Synthesis of Some New Phthalimides as Anti ...

British Journal of Pharmaceutical Research 4(16): 1923-1936, 2014 SCIENCEDOMAIN international www.sciencedomain.org

Synthesis of Some New Phthalimides as Anti-metabolic Agents with Chemotherapeutic Effects Fathy A. Yassin1*, Amal F. Seleim2, Ali M. Hassan3, Atif F. Hadad4, Nahed M. Fathy5 and M. Fayad3 1

Department of Chemistry, Faculty of Science, Zagazig University, Zagazig, Egypt. 2 Department of Chemistry, Faculty of Science, Najran Univeristy, Saudi Arabia. 3 Department of Chemistry, Faculty of Science, Al-Azhar University, Cairo, Egypt. 4 Department of Chemistry, Faculty of Science, Helwan University, Helwan, Egypt. 5 Department of Chemistry, National Research Center, Cairo, Egypt. Authors’ contributions

This work was carried out in collaboration between all authors. Authors FAY and MF designed the study, performed the statistical analysis, wrote the protocol, and wrote the first draft of the manuscript. Authors AFS, AMH, AFH managed the analyses of the study and managed the literature searches. All authors read and approved the final manuscript.

th

Original Research Article

Received 11 August 2013 rd Accepted 3 July 2014 th Published 8 August 2014

ABSTRACT A series of new phthalimides 1(a-f) were synthesized via reaction phthalic anhydride with different amino acids under fusion conditions. Esterification of N-phthaloyl acid derivatives 1(a-f) with methanol in the presence of SOCl2 to producing the corresponding esters 2(a-f). Which on reaction with hydrazine hydrate in boiling n-butanol afforded the corresponding N-phthaloyl acid hydrazides 4(a-f) Reaction of compound (4a) with different aldehydes and ketones yielded the corresponding hydrazone derivatives 5(a-d). Some new phthalimides linked to hetero cyclic moieties such as benzimidazoles, benzoxazines and quinazolines were synthesized. The structure of the synthesized compounds was 1 confirmed from their analytical and spectral data such as, IR spectra, H-NMR and mass spectra. Antimicrobial against two types of bacteria and anticancer activity for some of the synthesized imides were evaluated. The results showed that most of them have a good antimicrobial and anticancer activities. ____________________________________________________________________________________________ *Corresponding author: Email: [email protected];

British Journal of Pharmaceutical Research, 4(16): 1923-1936, 2014

Keywords: Phthalimide; phthaloyl ethyl glycinate; benzimidazoles; benzoxazines quinzolinones; anti-inflammatory; antihypertensive activity; antimicrobial; anticancer activities.

1. INTRODUCTION Imide group is an interesting functionality, due to its wide presence in natural products and in the pharmacologically active compounds. Compounds containing phthalimide moiety are distinguished by their potent antimicrobial action [1-3]. Phthalimides were found to possess anti-inflammatory, antiviral, anxiolytic, antibacterial and antitumor properties [4,5]. Also, phthalimides are important synthetic intermediate to prepare primary amines, agriculture pesticides. The use of phthalimide as primary amine protecting group is extensively documented in the chemical literature, especially for peptides, α-amino acids, amino glycosides and β-lactam antibiotics [6].

2. EXPERIMENTAL All melting points were measured on a Gallenkamp melting point apparatus and are uncorrected. The infrared spectra were recorded on a PVE Unicam SP 3300 and Shimadzu FT IR 8101 PC infrared spectrophotometers. The NMR spectra were recorded on a Varian Mercury VXR-300 NMR spectrometer at 300 MHz (DMSO-d6). Chemical shifts were related to that of the solvent. The biological and pharmaceutical activities were carried out at The Regional Center for Mycology & Biotechnology in Al-Azhar University, Cairo, Egypt, National Research Center, Giza, Egypt, Cairo University, Giza, Egypt and at Faculty of Science, Zagazig University, Zagazig, Egypt.

