INTRODUCTION:

In medicinal chemistry, the chief goal is to synthesize promising activity compounds acting as therapeutic agents with lower side effects¹. Nowadays, the world is depleted from efficacious antibiotics due to the emergence of resistant organisms^2,3. As a result, this led to an increase in resistant infections, which motivated the scientists to design analogs of compounds as alternative biological active agents to overcome these infections⁴.

Hydrazones have been considered an important class in medicinal chemistry⁵ and therefore Hydrazones are crucial organic functional groups, possessing an azomethine proton. It is used for designing a new biologically active compound. Hydrazones can be synthesized through the reaction of hydrazides or hydrazines with aldehydes and ketones by displacement of oxygen with =NNHR functional moiety⁶. Hydrazones have numerous activities, like antitubercular, antiviral, antibacterial, antitumoral, and antimalarial properties^7-10.

Elham S Darwish et al. have been evaluated new hydrazones of sulfonamide for gram - ve, gram + ve and antifungal activity¹¹. Gregory L. Backes et al. have been generated and synthesized a large library of hydrazone and hydrazide of benzoic acid derivatives. The prepared compounds showed potent antifungal activity with minimum mammalian cell toxicity¹². However, hydrazones synthesized from 2,4-dinitrophenylhydrazine by Sergio Ortiz et al., and Alberta Ade et al. showed weak antimicrobial properties^13,14.

On the one hand, sulfonamides are a well-known class in medicinal chemistry¹⁵ possessing the general formula A-SO2NHR. They exhibit various biological activities, like “antifungal, antibacterial, carbonic anhydrase inhibition, diuretic, antithyroid, anti-inﬂammatory, antiglaucoma, antiviral, and antineoplastic, hypoglycemic” etc.^16-18 Muhammad Abdul Qadir et al., Christiana Nonye et al., Rane YS et al., and Bhusari KP et al. have been developed novel sulfonamide derivatives with improved antibacterial^19-22

On the other hand, amides are an important part present in a large array of medicinal drugs. Amides are undoubtedly one of the popular essential pharmaceutical active cores in organic chemistry since it is found in essential molecules such as “peptides, pharmaceutical agents, naturally occurring molecules, proteins, and alkaloids”. As a result, one of the most promising changes in modern organic synthetic reactions is the building of an amide functional group in the molecule. Well-known examples of amides are benzamide C₆H₅–CONH₂, acetamide H₃C–CONH₂²³. Tahere et al. synthesized a group of novel benzamide derivatives having good inhibition against “the gram-negative (Escherichia coli), and gram-positive bacteria (Streptococcus and Enterococcus)” bacteria²⁴. A group of acetamide derivatives having noticeable inhibitory activities was designed and synthesized by Hui Lu et al. as well as by Jamkhandi CM et al.^25,26.

Hence, we aimed to make a hybrid molecule possessing both amide/ sulfonamide and hydrazone moiety. in an attempt to get improved antimicrobial derivatives of hydrazones. As shown in in figure 1:

Figure 1: Designed work of new (2,4-dinitrophenyl) hydrazine derivatives (B 1-4)

MATERIAL AND METHODS:

Chemicals were supplied by hyper-chem (China), Fluka-sigma Aldrich is for p-toluene sulfonyl chloride, and Merck-Schuchardt is for benzene sulfonyl chloride. Melting points were uncorrected and detected by using “Stuart SMP3 melting point apparatus. All synthesized derivatives were characterized by spectroscopic analyses (Fourier-transform Infrared (FTIR) spectra were made using FT-IR (IR Affinity-1) spectrometer, Shimadzu, and (Proton nuclear magnetic resonance (¹HNMR) using 500 MHz instruments and DMSO-d6” as a solvent.

PROCEDURES FOR SYNTHESIS OF THE TARGET COMPOUNDS:

Synthesis of compound 1:

Compound 1 was synthesized by dissolving (0.5gm, 4.13mmole) of p-amino benzaldehyde in dry chloroform (30ml) using a 250ml one neck flat bottom flask. Then, (0.57ml, 4.13mmole) of triethylamine was added dropwise with continuous stirring and simultaneous drop by drop addition of 0.6ml of acetyl chloride on an ice bath. The stirring was continued overnight. The solution’s color turned from bright yellow to beige suspension. The resulting mixture was filtered after evaporating some of the solvent volume, then rinsed with distilled water (D.W) and dried with anhydrous MgSO₄²⁷.

N-(4-formylphenyl) acetamide: Beige solid in yield 72%; melting point= 160°C;

R (cm⁻¹): 3236 (N-H of amide, stretching), 3086 (C-H aromatic, stretching), 2993, 2831 (C-H methyl, stretch.), 2731 (C-H aldehyde), 1701 (C=O aldehyde carbonyl stretch.), 1654 (C=O amide carbonyl stretch.), 1593 -1459 (C=C-C aromatic, stretch.), 1014, 759 (C-H aromatic in plane& out of plane).

