amino acids has received significant Yield 80% , Mp 160-162 oC ,IR for CO for acid and attention of organic chemists, who have tried to find out cost effective and less time consuming synthetic pathways. From this point of view the authors have made an attempt to J=7.7)( diastereotopic protons) , 4.2(dd,CH-COOH,methine investigate the reaction of 4-aryl-4oxo-but-2-enoic acids proton), 6.7(s,NH),7.6-8.1(m,9H,ArH) , 8.2 (s, 1H, COOH), with 2-amino-1,3,4-thiadiazole under aza-michael reaction 8.6 (s, 1H, C=O-NH). EIMS 3-6 as α-amino acid (C
types with acetic anhydride at different condition and N 20H18N4SO4 ): C 58.53, H 4.39; Found: C 58.50, H 4.40. to give the corresponding furanone, imidazolo[2,3-b]1,3,4- thiadiazole, 1,3,4-thiadiazolopyrimidine and pyridazinone 4-(4-Acetylaminophenyl)-4-oxo-2-(5-(4-chlorophenyl)-2-
derivatives, respectively with an aim to obtain some thiadiazolyl amino)butanoic acid(4)
interesting heterocyclic compounds with non-mixing and mixing system. Hence, keeping these reports in view and continuation of our earlier search work8 for aza-Michael Yield 75%. Mp. 174-174 oC. IR for CO for acid and ketone groups are at 1695–1630 cm-1. 1H NMR (DMSO-d6) exhibits signals at 2.5(s, 3H, CH3CO), 3.4 (2 dd, CH2-C=O, J=15.2, J=7.7) (diastereotopic protons), 4.2 (dd, CH-COOH, EXPERIMENTS
methine proton), 6.7 (s, NH), 7.6-8.1 (m, 8H, ArH), 8.2 (s, 1H, COOH), 8.6 (s, 1H, C=O-NH). m/z 358 (M+-(CO2 All melting points are uncorrected. Elemental analyses +CH2=CO). Anal.Calc. for (C20H17N4SO4 Cl): C 54.05, H were carried out in the Microanalytical Center, the center 3.83; Found: C 54.00, H 3.80. Eur. Chem. Bull. 2013, 2(9), 637-641
Synthesis and antimicrobial activities of novel -amino acids and heterocycles 4-(4-Acetylaminophenyl)-4-oxo-2-(5-styryl-2-thiadiazolyl
compound was separated and crystallized form ethanol. amino)butanoic acid (5)
M.wt=453 (C20H13N4O2SBr), M. 230 oC, yield 65%, calcd/found: C 52.98/52.80, H 2.86/2.62, N 12.63/12.52, Br Yield 70%. Mp. 180-182 oC. IR: CO for acid and ketone 17.66/17.45, S 7.06/6.88. IR: C=O are at 1772 ,1668 cm-1. groups are at 1694–1660 cm-1. 1H-NMR spectrum in H-NMR (DMSO-d6) exhibits signals at 5.2 (s, 2H, CH2-N), 6.7 (s, 1H, bridgeCH, 1,3-double bond shift), 7.2-7.7 (m, 6 exhibits signals at 2.5 (s, 3H, CH3CO), 3.4 (2 dd, 2C=O, J=15.2, J=7.7) (diastereotopic protons), 4.2 (dd, CH-COOH, methine proton), 6.7 (s, NH), 7.6-8.1 (m, 11H, ArH and olefinic protons), 9.5 (s, 1H, COOH), 10.2 (s, 1H, Pyridazinones 10 -12
m/z; 392 (M+-CO2). Anal.Calc. for (C22H20N4SO4): C 60.55, H 4.58; Found: C 60.50, H 4.60. An equimolar mixture of compound 7 (2.75 g;5mmol) and
hydrazine hydrate (1.7mL,0.015 mol) was refluxed in 4-(4-Acetylaminophenyl)-4-oxo-2-(5-phthalimido methyl-2-
boiling ethanol for 3 h and the solid that separated out was thiadiazolyl amino)butanoic acid(6)
filtered off, dried and then crystallized from ethanol . Yield 35%. Mp. 150-152 oC. IR: CO for imide, acid and ketone groups at are at 1770, 1690 and 1660 cm-1. 1H-NMR 6-(Acetylaminophenyl)-4-(5-phenyl-2-amino-1,3,4 thiadiazole)-
spectrum (DMSO-d6) exhibits signals at 2.5 (s, 3H, CH3CO), 2,3,4,5-tetrahydro 3(2H)-pyridazinones (10)
3.4 (2 dd, CH2-C=O, J=15.2, J=7.7) (diastereotopic protons, 4.2 (dd, CH-COOH, methine proton), 6.7 (s, NH), 7.6-8.1 Yield 70-75 %. IR(KBr) 1674,1708 (CO), 3177 (NH). 1H (m, 8H, ArH), 8.2 (s, 1H, COOH, 8.6 (s, 1H, C=O-NH). NMR (DMSO-d6): δ 2.2(s, 3H, CH3), 3.7 (2dd, 2H, CH2- m/z: 475 (M+-H2O). Anal.Calc. for (C23H19N5SO6): C 55.98, C=N), 4.2 (2 dd, CH, methine proton) 6.7 (s, NH, NH of thiadiazole moiety), 7.43-7.81 (m, 9H, Ar-H), 11.59 (brs, 2H, NH of acetamido and pyridazinone moieties). EIMS: m/z: 406 (M+), .Anal.: Calcd. C20H18N6SO2: C 59.11, H Compounds 7, 8
A mixture of 7 (3 g; 0.005 mol) and acetic anhydride (9.4
mL) was heated under reflux for 1 h upon water bath. The 6-(Acetylaminophenyl)-4-(5-(4-chlorophenyl)-2-amino-1,3,4-
solid that separated on cooling was crystallized from thiadiazole)-2,3,4,5-tetrahydro-3(2H)-pyridazinones (11)
pet.ether (80-100) to afford 7 and from ethanol to afford 8.