2.1 Synthesis of N-phthaloyl Amino Acids 1(a-f) Method (A): A mixture of equimolecular quantities of phthalic anhydride, appropriate amino acids (glycine, alanine, asparagine, methionine, tyrosine, and valine) was heated under fusion condition in an oil bath at 170-190ºC for 30 minutes. The reaction mixture was kept at room temperature, overnight. The unreacted raw material removed by repeatedly shaking with 50 ml portions of benzene and then with 50 ml portions of chloroform. The solid separated was filtered, dried and recrystallized from the proper solvents. Method (B): A mixture of phthalic anhydride 74 g (0.5 mole) and (0.5 mole) of respective amino acids namely, glycine, alanine, asparagine, methionine, tyrosine, and valine was refluxed in 100 ml toluene/and or acetic acid in presence of 6.5 ml of triethylamine for 2 hours, the organic solvents were removed in vacuum, then 100 ml of H2O and 10 ml of concentrated HCl were added. The solid separated was filtered, dried and recrystallized from the proper solvents.

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2.2 Synthesis of N-phthaloyl Amino Acid Methyl Esters 2(a-f) Method A: To a stirred solution of N-phthaloyl amino acids 1(a-f) (0.1 mole) in absolute methanol (30 ml), thionyl chloride (0.02 mole) was added dropwise with stirred at room temperature for 4 hours. The reaction, the mixture was allowed to stay overnight then poured on crushed ice. The solid separated recrystallized with petroleum ether. Method B: A mixture of N-phthaloyl amino acids 1(a-f) (0.03 mole) in acetone, dimethyl sulphate (0.07 mole) anhydrous potassium carbonate (0.02 mole) was refluxed on a water bath for 2 hours with occasional stirring. After the completion of the reaction, the mixture was allowed to cool at room temperature and poured into crushed ice. The solid separated was recrystallized with petroleum ether.

2.3 Synthesis of N-phthaloyl Acetyl Chloride Derivatives 3(a-f) Method (A): A mixture (0.01 mole) of phthaloyl acetic acid derivatives 1(a-f) and 10 ml of thionyl chloride was heated on water bath till evolution of hydrogen chloride gas ceased. The excess of thionyl chloride was distilled off under reduced pressure using vacuum pump. The acid chloride left behind as residue was used in the next experiment without further purification. Method (B): To a stirred solution of N-phthaloyl amino acids 1(a-f) (0.1 mole) in cyclohexane-benzene (1:1) (40 ml), oxalyl chloride (0.02 mole) was added dropwise and then freshly distilled DMF (0.02 mole) was added. The reaction mixture was stirred at room temperature for 4 hours. The solvents were evaporated to dryness under vacuum to give acid chlorides 3(a-f).

2.4 Synthesis of N-phthaloyl Amino Acid Hydrazides 4(a-f) Method A: To a solution of the phthaloyl aectic acid esters 2(a-f) (0.02 mole) in absolute n-butanol (20 ml) hydrazine hydrate (0.02 mole) was added. The reaction mixture was refluxed for 5hours. The solid separated was filtered washed with water, dried and crystallized from ethanol. Method B: To a solution of the acid chloride 3(a-f) (0.02 mole) in absolute ethanol (20 ml) hydrazine hydrate (0.02 mole) was added. The reaction mixture was refluxed for 5hours. The solid separated was filtered washed with water, dried and crystallized from ethanol.

2.5 Synthesis of N-phthaloyl Amino Acid Hydrazones 5(a-d) To a solution of the acid hyrazide 4a (0.01 mole) in 30 ml ethanol and few drops of acetic acid, (0.02 mole) of aromatic aldehydes namely salicyaldhyde, o-chlorobenzaldehyde and pmethoxybenzaldehyde also with ketone as acetyl acetone was added. The reaction mixture was heated under reflux for 5 hours and then cooled. The solid separated was filtered, dried and crystallized from the proper solvents.