¹HNMR (DMSO) (δ, ppm): 10.74 (s, 1H, NH), 9.91 (1H, s, HCO), 7.81-7.90 (4H, m, Ar-H), 2.32 (s, 3H, CH3).

Synthesis of compound 2:

In a flat dry round flask at 0°C, triethylamine (0.23 ml, 1.65 mmoles) and benzoyl chloride (0.2 ml, 1.8 mmoles) in chloroform (15ml) were added slowly to the p- amino benzaldehyde (0.2gm, 1.65mmoles) solution. The resultant mixture was stirred all night. The precipitate was dried in an oven at 60°C after it was filtered, washed with D.W²⁸.

N-(4-formylphenyl) benzamide: Faint yellow solid in yield 40%; melting point = 240-244°C;

FTIR (cm⁻¹): 3294 (N-H of amide, stretching), 3055 (C-H aromatic, stretch.), 2738 (C-H aldehyde stretch.), 1693 (C=O aldehyde carbonyl stretch.), 1651 (C=O amide carbonyl, stretch.), 1593 -1473 (C=C-C aromatic, stretch.), 1033, 806 (C-H aromatic in the plane and out of plane bending).

¹HNMR (DMSO) (δ, ppm): 11.06 (s, 1H, NH), 10.88 (1H, s, HCO), 7.92-9.36 (9H, m, Ar-H).

Synthesis of compounds 3 and 4.

In flat dry round flask benzene at 0°C, sulfonyl chloride (0.3ml,1.65 mmoles) for compound (3) and p- toluene sulfonyl chloride (0.3gm,1.65mmoles) for compound (4) were gradually added to the solution of p-amino benzaldehyde (0.2gm, 1.65 mmoles) in pyridine (1mL) respectively. At room temperature, the mixture was stirred for 12 hours. The suspension was then filtered, and the precipitate was mixed with 10% HCl before being filtered. In a desiccated jar, the precipitate was kept dry^29,30.

N-(4-formyl phenyl) benzene sulfonamide:

Bright orange solid in yield 48%; melting point =124-128°C; FTIR (cm⁻¹): 3236 (N-H of amide, stretch.), 3062 (C-H aromatic, stretch.), 2916, 2877 (C-H methyl, stretch.), 2765 (C-H aldehyde stretch.), 1685 (C=O aldehyde carbonyl), 1597 -1477 (C=C-C aromatic, stretch.), 1342 (S=O asymmetric stretch.),1157 (S=O, symmetric stretch.), 1087, 721 (C-H aromatic in plane& out of plane).

¹HNMR (DMSO) (δ, ppm): 10.07 (s, 1H, NH), 9.82 (1H, s, HCO), 7.27- 7.86 (9H, m, Ar-H).

N-(4-formylphenyl) 4-methylbenzene sulfonamide:

Brown solid in yield 63%; melting point = >300°C decomposed; FTIR (cm⁻¹): 3309 (N-H of amide, stretch.), 3140 (C-H aromatic, stretch.), 2742 (C-H aldehyde stretch.), 1685 (C=O aldehyde carbonyl), 1593 -1473 (C=C-C aromatic, stretch.), 1334 (S=O asymmetric stretch.),1153 (S=O, symmetric stretch.), 1013, 709 (C-H aromatic in plane& out of plane). ¹HNMR (DMSO) (δ, ppm): 9.57 (s, 1H, NH), 9.34 (1H, s, HCO), 6.61- 7.56 (8H, m, Ar-H), 2.29 (s, 3H, CH3).

Synthesis of compound B1:

(2,4-dinitrophenyl) hydrazine (0.12 gm, 0.61 mmoles) was mixed with the ethanolic solution of compound 1 (0.1 gm, 0.61 mmoles) with 2 drops of glacial acetic acid, the mixture was then refluxed for an hour and cooled in ice bath, filtration was used to obtain the precipitate, which was then rinsed with ethanol and air-dried ³⁰.

N-(4-((2-(2,4-dinitrophenyl) hydrazinylidene) methyl) phenyl) acetamide:

orange solid in yield 79%; melting point 260-263 ◦C ; FTIR (cm⁻¹): 3236 ??(N-H of amide, stretch.), 3200 (NH, hydrazone stretch.) 3093 (C-H aromatic, stretch.), 2943, 2877(C-H methyl, stretch.), 1670 (C=O amide carbonyl stretch.), 1621 (N-H, imine stretching),1589 -1411 (C=C-C aromatic, stretch.), 1053, 702 (C-H aromatic in plane& out of plane).