Yield 70-75 %. IR(KBr) 1674, 1708 (CO), 3177 (NH). 1H 2-(5-Acetylaminophenyl-2-oxo-furan-3-yl)amino-5-phenyl-
NMR (DMSO-d6): δ 2.2(s, 3H, CH3), 3.7(2 dd, 2H, CH2- 1,3,4-thiadiazole (7)
C=N), 4.2 (2 dd, CH, methine proton), singlet broad band at 6.5 ppm assigned for NH of thiadiazole moiety.) 7.6-8.1 (m, 8H, ArH), singlet at 10.2 was assigned for the two acidic protons of acetamido and pyridazinone moieties. EIMS NH 3297-3100, CH 3055-2890, the band at 1767and 11 C20H17N6SO2Cl: C 54.54,
groups, respectively, and 1H-NMR spectrum(DMSO-d exhibits signals at δ 2,1 (s 3H, CH3CO), 4 (dd, 1H, -CH-NH, J=8.5), 6.7 (bs, NH), 7.5-7.9 (m, 9H of Ar), 6.9 (d, 1H, CH furanone moiety, J=8.5), 12.7 (s, 1H, –C=O-NH) acidic 6-(Acetylaminophenyl)-4-(5-styryl-2-amino 1,3,4 thiadiazole)-
2,3,4,5-tetrahydro-3(2H)-pyridazinones (12)
61.5, H 4.3, N 14, S 8.3; Found C 61.4, H 4.2, N 13.8, S 8.2. Yield 70-75%. IR (KBr) 1674, 1708 (CO), 3177 (NH). 1H 5-(4-Acetylaminophenylmethyl)-2-Phthalimidomethyl-4-oxo-
C=N), 4.2 (2 dd, CH, methine proton), singlet broad band at imidazolo[2,1-b]-1,3,4-thiadiazole (8)
6.5 ppm assigned for NH of thiadiazole moiety.) 7.6-8.1(m, 11H, ArH and olefinic protons), singlet at 10.2 assigned for M.wt = 497 (C21H13N4O4SBr), Mp. 230-232 oC, yield 35%. two acidic protons of acetamido and pyridazinone moieties. calcd/found: C 50.89/51.00, H 2.64/2.22 , N 11.30/11.62, EIMS: m/z: 432 (M+). Anal. Calc. C22H20N6SO2: C 61.11, H 1691 and 1668 cm-1. 1H-NMR (DMSO-d6) exhibits signals at 3.2 (2dd, CH2-C=O, J=7.7)( diastereotopic protons), 3.9 (dd, CH-COOH, methine proton), 5.2 (s, 2H, CH Ethyl N-[6-(4-acetylaminophenyl)-3-oxo-pyridazin-4-yl)]-N-[(5-
1H, bridgeCH, 1,3-double bond shift), 7.2-7.7 (m, 8H, ArH). phenyl-1,3,4-thiadiazol-2-yl)] glycinate (13)
The EI-MS shows the molecular ion peak at m/e 498, 496 corresponding to (M+2)+ and (M.+), respectively .