2.6 Synthesis of Benzimidazoles 6(a-f) Method (A): A mixture of (0.0l mole) of 0-Phenylenediamine, (0.01 mole) N-phthaloyl amino acids 1(a-f), 5ml of dilute hydrochloric acid were taken into a 250ml round bottomed flask. The mixture was refluxed for two hours. The reaction mixture

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was cooled and 10% sodium hydroxide solution was added slowly with constant stirring of the flask, until the mixture was just alkaline to litmus paper. The solid separated was filtered, washed with ice cold water, dried and recrystallized from ethanol. Method B: A mixture of o-phenyldiamine (0.01 mole) p-nitrobenzaldehyde (0.01 mole) and zinc acetate (0.03 mole) was stirred magnetically at room temperature. The reaction mixture was poured up on cooled water and extracted with ethyl acetates. The combined ethyl acetates were evaporated under vacuum and the solid separated was dried and recrystallized from ethanol.

2.7 Synthesis of Bezoxazinone 7(a-f) To a solution anthranilic acid (0.01 mole) in 30 ml dry pyridine and (0.01 mole) each of Nphthaloyl amino acids 1(a-f). The reaction mixture was heated under reflux for 5 hours, and then cooled. Then the reaction mixtures were poured upon ice /HCl. The solid separated was filtered, dried and crystallized from the proper solvents.

2.8 Synthesis of Quinazolinones 8(a-d) To a solution of the bezoxazinone 7a (0.01 mole) in 30 ml n-butanol and (0.02 mole) of different amines namely formamide, hydrazine hydrate, phenyl hydrazine and aniline was added. The reaction mixture was heated under reflux for 5hours and then cooled. The solid separated was filtered, dried and crystallized from the proper solvents.

3. RESULTS AND DISCUSSION In view of tremendous importance of phthalimides due to their medicinal and bioactive properties for both phthalimide moiety and the side chain hetero cyclic moieties. The target of the present work has been directed towards building of new molecules containing these two active moieties (phthalimide and N-substituted alkyl derivatives) via applying different strategies. A variety of reagents have been reported for the transformation of amino acids into Nphthaloyl amino acids, which include thermal conditions [7,8], acid environment [10] and basic catalyst [11]. In this work, we present an efficient synthesis of N-phthaloyl amino acid derivative using economical experimental conditions via reaction phthalic anhydride and different amino acids namely, glycine, alanine, asparagine, methionine, tyrosine, and valine by heating at high temperature under fusion conditions at 170-190ºC. The structure of compounds 1(a-f) was confirmed from its correct analytical and spectral data, IR spectra of compounds 1(a-f) showed bands at 3330-3273 (OH) of carboxylic acids, 1774-1710 due to two (N-C=O), 1700-1690 (C=O) of carboxylic acid), 1553-1544(C=C 1 aromatic) and at 1468-1464 (C-N).While H-NMR spectrum of compound 1a showed signals at 5.1 (s, 2H, CH2), 7.1-8.6 (m, 4H, aromatic protons) and at 10.5 (s, 1H, COOH). Methylation of N-phthaloyl amino acids 1(a-f) was easily accrued on refluxing with absolute methanol afforded the corresponding methyl esters 2(a-f).The structure of compounds 2(a-f) was confirmed from its correct analytical and spectral data. IR spectra of compounds