¹HNMR (DMSO) (δ, ppm): 11.64 (s, 1H, NH-N), 10.55 (1H, s, NH-C=O), 7.64 - 8.89 (7H, m, Ar-H), 8.66 (s, 1H, CH=N), 2.31 (s, 3H, CH3).

Synthesis of compound B2:

In 5 ml of methanol, Equimolar of compound (2), (0.1 gm, 0.44 mmole) and (2,4-dinitrophenyl) hydrazine (0.087 gm, 0.44 mmole) were dissolved, and to the resulting mixture, 3-4 drops of piperidine were added. The resultant mixture was refluxed for an hour. When the reaction is completed, it was left to stand for overnight, then the precipitated product was obtained by filtration, rinsed with ethanol, then dried at 60°C ³¹.

N-(4-((2-(2,4-dinitrophenyl) hydrazinylidene) methyl) phenyl) benzamide:

Dark orange-red solid in yield 81%; melting point= 215-220°C; FTIR (cm⁻¹): 3286 (N-H of amide, stretching), 3200 (NH, hydrazone stretch.) 3001 (C-H aromatic, stretch.), 1689 (C=O amide carbonyl stretch.), 1624 (N-H, imine stretch.), 1597 -1415 (C=C-C aromatic, stretch.), 1010, 721 (C-H aromatic in plane& out of plane). ¹HNMR (DMSO) (δ, ppm): 11.68 (s, 1H, NH-N), 11.52 (1H, s, NH-C=O), 7.48- 8.88 (12H, m, Ar-H), 8.5 (s, 1H, CH=N).

Synthesis of compound B3:

In a round bottom flask, compound 3(0.12gm, 0.46 mmole) was added to 20ml of methanolic solution of 2,4-dinitrophenyl hydrazine (0.091gm, 0.46mol). And then five ml of 10% HCl was added to above solution. It was then refluxed for an hour and left overnight. Filtration was used to obtain the precipitate, which was then rinsed with ethanol and air-dried ³².

N-(4-((2-(2,4-dinitrophenyl) hydrazinylidene) methyl) phenyl) benzene sulfonamide:

Orange solid in yield 70%; melting point =239- 242◦C; FTIR (cm⁻¹): 3290(N-H of amide, stretch.), 3290 (NH, hydrazone stretch.) 3105 (C-H, aromatic stretch.), 1612 (N-H, imine stretch.), 1558 -1423 (C=C-C aromatic, stretch.), 1018, 717 (C-H aromatic in plane& out of plane). ¹HNMR (DMSO) (δ, ppm): 11.53 (s, 1H, NH-N), 10.67 (1H, s, NH-S=O), 6.82- 8.84 (12H, m, Ar-H), 8.73 (s, 1H, CH=N), 2.29 (s, 3H, CH3).

Synthesis of compound B4:

The compound was prepared following the reported reference with modification. In 20ml beaker, (2,4-dinitrophenyl) hydrazine (0.1gm,0.5 mmoles) was added with continuous stirring to 1.5mL of water and 5mL of 95% ethanol and 0.5ml H2SO4, the mixture was filtered and added to compound 4 (0.125gm, 0.45mmole) in a round bottom flask. And then it was refluxed for one hour and left to stand overnight. The residue was filtered and rinsed with ethanol, and then dried in the oven at 60°C ³³.

N-(4-((2-(2,4-dinitrophenyl) hydrazinylidene) methyl) phenyl)-4 methylbenzene sulfonamide:

Orange solid in yield 87%; melting point = > 300°C decomposed; FTIR (cm⁻¹): 3375 (N-H of amide, stretch.), 3282 (NH, hydrazone stretch.) 3093 (C-H, aromatic stretch.), 2943, 2850(C-H methyl, stretch.), 1612 (N-H, imine stretch.), 1558 -1419 (C=C-C aromatic, stretch.), 1006, 717 (C-H aromatic in plane and out of plane). ¹HNMR (DMSO) (δ, ppm): 11.68 (s, 1H, NH-N), 9.57 (1H, s, NH-S=O), 6.62- 8.88 (11H, m, Ar-H), 8.7 (s, 1H, CH=N), 2.29 (s, 3H, CH3).

RESULTS AND DISCUSSION:

Chemistry:

As shown, scheme 1 demonstrates the synthesis steps of compounds B1–B4. The synthesis involves amide formation starting from p-amino benzaldehyde reaction with acyl chlorides (benzoyl or acetyl chloride), or reaction with sulfonyl chlorides derivatives (benzene or p-toluene sulfonyl chloride) to afford acetamide derivative (compound 1), benzamide derivative (compound 2), benzene sulfonamide derivative (compound 3) and 4-methylbenzene sulfonamide derivative (compound 4), respectively. Then, new hydrazones hybrids with amide/sulfonamide moieties were prepared by condensation of the lately synthesized compounds (1,2,3 and 4) with (2,4-dinitrophenyl) hydrazine giving final compounds (B1, B2, B3, and B4), respectively.

