SYNTHESIS AND CHARACTERIZATION OF BENZIMIDAZOLE DERIVATIVES WITH POTENT ANTIFUNGAL ACTIVITY

Abstract

The present invention relates to the synthesis and characterization of novel benzimidazole derivatives exhibiting potent antifungal activity. The derivatives are synthesized by reacting o-phenylenediamine with organic acids, such as 3,5-dinitrosalicylic acid or adipic acid, in an acidic medium under reflux conditions. The process is optimized by introducing catalytic amounts of potassium ferrocyanide for improved yields. The synthesized compounds, including 4-(2,3-dihydro-1H-benzo[d]imidazole-2-yl)-2,5-dinitrophenol and 3-(2,3-dihydro-1H-benzo[d]imidazole-2-yl)phenol, are characterized using IR, 1H NMR, and mass spectrometry to confirm their structure and purity. These derivatives exhibit excellent solubility in ethanol or water and show significant antifungal properties, as demonstrated through biological assays. The invention addresses the limitations of existing antifungal agents, offering a novel, efficient, and scalable synthetic method for developing effective antifungal compounds suitable for medical and agricultural applications.

Specification

Description:FIELD OF INVENTION
The present invention relates to the field of medicinal chemistry, specifically focusing on the synthesis and characterization of benzimidazole derivatives exhibiting potent antifungal activity.
BACKGROUND OF THE INVENTION
Fungal infections, particularly those caused by opportunistic pathogens, have become a growing concern in clinical and agricultural settings. The rise in antifungal resistance due to overuse of existing therapies like azoles and polyenes has significantly diminished the efficacy of conventional treatments. This situation is further exacerbated by the limited diversity of available antifungal drugs, making the discovery of novel therapeutic agents imperative. Patients with compromised immune systems, such as those undergoing chemotherapy or living with HIV, are especially vulnerable, underscoring the urgency for new, effective antifungal compounds.
The benzimidazole scaffold has garnered considerable attention in medicinal chemistry for its diverse pharmacological properties, including antifungal activity. Despite its potential, current derivatives either lack specificity or exhibit suboptimal pharmacokinetics, limiting their application. Many benzimidazole compounds fail to achieve the required potency at safe dosage levels, resulting in a need for extensive research to modify their structure while improving selectivity and safety. Addressing these challenges demands a systematic approach to designing derivatives with enhanced antifungal profiles.
To overcome these limitations, the present invention focuses on the rational design, synthesis, and characterization of novel benzimidazole derivatives. By introducing specific substituents that target fungal metabolic pathways and leveraging advanced analytical techniques for validation, the invention aims to provide potent and reliable alternatives to current antifungal agents. This research not only addresses the growing threat of resistant fungal infections but also paves the way for new therapeutic strategies in antifungal drug development.
OBJECTS OF THE INVENTION
Some of the objects of the present disclosure, which at least one embodiment herein satisfies, are as follows.
It is an object of the present disclosure to ameliorate one or more problems of the prior art or to at least provide a useful alternative
An object of the present disclosure is to
Another object of the present disclosure is to provide a novel synthesis method for benzimidazole derivatives with enhanced antifungal activity.
Still another object of the present disclosure is invention offers a scalable and efficient process for synthesizing antifungal agents using readily available starting materials.
Another object of the present disclosure is the incorporation of catalytic amounts of potassium ferrocyanide significantly improves product yield and reaction efficiency.
Still another object of the present disclosure is to synthesis the compound the with high purity and high efficacy.
Still another object of the present disclosure is to provide that the synthesized derivatives exhibit excellent solubility in ethanol and water.
Yet another object of the present disclosure is the synthesized derivatives demonstrate superior antifungal properties, making them highly effective against resistant fungal strains.
Yet another object of the present disclosure is to the method reduces dependency on conventional antifungal agents, addressing the issue of resistance in pathogens.