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showed the disappearance of the brood band (3330) of OH of the carboxylic group in all amino acids, and showed bands at range 1743-1715 ( C=O, ester ), 1720-1708 due to two 1 (N-C=O), 1585-1550 (C=C aromatic) and at 1492-1454 (C-N).While H-NMR spectrum of 2a showed signals at 4.5(S, 3H,CH3), 5.3(s, 2H, CH2-), and 7.8-8.4 (m, 4H aromatic protons). Acid chlorides are considered very active intermediate in organic chemistry to achieve transformation to new function groups so; we aimed to synthesis of N-phthaloyl amino acid chloride derivatives through the reaction of N-phthaloyl amino acids 1(a-f) with thionyl chloride by heating on a water bath. The excess thionyl chloride was distilled under reduced pressure. The acid chlorides 3(a-f) formed as residue was used in the next reactions without further purifications. Hydrazide derivatives exhibit miscellaneous biological activity, analgesic and antiinflammatory activity. Acetic acid hydrazide derivative is known to play an important (11) intermediate in medicinal chemistry . Hence it was thought of interest in merging of both phthalimide and acetic acid hydrazide moieties may enhance the drug activity. From this point of view, The objective of the present work is to prepare new derivative of N-phthalimide attached to different acid hydrazide derivatives through the reaction of both N-phthaloyl amino acid methyl esters 2(a-f) and N-phthaloyl amino acid chloride derivatives 3(a-f) with hydrazine hydrate in boiling n-butanol to give the corresponding acid hydrazides 4(a-f). Hydrazones 5(a-d) were prepared via the reaction of the acid hydrazide(4a) with appropriate aldehydes namely, salcyaldhyde, o-chlorobenzaldehyde and p-methoxybenzaldehyde also with ketone as acetyl acetone in refluxing ethanol/acetic acid mixture (Scheme 1). The structure of compounds 4(a-f) was confirmed from its correct analytical and spectral data, The IR spectra of acid hydrazides 4(a-f) showed two strong absorption bands at 33603339 (NH2), 3185-3165 (NH) Other absorption bands appeared at 1725-1710, 1595-1588, -1 and 1390 -1384cm , due to asym. (C=O) imide, (C=C) aromatic,), (C-N) respectively. While 1 H-NMR spectrum of (4a) showed signals at 3.8 (br, 2H, NH2), 5.1 (s, 2H, -CH2-), 7.3-8.2 (m, 4H aromatic protons), 8.6 (br, 1H, NH, CONH). The structure of compounds 5(a-d) was confirmed from its correct analytical and spectral data, The IR data of the newly synthesized hydrazones provided functional group evidence for the formation of the expected structures. The IR spectra of compounds 5(a-d) showed -1 disappearance of the two characteristic absorption bands at 3359 and 3265 cm due to (-NH-NH2) group in hydrazine compound 4a and appearance of new clear absorption band -1 at (1544-1490) cm due to (C=N) imine. Also, IR spectra showed significant stretching -1 -1 -1 bands at 3429–3160 cm , 1718–1600 cm and 1487–1334 cm , 1300-1290 due to N–H, C=O, C=C and C-N respectively. Moreover IR spectrum of 5b showed clear absorption band -1 -1 at 1076 cm due to (C-Cl).While compound 5c showed clear absorption band at 1072 cm 1 due to (C-O-C) ether. While H-NMR spectrum of 5a showed signal at 5.8 (s, 2H, NCH2) 7.38.5 (m, 9H aromatic protons), 8.5(s, 1H, CH=N- proton), 9.9(s, 1H, NH, NH-N=) and at 13.03 (br, 1H, OH).

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O

O H

O

+

H N C

H2N C COOH

COOH

R

R O

O

1(a-f) O

O H

N C

H MeOH

+

COOH

N C COOCH3

R

R

O

O

2(a-f)

1(a-f) O SOCl2

H N C COCl R O

3(a-f) Intermediates

H2N

in n-butanol or ethanol

O H O N C C

NH2.H2O

NH

N CH

Ar

R

ArCHO

O

O H

5(a-c)

N C

CONHNH2

R O

O H

O

N C

C

CH3

O

Acetyl acetone

NH N C CH2 C CH3

4(a-f)

H O

5d R = a)-H, b)-CH3, c)-CH2-CONH2, d)-CH2-CH2-S-CH3, e)-CH2-C6H4-OH-4-, f)-CH-(CH3)2 Ar = a)-C6H4-OH-2-, b)-C6H4-Cl-2-, c)-C6H4-OCH3-4-

Scheme 1 The synthesis of novel benzimidazole derivatives remains a main focus of medical research. Recent observations suggest that substituted benzimidazoles and heterocyclic are possess potential activity with lower toxicities in the antihypertensive activity approach [12]. Also, it has been reported that imidazoles are exhibit a variety of biological activity such as antibacterial, antifungal, antiviral, anticancer and anti-inflammatory activities. Benzimidazoles are present in various bioactive compounds possessing antiviral, anti-hypertension and

