INTRODUCTION:

In recent years, scientists have been focusing on the development of multidrug microbial resistance by different pathogens as a major problem. Microbial resistance to antimicrobial drugs has become a main cause of mortality and morbidity. The fact that various pathogenic microbes responsible for numerous human and animal diseases have caused resistance mechanisms to the conventional therapies have encouraged hard work investigations in the evolution of a new generation of drugs^1-6.

There is still an increasing need for synthesis of compounds that show promising activity as therapeutic agents with lower toxicity and better pharmacodynamic and kinetic properties^7,8. Phthalimides consist of a benzene ring fused to a strained five membered ring having two carbonyls functional group and nitrogen bonded to a side chain. The structural core (-CO-N(R)-CO-), an imidic linkage assists phthalimides to be biologically active because of its hydrophobicity and this enhances their ability to pass across biological membranes^9,10. As a result, phthalimide unit has been designed to be linked with other molecules to give synergistic, additive or new biological activity. Hybridization techniques of phthalimide with other moieties or drugs have been used widely. Several research groups developed new analogues drugs using hybridization techniques; based on the concept that phthalimide moiety is the one that is considered a pharmacologically active core as demonstrated in thalidomide^11,12. Phthalimide derivatives have many uses including: antimicrobial^13-15, anti-inflammatory agents ^16,17, anticonvulsant¹⁸, antioxidant¹⁹, antidiabetic²⁰, HIV-1 Reverse Transcriptase Inhibitor²¹, and as an analgesic agents²². On another hand, Schiff base derivatives have been reported to show several of biological activities that include: antiviral²³, antimicrobial^24,25, antimalarial ²⁶, antioxidant²⁷, anti-inflammatory²⁸, anthelmintic²⁹, and anticancer³⁰. The imine or azomethine (-C=N-) group present in Schiff base derivatives have been proven to be important to their activities.^31-33

EXPERIMENT:

MATERIALS AND METHODS:

Phthalic anhydride, aldehydes, and thiosemicarbazide were purchased from (Hyper Chem, China), while other chemicals and solvents were purchased commercially and utilized without further purification. The thin-layer chromatography ((254F) plates/Merck Germany) was used to follow up the reactions and determine the purity of intermediate and end derivatives and the elution system used was A (Methanol: Ethyl acetate: n-Hexane (1:2:3)) and B (Methanol: Ethyl acetate: Petroleum ether (0.5:1:3)) . Melting points were measured (uncorrected) by using the capillary tube on Stuart SMP30 Electronic Melting Point Apparatus. IR spectra were made using FT-IR (IR Affinity-1) spectrometer, Shimadzu, Japan at the University of Baghdad - College of Pharmacy. A BRUKER model Ultra shield 400 MHz spectrophotometer was used to obtain ¹HNMR spectra and DMSO-d6 used as a solvent and it was performed at the central instrumental laboratory, “School of Chemistry, College of Science, University of Tehran, Iran”.

Chemical synthesis:

Synthesis of 4-(1,3-dioxoisoindolin-2-yl)benzaldehyde (I)³⁴

A mixture of equimolar quantities of phthalic anhydride and p-amino benzaldehyde (20mmol) was reflux in acetic acid (50mL) for 4hours. After cooling and addition of cold distilled water (DW) the solid particles obtained was filtered, then rinsed with DW many times, dried and recrystallized using ethanol to yield a bright yellow powder.

Yield 60%; mp203-205^oC; Rf = 0.8 A; IR (v, cm^-1): 3015 (Ar. (C-H) str.), 2755 (Ald. (C-H) str.), 1780, 1698 (imide (C=O) asym. and sym. str.), 1720 (ald. (C=O) str.), 1601-1468 (Ar. (C=C) str.). ¹HNMR (δ,ppm):10.06 (s,1H, HCO), 7.7-8.07 (m, 8H, -H).