Other objects and advantages of the present disclosure will be more apparent from the following description, which is not intended to limit the scope of the present disclosure.

SUMMARY OF THE INVENTION
The following presents a simplified summary of the invention in order to provide a basic understanding of some aspects of the invention. This summary is not an extensive overview of the present invention. It is not intended to identify the key/critical elements of the invention or to delineate the scope of the invention. Its sole purpose is to present some concept of the invention in a simplified form as a prelude to a more detailed description of the invention presented later.
The present invention is generally relates to a novel benzimidazole derivatives with potent antifungal activity to address limitations in existing antifungal treatments. These compounds are designed to combat resistant fungal pathogens.
An embodiment of the present invention the synthesis involves reacting o-phenylenediamine with organic acids like 3,5-dinitrosalicylic acid or adipic acid in an acidic medium, ensuring efficient production of desired derivatives.
Another embodiment of the invention is Potassium ferrocyanide is employed as a catalyst to enhance reaction efficiency and product yield, streamlining the overall synthesis process for scalability.
Yet another embodiment of the invention is the synthesized compounds, including 4-(2,3-dihydro-1H-benzo[d]imidazole-2-yl)-2,5-dinitrophenol, are characterized for their purity using advanced spectroscopic methods like IR, 1H NMR, and mass spectrometry.
Yet another embodiment of the invention is the derivatives exhibit favorable physicochemical properties, such as solubility in ethanol or water, and maintain stability under standard storage conditions.
Yet another embodiment of the invention is biological assays validate the antifungal efficacy of these derivatives, demonstrating significant activity against various fungal pathogens.
DETAILED DESCRIPTION OF THE INVENTION
The following description is of exemplary embodiments only and is not intended to limit the scope, applicability or configuration of the invention in any way. Rather, the following description provides a convenient illustration for implementing exemplary embodiments of the invention. Various changes to the described embodiments may be made in the function and arrangement of the elements described without departing from the scope of the invention.
The invention focuses on the development of novel benzimidazole derivatives with potent antifungal properties to address the growing challenge of fungal resistance and the limited efficacy of existing antifungal agents. These derivatives are synthesized through a streamlined process involving the reaction of o-phenylenediamine with organic acids, such as 3,5-dinitrosalicylic acid or adipic acid, in an acidic medium. The method incorporates advanced catalytic techniques using potassium ferrocyanide to enhance reaction efficiency and yield. This systematic approach enables the production of compounds with high purity, confirmed through analytical techniques like IR and 1H NMR spectroscopy, ensuring their suitability for therapeutic applications.
Key derivatives synthesized through this method include 4-(2,3-dihydro-1H-benzo[d]imidazole-2-yl)-2,5-dinitrophenol and 3-(2,3-dihydro-1H-benzo[d]imidazole-2-yl)phenol, which exhibit distinct structural features and exceptional antifungal activity. These compounds have been characterized by their molecular formulas, melting points, and solubility profiles, showing compatibility with ethanol and water. Rigorous structural confirmation through spectroscopic and mass analysis has validated the effectiveness of the synthesis. The biological assays conducted demonstrate their potential in combating fungal pathogens, making them promising candidates for pharmaceutical development.
This invention provides a robust solution to the urgent need for new antifungal agents. The synthesized benzimidazole derivatives not only address the limitations of existing treatments but also open new avenues for the scalable production of antifungal drugs. By leveraging an innovative synthetic methodology and precise analytical validation, this invention bridges a critical gap in antifungal drug discovery, offering reliable and efficient compounds for both medical and agricultural applications.
EXAMPLE 1: General Procedure of 4-(2, 3dihydro-1H-benzo[d]imidazole-2-yl)-2, 5-dinitrophenol
Mixture of o-phenylenediamine (0.157gm) and 3,5dinitrosalicylic acid (0.157gm) was taken in a solution of 4NHCL (10ml), refluxed in water bath for 2h. After completion of the reaction as indicated by TLC, the solvent was evaporated on room temp. . The solid was then cooled to ice and recrystallized with ethanol. A light green residue was obtained by filtration and washed with water. The structure of the products were confirmed by IR and 1H NMR spectral data and physical properties,Yellowish, (yield145.2%)
4-(2, 3dihydro-1H-benzo[d]imidazole-2-yl)-2, 5-dinitrophenol: Molecular formula; C13H10N4O5, molecular weight; 302gm, Yellowish, (yield145.2%), mp 240Oc, solubility ethanol. . IR(KBr, Vmax cm-1): 3334(N-H), 2914(C=C),1401(NO2), H NMR (DMSO-d6,300 MHz) d: 2.27(s, 2H, CH2), 4.54(s, 1H, NH aromatic),6.76(s, 1H, NH .), 6.1-7.13(m, 8H, Ar-H);