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anticancer properties [13,14]. This promoted us to synthesize some benzimidazole derivatives attached to the N-phthalimide moieties likely to get biologically active compounds. In this present study, a series of benzimidazoles were synthesized and screened for their antimicrobial activities. The reaction occurs via through the reaction of N-phthaloyl amino acids 1(a-f) with o-phenylenediamine in boiling n-butanol for 5 hours to give the corresponding benzimidazoles 6(a-f). The structure of compounds 6(a-f) was confirmed from their correct analytical and spectral data. IR spectra of compounds 6(a-f) showed the disappearance of the brood band (3330) of OH of the carboxylic group in all amino acids and the appearance of band at (3240–3100) attributed to N-H group. Also IR spectra of compounds 6(a-f) showed clear absorption bands at (1725-1697), (1600-1550), (1550-1490) and (1380-1311) due to (C=O) imide, (C=N) in 1 imidazole, (C=C) aromatic and (C-N) imide respectively. While H-NMR spectrum of compound 6a showed signal at, 3.6 (s, 1H, NH), 4.4 (S, 2H, CH2) and 7.8-8.1 (m, 8H) due to aromatic ring protons. The present work deals with synthesis of N-phthalimide carrying a new 3, 1-benzoxazineone derivatives likely to increase the pharmaceutical affect of new products produced. 4H -3, 1Benzoxazin-4-ones have been known for more than a century to possess biological activity. Also, substituted benzoxazinones have become of great importance due to their wide range of biologically active compounds. Previous studies have reported that they exhibit antitubercular, anticancer and antifungal activities [15]. Besides, they were used as analgesics, inhibitors for cathepsin G, Human leukocyte elastase [16]. On the other hand, it has been stated that compounds containing aromatic sulfonate or sulfonamide moieties possess high a caricidal as well as insecticidal activit [17]. 4H-3, 1-Benzoxazine-4-one derivatives bear methyl or alkyl groups at position 2 are called benzoxazines. According to all these facts and as a part of our interest on the synthesis of biologically active molecules, the present investigation aims to synthesize a series of products bearing both benzoxazinone and phthalimide moieties in the same molecules that, these new products might show high biocide activity. Thus reaction phthaloyl acetic acid on treatment with anthranilic acid in presence of dry pyridine afforded the benzoxazin-4-ones 7(a-f). The structure of the synthesized compounds 7(a-f) was confirmed from their correct analytical and spectral data. IR spectra of compounds 7(a-f) showed clear absorption bands at (1725-1697), 1685-1655, (1580-1540) and (1375-1311) due to (C=O) imide, (C=N) in 1 benzoxazine, (C=C) aromatic and (C-N) imide respectively. While H-NMR spectrum of compound 7a showed signal at δ= 3.8 ppm due to (-CH2-) protons and signals at δ= (7.7-8.1) ppm due to aromatic ring protons. Quinazolinone derivatives have been well known for antihypertensive activity such as Prazosin, Terazosin, Doxazosin and Alfuzosin which are available in medicinal markets. So it was planned to synthesize newer quinazolinone analogous attached to N-phthalimide moieties and evaluate their antimicrobial and pharmaceutical activities.

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Quinazolinone derivatives 8(a-d) were prepared via the reaction of benzoxazinone (7a) with different nitrogen nucleophiles namely, formamide, hydrazine hydrate, phenyl hydrazine and aniline (Scheme 2). The structure of quinazolinone derivatives 8(a-d) was established from their correct analytical and spectral data. The IR spectrum of 8a revealed stretching frequencies at 3320, -1 cm characteristic for the -NH- groups, respectively. This illustrates that quinazolinone derivative 8a exists in a lactam- lactim tautomeric equilibrium. IR spectra of compounds 8(a-d) showed clear absorption bands at (1725-1710), (1616-1600), (1580-1540) and (13921 1340) due to (C=O) imide, (C=N), (C=C) aromatic and (C-N) imide respectively. While HNMR spectrum of compound 8a showed signal at 4.8 (S, 2H, CH2), 6.5 (br, 1H, NH), and 7.8-8.1 (m, 8H) due to aromatic ring protons. Characterization and physical data are listed in Table 3. O