Synthesis of 2-(4-(1,3-dioxoisoindolin-2-yl) benzylidene)hydrazine carbothioamide (II)³⁵.

A mixture of thiosemicarbazide HCl (2.5mmol) and equimolar amount of sodium acetate (2.5mmol) in 25ml absolute ethanol was stirred for few minutes, then a hot ethanolic solution of compound I (2.5mmol) was added gradually. The resulting mixture was refluxed for two hours. The obtained solid particles were filtered and then rinsed with ethanol and it was left to dry to yield a bright yellow powder.

Yield 85 %; mp250^oC dec.; Rf = 0.7 B; IR (v,cm^{- 1}): 3263, 3159 (asym. and sym. primary amide (N-H) stretch.), 3375 (amide (N-H) stretch.), 3055 (Ar-(C-H) stretch.), 1778 and 1708 (asym. and sym. of imide (C=O) stretch.), 1593 ((C=N) stretch.), 1550- 1462 (Ar-(C=C) stretch.), 1219 ((C=S) stretch.). ¹HNMR (δ,ppm): 10.32 (s,1H, NHCO), 7.45-7.98 (m,8H, 2Ar-H and 1H, CH=N), 6.52 (2H,br,NH2)

Synthesis of 2-(4-(5-amino-1,3,4-thiadiazol-2-yl) phenyl)isoindoline-1,3-dione (III)^36,37.

The compound III was synthesized with little modifications to the reported methods by suspending compound II (1.621mmol) and sodium acetate (1.621 mmol) in GAA (50mL) and (12ml) of DMF. With a syringe (0.041ml, 1.621mmol) of bromine, dissolved in GAA (1.33mL), was added gradually and stirring was continued for 10 hours. The crude resultant particles were filtered and the filtrate was completely dried to obtain brown solid fine particles that were kept under silica gel vacuumed jar.

Yield 56%; mp 237-240^oC; Rf = 0.83 B; IR(v,cm- 1): 3337, 3275 (asym. and sym. primary amine (N-H) stretch.), 3074.5 (Ar-(C-H) stretch.), 1789, 1709 (asym. and sym. of imide (C=O) stretch.), 1643 ((C=N) stretch.), 1608-1465 (Ar-(C=C) stretch.). ¹HNMR: 7.63 -7.99 (m, 8H, 2Ar-H), 7.3 (s, 2H, NH2).

Synthesis of 2-(4-((4'-aminobiphenyl-4-ylimino) methyl)phenyl) isoindoline-1,3-dione (IV) ^38,39.

A mixture of compound I (10mmol) and benzidine (10 mmol) in 25ml ethanol was place in around bottom flask with addition of few drops of GAA and refluxed for 12 hours. Upon cooling the solid particles were obtained by filtration, dried and recrystallised using ethanol to give an olive powder.

Yield 87%; mp 260^oC dec.; Rf =0.38 A; IR (v,cm- 1): 3441, 3360 (asym. and sym. primary amide (N-H) stretch.), 3032 (Ar-(C-H) stretch.), 1766, 1708 (asym. and sym. of imide (C=O) stretch.), 1622 ((C=N) stretch.), 1604.7 - 1465 (Ar-(C=C) stretch.). ¹HNMR: 8.75 (s,1H, CH=N), 6.55-8.09 (m,16H, Ar-H), 5.26 (2H, br, NH2).

Synthesis of compounds (V, VI):

An ethanolic solution of compound I and p-nitrobenzaldehyde (2mmol) was added separately to hot absolute ethanolic solution of compound IV (2mmol) and five drops of GAA. The resulting mixture was refluxed for 8 hours, and then it was concentrated and allowed to cool to give solid particles that were obtained by filtration, dried and then recrystallized using hot ethanol to give green and dark green powder respectively.