An equimolar mixture of compound 10 (2.0 g; 5 mmol)
and ethylchloroacetate (1.4 mL, 0.015 mol) in 50 mL dry pyridine was refluxed for 3 h. The reaction mixture was 1-(4-Acetylaminophenyl-6-(N-phthalimido)methyl-) 1,3,4-
poured on to ice/HCl and the solid that separated out was thiadiazolo [3,2-a] pyrimidine (9)
filtered off, dried and then, crystallized from ethanol. Yield 35 %. Mp. 190-192. IR (KBr) 1630 (C=N), 1650, 1743 (CO), Boiling of 3 (3 g; 0.005 mol) with acetic anhydride (9.4 3320, 3188 (NH). 1H NMR (DMSO-d6): δ 1.12 (t, 3H, CH3),
mL ) on a hot plate was heated under reflux for 4 h. The 2.08 (s, 3H, CH3), 3.72-3.86 (m, 3H, CH2CH), 4.13 (s, 2H, reaction mixture was poured on to H2O and the solid CH2-N), 4.80 (q, 2H, CH2-O), 7.46-7.92 (m, 9H, Ar-H), Eur. Chem. Bull. 2013, 2(9), 637-641
Synthesis and antimicrobial activities of novel -amino acids and heterocycles 11.36 (brs, 2H, NH of acetamido and pyridazinone moieties). antioxidant and anti-inflammatory agents. In the synthesis Anal.: Calcd. for C24H24N6SO4: C 58.53, H 4.87, N 17.07; of lactone derivatives related to ascorbic acid, the NH group in the position 3 is acting as OH group in ascorbic
acid, we also have found out that some 3,5-diaryl-2(3H) furanone possess significant anti-inflammatory and anti- 3-Oxo-4-(5-phenyl-1,3,4-thiadiazol-2-yl)-6-(4-acetyl-aminophe-
nyl)-)1,2,3,4tetrahydro1,4-oxazino[2,3-c]pyridazine (14)
An equimolar mixture of compound 10 (2.0 g; 5 mmol),
ethylchloroacetate (1.4 mL, 0.015 mol) and anhydrous K2CO3 (4 g) in 50 mL dry acetone was refluxed for 24 h. The reaction mixture was then poured on to H2O/ice. The solid that separated out was filtered off, dried and then, crystallized from benzene. Yield 65 %. Mp. 162-164 °C. IR (KBr) 1630 (C=N), 1650, 1685 (CO), 3320, 3188 (NH). 1H NMR (DMSO-d6): δ 2.08(s, 3H, CH3), 3.72-3.76(m, 3H, CH2CH), 5.933 (s, 2H, OCH2CO), 7.46-7.92 (m, 9H, Ar-H), 11.36 (brs, 1H, NH of acetamido moiety). Anal.: Calcd. for C22H18N6SO3: C 59.19, H 4.03, N 18.83; Found: C 59.30, H 1-((2-(4-Acetylaminophenyl))-2-oxo)ethyl-7-oxo-quinoxalino-
[1,2-b]-quinazoline (16)
A mixture of benzoxazinone 15 (0.01 mol) and o-
phenylene diamine (0.01mol) in ethanol (50 mL) was heated and refluxed for 5h. The reaction mixture was allowed to cool and the product was filtered, dried and recrystallized from ethanol. Yield 70 %. Mp. 126-128 °C. IR (KBr) 1709, Scheme 2.
1735 (CO), 3423 (NH). 1H-NMR (DMSO-d6): δ 2.5 (s, 3H, CH3), 3.4 (m, 3H, CH2-CH), 6.2 (s, 1H, pyrazine moiety), 7.46-8.11 (m, 12H, Ar-H), 12.40 (brs, 1H, NH of acetamido moiety). Anal.: Calcd. for C25H20N4O3: C 70.75, H 4.71, N RESULTS AND DISCUSSION
When 4-(4-acetylaminophenyl)-4-oxo-but-2-enoic acid (1) was allowed to react with 2-amino 5-aryl thiadiazole
derivatives (2), it produced 3-(4-acetamidobenzoyl)-2-(5-
aryl 2-thiadiazolylamino)propanoic acids (3-6) as α-amino
acid types that differ in biological activity by differing the aryl groups. Outline in Table 1 the presence of halogen atom enhances the antibacterial activity rather than chromophore Scheme 1.
The recent efforts made for the development of new ascorbic acid analogues in obtaining anti-oxidant9–13, anti- tumour14 agents have resulted 2(3H)-furanones as a new Scheme 3.
Eur. Chem. Bull. 2013, 2(9), 637-641
Synthesis and antimicrobial activities of novel -amino acids and heterocycles Table 1. Antibacterial and Antifungal activities for some important synthesize compounds
Compound / Ar
Escherichia coli G- Staphylococcus
aureus
Aspergillus flavus
Candida albicans
G+
(Fungus)
(Fungus)
3/C6H5- 14
4/4-ClC6H4 16
5/Phthalimidoylmethyl 14
6/-styryl 14
The antimicrobial screening of all the synthesized compounds can be done using the agar diffusion assay. Tetracycline (Antibacterial agent): 32-30, Amphotericin (Antifungal agent): 18-16 These results prompted us that lactones can be obtained by Treatment of the benzoxazinone 15 with o-phenylene
the lactonization of hydroxyl acids. Thus, the adduct 3 (new
diamine in boiling ethanol can be produced with new α-amino acid) with design and synthesize new furanones. derivative of quinoxaline 16 (Scheme 4).
The synthesis of freshly distilled acetic anhydride afforded 2-(5-acetylaminophenyl-2-oxo-furan-3-yl)amino-5-phenyl 1,3,4- thiadiazole (7) and 2-phenyl-4-oxo-5-(4-
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