H

O H2N

H N C COOH

H

+

N

N C H2N

R

N

R

O

O

1(a-f)

6(a-f)

HOOC O H2N

O

O

O H O

N C H

Rl-NH2

l

R

N CH2

N

O

N N

O

8(a-d)

7a

Rl = a)-H, b)-NH2, c)-HNPh, d)-Ph

Scheme 2

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Table 1. Antibacterial activities of compounds Drugs Ciproflaxacin (Standard) 1a 1e 2b 2c 2e 4a 4b 4d 5a 5b 5c 6a 6c 6e 8a 8b

Escherichia coli 20

Klebsiella 20

Staphylococcus epidermidis 22

Bacillus cereus 20

Micrococcus luteus 24

Staphylococcus aureus 22

15 15 13 15 15 18 15 15 18 20 20 16 20 20 16

18 18 18 20 15 18 22 22 20 24 18 20 16 15

15 15 20 22 15 20 15 15 20 18 24 22 22 20

18 17 15 15 13 18 15 14 20 18 20 22 18 15 18 22

15 15 20 12 15 20 18 20 18 18 16 16 24 23

20 15 12 15 15 15 18 12 20 22 20 15 15 15 14

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3.2 Biological Activity 3.2.1 Antimicrobial activity All the newly synthesized derivatives were screened for their in vitro antimicrobial activity against Escherichia coli, Klebsiella, Staphylococcus epidermidis, Bacillus cereus, Micrococcus luteus, and Staphylococcus aureus by measuring the zone of inhibition in mm. The antibacterial activity was studied by using cup plate agar diffusion method by measuring diameter of zone of inhibition in mm. The compounds were tested at the concentration of 200 ppm in 5% DMF. The solution was poured in the cup/well of bacteria seeded agar plates. The plates were incubated at 37ºC for 24 hours for E. coli where is the plates of other three bacteria were incubated at 27±2ºC for 24 hours. The activity is reported by measuring the diameter for zone of inhibition in mm. Ciprofloxacin was used as standard drug for antibacterial activities. Nutrient agar was employed as culture medium and DMSO were used as solvent. While, antifungal activity was screened for all the newly synthesized compounds. The cup plate method was employed to study the preliminary antifungal activity of Candida albicans and Aspergillus nigar. Each test compound was dissolved in 5ml of Dimethyl Sulfoxide (1000ug/ml) Volume of and 1mg/ml of each compound were used for testing. Ciprofloxacin was used as standard drug (50 & 100ug/ml) and dimethyl sulfoxide as a control. The observed zone of inhibition was measured in mm. Results showed that the synthesized compounds are active against all microorganisms when compared to standards. From the result it is evident that the compounds1a, 1e, 3c, 3e, 3e, 4a, 4b, 4d, 5a, 5b, 5c, 6a, 6c, 6e, 8a and 8b exhibit significant antibacterial activity against all microorganisms as listed in Table 1. Results showed evident that the compounds 1b, 1e, 3c, 3d, 4d, 4f, 5b, 5c, 6a, 6f, 8b, 8c and 8d exhibit significant antifungal activity against Candida albicans and Aspergillus nigar. The result of compounds showed any significant antifungal effect with reference to Ketaconazole at a 1mg/ml concentration. The results are listed in Table 2. Table 2. Antifungal activity of compounds Drug Ketaconazole (standard) 1b 1e 2c 2e 4d 4f 5b 5c 6a 6f 8b 8c 8d