The synthesized compounds were characterized, and their structures were verified by “FTIR and ¹HNMR” spectral analyses. IR spectra for compounds (1 and 2) show characteristic bands: 3236 and 3294 for (N-H of amide, stretching); 2731 and 2738 for (C-H aldehyde); 1701 and 1693 for (C=O aldehyde carbonyl stretching); 1654 and 1651 for (C=O amide carbonyl stretching), respectively. However, compound 1 shows additional two bands at 2993, 2831 attributed to (C-H methyl, stretching). Whereas compounds (3 and 4) show the following bands: 3236 and 3309 for (N-H of amide, stretching); 2765 and 2742 for (C-H aldehyde stretching); 1685 and 1685 for (C=O aldehyde carbonyl); 1342 and 1334 for (S=O asymmetric stretching), 1157 and 1153 for (S=O, symmetric stretching), respectively. However, compound 4 has additional two bands at 2916, 2877 accounted for (C-H methyl, stretching). For compounds (B1-B4), the disappearance of the characteristic aldehyde band and appearance of bands (1612-1624) cm-1 was a strong clue for Schiff base formation, i.e., the linkage has occurred between the amide/ sulfonamide core and (2,4-dinitrophenyl) hydrazine. ¹HNMR spectra of the compounds were agreeable with the assigned structures: Compounds (1 and 2) show singlet signals at δ= 10.74 and 11.06 ppm attributed to the proton of the amide group. While the proton signal due to CHO of the aldehyde appears as a singlet at δ= 9.91 and 10.88 ppm, respectively. A sharp singlet peak integrated for 3H at δ= 2.32 is related to the methyl group in compound 1. While Compounds (3 and 4) show singlet signals at δ= 10.07 and 9.57 ppm attributed to the proton of the amide group. While the proton signal due to CHO of the aldehyde appears as a singlet at δ= 9.82 and 9.34 ppm, respectively. A singlet band of 3H at δ= 2.29 is related to the methyl group in compound 4. For compounds (B1-B4), the disappearance of the characteristic aldehyde signal and the appearance of singlet signal at δ= (8.66, 8.5, 8.73, and 8.7 ppm, respectively) were a sign for Hydrazone formation.

Table 1: In Vitro Antibacterial Activity and Antifungal Activity

Compound Name	Conc. µg/ml	*S. aureus*	*S. epidermidis*	*E. coli*	*K. pneumoniae*	*C.albicans*
Compound Name	Conc. µg/ml	Zone of inhibition(mm)
Compound 1	250	15	12	12	11	12
Compound 2	250	-	12	12	12	-
Compound 3	250	12	11	11	10	-
Compound 4	250	15	12	12	10
Compound B1	250	14	11	12	10	11
Compound B2	250	-	-	11	-	-
Compound B3	250	-	-	11	-	-
Compound B4	250	18	17	13	13	16
Amoxicillin	10	39	17	37	-	33
Streptomycin	300	19	24	20	15	31
Fluconazole	25	18	18	14	10	14
DMSO	-	-	-	-	-	-

(-) = No activity – slightly active (zone of inhibition between 5 – 10 mm),

moderately active (zone of inhibition between 10-20 mm),

highly active (zone of inhibition more than 20 mm)

ANTIMICROBIAL STUDY:

The Antimicrobial activity was performed using well diffusion method. Two types of “Gram-negative bacteria Klebsiella pneumonia and Escherichia Coli and two types of Gram-positive bacteria Staphylococcus aureus and staphylococcus epidermidis were used for testing the in-vitro antibacterial activity, and the fungi species Candida albicans” for testing the in-vitro antifungal activity, using amoxicillin and streptomycin as antibacterial standards and Fluconazole as antifungal standard while DMSO is used as a solvent. The result shown in table 1 indicates the majority of the compounds had a moderate level of activity against the aforementioned compounds using concentrations of 250 µg\ml.

CONCLUSIONS:

To briefly summarize, a group of new hydrazones derivatives, having amide/ sulfonamide functionality, were synthesized by reacting aldehyde-containing amide/sulfonamide moiety with (2,4-dinitrophenyl) hydrazine. The synthesized compounds were evaluated in vitro for their antimicrobial effects against “Gram-positive bacteria Staphylococcus Aureus, and staphylococcus epidermidis, Gram-negative bacteria Escherichia coli, and Klebsiella pneumoniae, and fungi species Candida albicans”. According to the antimicrobial activity data, the majority of the compounds are moderately active against the aforementioned pathogens.

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Received on 19.07.2021 Modified on 30.09.2021

Research J. Pharm.and Tech 2022; 15(4):1743-1748.

DOI: 10.52711/0974-360X.2022.00292