2,2'-(4,4'-(biphenyl-4,4'-diylbis(azan-1-yl-1-ylidene))bis(methan-1-yl-1-ylidene) bis(4,1-phenylene))diisoindoline-1,3-dione (V)

Yield 44 %; mp >300 dec. ^oC; Rf= 0.25 A; IR (v,cm- 1): 3071 (Ar-(C-H) stretch.), 1778, 1716 (asym. and sym. of imide (C=O) stretch.), 1632 and 1609 ((C=N) stretch.) of two imine, 1577- 1465 (Ar-(C=C) stretch.). ¹HNMR: 8.78 (s, 2H, for first CH=N), and 7.47- 8.86 (m, 24H, Ar-H).

2-(4-((4'-(4-nitrobenzylideneamino) biphenyl-4-ylimino) methyl) phenyl) isoindoline-1, 3-dione (VI)

Yield 62%; mp >300 char. ^oC; Rf= 0.28 A; IR(v,cm^- 1): 3070 (Ar- (C-H) stretch.), 1786, 1716 (asym. and sym. of imide (C=O) stretch.), 1624 and 1597 ((C=N) stretch.) of two imine, 1593- 1465 (Ar-(C=C) stretch.), 1512, 1342 (asym. and sym. of nitro (NO₂) str.)¹HNMR (δ,ppm): 8.91 (s,1H, for first CH=N), and 8.89 (s,1H, for second CH=N), 7.43- 8.40 (m,20H, Ar-H).

Antimicrobial activity⁴⁰

All derivatives were evaluated for their antimicrobial effect using well diffusion methods against two “Gram-positive bacteria (Staph. Aureus, and Bacillus subtilis), two Gram-negative bacteria (Klebsiella pneumoniae and Escherichia coli), and two fungi species (Candida tropicalis, and Candida albicans)” were kept on nutrient agar medium for evaluation the antibacterial effect and PDA medium for antifungal effect. Cefotaxime and Miconazole used as standards against antibacterial and antifungal respectively, and DMSO as a solvent. The results for antibacterial and antifungal activity outlined in Tables 1 and 2. The antimicrobial activity tests of all compounds were carried out at “University of Baghdad, College of Education for Pure Sciences Ibn Al-Haitham, central service laboratory”.

RESULTS AND DISCUSSION:

Chemistry of synthesis:

The synthetic pathway of compounds (II-VI) is demonstrated in scheme l. The synthesis started by the preparation of compound (I) “aldehyde of phthalimide” by using GAA as solvent and catalyst. This method displayed good yield with ease of production. The Schiff bases (compound II and IV) and (compound V and VI) were prepared by reaction of (compound (I) with thiosemicarbazide and benzidine) and (compound (IV) with compound (I) and p-nitro benzaldehyde) respectively with the addition of few drops of GAA. The reaction involves elimination of one water molecule in order to form (imine or Schiff base) R₁R₂C=NR'. On the other hand, the phthalimide containing (1,3,4-thiadiazole ring) compound (III) was formed by bromine mediated “oxidative intramolecular cyclization” of compound (I) in the presence of sodium acetate. All structures of the titled compounds were established by “FTIR and ¹HNMR” spectral analyses.

Scheme 1: General synthetic pathway of the target compounds

The IR spectra for compound (I) demonstrated two characteristic absorption bands of asymmetrical and symmetrical imide (C=O) stretching displayed at (1780 and 1698) cm^-1. In addition, 1720 and 2754 cm^-1 are accounted for (C=O) and (CH) stretching of aldehyde respectively. For compounds (II) and (IV) the disappearance of the characteristic band of aldehyde and appearance of band at 1620 cm^-1 is an indication for formation of Schiff base. The compound (II) displayed sec. amide (N-H) stretching at 3375 cm^-1, primary amide (N-H) asym. and sym. stretching at (3263 and 3159) cm^-1, with one band of (C=S) stretching at 1219 cm^-1. While, compound (III) showed the characteristic two absorption bands of side-chain primary amine (NH₂) stretching at 3367, 3263cm^-1 asym. and sym. stretching.