Candida albicans 8.25 7.25 8.15 8.28 8.15 7.15 8.25 7.35 7.33 6.8 8.25 7.15

Aspergillus nigar 7.25 7.15 7.25 9.21 5.40 5.40 -

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Table 3. Characterization and physical data Analysis % calculated/ found N H C 6.83 3.44 58.54 6.58 3.25 58.11 6.39 4.14 60.27 6.16 4.03 60.12 10.68 3.84 54.97 10.45 3.77 54.75 5.01 4.69 55.90 4.77 4.58 55.66 4.50 4.21 65.59 4.26 4.08 65.33 5.67 5.30 63.15 5.46 5.16 62.71 6.39 4.14 60.27 6.18 4.06 59.85 6.01 4.75 61.80 5.84 4.58 61.37 10.14 4.38 56.52 9.89 4.21 56.12 4.77 5.15 57.32 4.54 5.02 57.16 4.31 4.65 66.46 4.16 4.51 66.13 5.36 5.79 64.36 5.19 5.66 63.88 19.17 4.14 54.79 18.81 4.01 54.44 18.02 4.75 56.65 17.76 4.59 56.21 20.28 4.38 52.17 19.84 4.22 51.44 14.32 5.15 53.23 14.02 5.03 52.76 12.92 4.65 62.76 12.45 4.45 62.55 16.08 5.79 59.76 15.66 5.57 59.43 13.00 4.05 63.16 12.75 3.91 62.66 12.30 3.54 59.75 12.03 3.44 59.33 12.46 4.48 64.09 12.19 4.32 63.72 13.95 5.02 59.79 13.56 4.84 59.54 15.15 4.00 69.31 14.81 3.79 68.89 14.42 4.50 70.09

Mol. formula/ formula wt. C10H7NO4 205.17 C11H9NO4 219.19 C12H10N2O5 262.22 C13H13NO4S 279.31 C17H13NO5 311.29 C13H13NO4 247.25 C11H9NO4 219.19 C12H11NO4 233.22 C13H12N2O5 276.24 C14H15NO4S 293.34 C18H15NO5 325.32 C14H15NO4 261.28 C10H9N3O3 219.2 C11H11N3O3 233.22 C12H12N4O4 276.25 C13H15N3O3S 293.34 C17H15N3O4 325.32 C13H15N3O3 261.28 C17H13N3O4 323.3 C17H12ClN3O3 341.75 C18H15N3O4 337.33 C15H15N3O4 301.3 C16H11N3O2 277.28 C17H13N3O2

M. p. (ºC)/ solvent 190-192 Ethanol 152-154 Ethanol 160-162 Ethanol 232-234 Ethanol 122-124 Ethanol 199-201 Ethanol 111-113 Petroleum ether 105-107 Petroleum ether 93-95 Petroleum ether 85-87 Benzene 121-123 Benzene 110-112 Benzene 222-224 Ethanol 245-247 Ethanol 265-267 Ethanol 275-277 Ethanol 235-237 Ethanol 250-250 Ethanol 245-247 Ethanol 256-258 Ethanol 266-268 Ethanol 276-278 Ethanol 222-224 Ethanol 230-232

Yield (%) 83

Compds 1a

82

1b

75

1c

7o

1d

66

1e

66

1f

82

2a

76

2b

83

2c

80

2d

77

2e

72

2f

70

4a

74

4b

66

4c

68

4d

66

4e

63

4f

82

5a

80

5b

78

5c

75

5d

79

6a

77

6b 1933


Analysis % calculated/ found N H C 14.22 4.35 69.56 16.76 4.22 64.66 16.54 4.03 64.23 11.96 4.88 64.94 11.76 4.68 64.66 10.96 4.47 72.05 10.67 4.29 71.56 13.16 5.37 71.46 12.86 5.23 71.17 9.15 3.29 66.67 8.85 3.12 66.28 8.75 3.78 67.50 8.53 3.53 67.15 11.57 3.61 62.81 11.29 3.39 62.48 7.36 4.24 63.14 7.06 4.04 62.67 6.79 3.91 69.90 6.53 3.66 69.52 8.04 4.63 68.96 7.78 4.43 68.49 13.76 3.63 66.88 13.57 3.52 66.44 17.49 3.78 63.75 17.21 3.55 63.28 14.13 4.07 69.69 13.84 3.78 69.29 11.02 3.96 72.43 10.76 3.72 72.05

Mol. formula/ formula wt. 291.3 C18H14N4O3 334.33 C19H17N3O2S 351.42 C23H17N3O3 383.4 C19H17N3O2 319.36 C17H10N2O4 306.27 C18H12N2O4 320.3 C19H13N3O5 363.32 C20H16N2O4S 380.42 C24H16N2O5 412.39 C20H16N2O 348.35 C17H11N3O3 305.29 C17H12N4O3 320.3 C23H16N4O3 396.12 C23H15N3O3 381.38

M. p. (ºC)/ solvent Ethanol 240-242 Ethanol 244-246 Ethanol 235-237 Ethanol 247-249 Ethanol 226-228 Acetic acid 234-236 Acetic acid 255-257 Acetic acid 238-240 Acetic acid 266-268 Acetic acid 272-274 Acetic acid 240-242 Methanol 256-258 Methanol 264-266 Methanol 269-271 Methanol

Yield (%)

Compds

72

6c

69

6d

62

6e

65

6f

83

7a

78

7b

76

7c

70

7d

67

7e

62

7f

83

8a

79

8b

78

8c

73

8d

3.2.2 Anticancer screening Five of newly synthesized phthalimdes derivatives were selected for testing for their anticancer activity, at The Regional Center for Mycology & Biotechnology in Al-Azhar University, Cairo, Egypt. One cell lines was used for the evaluation (human liver carcinoma cell line HePG2) according to the method described by Skehan et al. [18] . The results are expressed in the form of the concentration of compound that causes 50% inhibition of cells growth. Significant anticancer activities against of the liver cancer. The data of the selected five phthalimides evidenced that compounds 4a, 5b, 5c, 6a, and 8b were the most effective against HepG2 carcinoma cell lines showing IC50 1.2 µg for doxorubicin standard, giving these values 6.5, 4.1, 4.6, 3.5, and 2.8 µg respectively. All other compounds were possessing moderate activity compared to the standard.

4. CONCLUSION The present work involved synthesis of phthalimides linked to different open chains through reactions of phthalic anhydride with different amino acids to give phthaloyl amino acid derivatives such as methyl ester, acetyl chloride, hydrazide and hydrazine derivatives. Also

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the present work involved synthesis of new phthalimides linked to hetero cyclic moieties such as benzimidazoles, benzoxazines, quinazolines, triazoles and organo metallic compounds likely to possess antibacterial, antifungal and anticancer activities. One of the objectives of the present work was evaluation of the biological, antimicrobial and pharmaceutical activities for the newly synthesized compounds. Results showed that the synthesized compounds are active against all microorganisms when compared to standards. From the result it is evident that the compounds1a, 1e, 3c, 3e, 3e, 4a, 4b, 4d, 5a, 5b, 5c, 6a, 6c, 6e, 8a and 8b exhibit significant antibacterial activity against all microorganisms. Also, results showed evident that the compounds 1b, 1e, 3c, 3d, 4d, 4f, 5b, 5c, 6a, 6f, 8b, 8c and 8d exhibit significant antifungal activity against Candida Albicans and Aspergillus Nigar. The result of compounds showed any significant antifungal effect with reference to Ketaconazole at a 1mg/ml concentration. The data of the selected five phthalimides evidenced that compounds 4a, 5b, 5c, 6a, and 8b were the most effective against HepG2 carcinoma cell lines showing IC50 1.2 µg for doxorubicin standard, giving these values 6.5, 4.1, 4.6, 3.5, and 2.8 µg respectively. All other compounds were possessing moderate activity compared to the standard.

CONSENT No manuscripts will be peer-reviewed if a statement of patient consent is not presented during submission.

ETHICAL APPROVAL Not applicable.

ACKNOWLEDGMENTS We wish to thank Prof. Ashraf Sabry, Department of Microbiology, Zagazig University, Egypt and Prof. Mohamed Hashem Dean of Textile Research Division, National Research Centre, Giza, Egypt for their help in the antimicrobial studies and providing the Laboratory Facilities. Also the authors express deep thanks to The Regional Center for Mycology & Biotechnology in Al-Azhar University, Cairo, Egypt.

COMPETING INTERESTS Authors have declared that no competing interests exist.

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