Compound (IV) showed the characteristic two absorption bands of primary amine (NH₂) stretching at 3441, 3360 cm^-1 asym. and sym. stretching and disappearance of the characteristic band of aldehyde and appearance of the band at 1620 cm^-1 of imine. For compounds (V) and (VI) the disappearance of the characteristic band of primary amine and appearance of two bands of imine at (1631, 1608 cm^-1) and at (1624, 1597cm^-1) is a good indication for formation of double Schiff bases.

The synthesized compounds were identified by ¹HNMR spectroscopy in which the compounds (I) showed characteristic signal at δ =10.06ppm, due to CHO of aldehyde, and the aromatic protons displayed characteristic signals at δ =7.7- 8.07ppm. While compound (II) has a singlet for one proton of CH=N which is masked within the region of aromatic peaks and a broad peak due to two protons of amino group (NH2) as singlet at δ =6.52ppm and singlet peak at δ =10.32 ppm indicates the presence of one proton of NHCO group. ¹HNMR of compound (III) displayed a broad peak due to NH2 as singlet at δ =7.3ppm of two protons with the disappearance of imine (CH=N) peak, indicating cyclization. Compound (IV) displayed CH=N peak as a singlet at δ =8.75 ppm and a broad peak due to two protons of NH2 as singlet at δ =5.26ppm. On the other hand, the ¹HNMR for compound (VI) showed two singlet peaks at δ =8.91ppm and δ =8.89ppm for two CH=N groups.

Antibacterial activity:

The results from tables 1 and 2 reveal that all the synthesized derivatives showed variable antibacterial and anti-fungal activity.

Table l The antibacterial effect of the screened compounds

Compound Name	Concentration μg/ml	Inhibition Zone in mm
Compound Name	Concentration μg/ml	S. *aureus*	B. *subtilis*	E. *coli*	K. *pneumoniae*
I	125	-	-	12	-
II	125	-	-	12	11
III	125	-	-	-	12
IV	125	-	-	10	12
V	125	-	-	-	10
VI	125	-	-	10	11
Cefotaxime	2µg/ml	49	43	51	25
DMSO		-	-	-	-

Table 2 The antifungal effect of the screened compounds

Compound Name	Concentration μg/ml	Inhibition Zone in mm
Compound Name	Concentration μg/ml	*Candida* *tropicalis*	*Candidia* *albicans*
I	125	24	-
II	125	-	-
III	125	-	12
IV	125	13	-
V	125	-	-
VI	125	12	-
Miconazole	100	15	23
DMSO	-	-	-

(-) = No activity- slightly active (zone of inhibition between 5-10mm), moderately active (zone of inhibition between 10-20mm), highly active (zone of inhibition more than 20mm).⁴¹

For antibacterial activity: At concentration (125μg\ml), compounds (II, IV and VI) had moderate activity against G-negative “Escherichia coli, and Klebsiella pneumonia”, while compounds I was moderately active against E. coli., and compounds III and V were moderately active against Klebsiella pneumonia. However, all of the tested compounds exhibited no activity against G-positive (Staph. aureus, and Bacillus subtilis). Compounds (IV and VI) had moderate effect against Candida tropicalis, and compound III had only moderate activity against Candida albicans. While compound II had no antifungal effect against both “Candida tropicalis and Candida albicans”. Finally, the best antifungal activity was obtained from compound I which has high activity against Candida tropicalis.

CONCLUSION:

New N-substituted phthalimide compounds were successfully synthesized, characterized and screened for their antimicrobial effects. All synthesized compounds displayed no antibacterial effect against the tested G-positive bacteria. Most compounds have moderate antibacterial effect against tested G-negative bacteria and Candida tropicalis. While compound I showed high antifungal activity towards Candida tropicalis.

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Received on 06.07.2021 Modified on 24.09.2021

Research J. Pharm. and Tech 2022; 15(9):3861-3865.

DOI: 10.52711/0974-360X.2022.00647