EXAMPLE 2: General Procedure of 3-(2, 3dihydro-1H-benzo[d]imidazole-2-yl) phenol: A mixture of o-phenylenediamine (0.157gm) and adipic acid (0.157gm) was taken in a solution of 4NHCL (10ml), refluxed in water bath for 2h. After completion of the reaction as indicated by TLC, the solvent was evaporated on room temp. . The solid was then cooled to ice and recrystallized with ethanol. A light green residue was obtained by filtration and washed with water. The structure of the products were confirmed by IR and 1H NMR spectral data and physical properties; Light green, (yield17%), mp 220c, sol.
Molecular formula; C13H12N2O, molecular weight; 212gm, Light green, (yield17%),mp 220c, solubility water. 1H NMR(deltappm) : 6.36 (2CH), 6.21 (CH), 4.0(2NH), 5.0(OH), MASS Spectroscopy (m\z):212. 1H NMR(DMSO-d6, 300 MHz) d: 2.70(s, 2H, CH2), 4.64(s, 1H, NH aromatic), 5.70(s, 1H, NH benzimidazole), 6.9-7.72(m, 8H), 4.75(s, 2H, SO2NH2);
EXAMPLE 3: General Procedure of 4-(2, 3dihydro-1H-benzo[d]imidazole-2-yl)-2, 5-dinitrophenol:
A mixture of o-phenylenediamine (5gm) and 3,5dinitrosalicylic acid (5gm) and catalytic amount of potassium ferro-cyanide (5gm) continue grinding of the mixture. The mixture washed with normal distilled water, than desiccator (15 to 20 min.) and heat with ethylacetate (20ml). After completion of the reaction as indicated by TLC. A light green residue was obtained by filtration. The structure of the products were confirmed by IR and 1H NMR spectral data and physical properties, Yellowish, (yield145.2%), mp 240Oc, solubility ethanol.
Molecular formula; C13H10N4O5, molecular weight; 302gm, Yellowish, (yield145.2%), mp 240Oc, solubility ethanol. . IR(KBr, Vmax cm-1): 3334(N-H), 2914(C=C),1401(NO2), H NMR (DMSO-d6,300 MHz) d: 2.27(s, 2H, CH2), 4.54(s, 1H, NH aromatic),6.76(s, 1H, NH .), 6.1-7.13(m, 8H, Ar-H);
EXAMPLE 4: General Procedure of 3-(2, 3dihydro-1H-benzo[d]imidazole-2-yl) phenol
A mixture of o-phenylenediamine (5gm) and adipic acid (5gm) and catalytic amount of potassium ferro-cyanide (5gm) continue grinding of the mixture. The mixture washed with normal distilled water, than desiccator (15 to 20 min.) and heat with ethylacetate (20ml). After completion of the reaction as indicated by TLC. A light green residue was obtained by filtration. The structure of the products were confirmed by IR and 1H NMR spectral data and physical properties; Light green, (yield17%), mp 220c, solubility water.
Molecular formula; C13H12N2O, molecular weight; 212gm, Light green, (yield17%),mp 220c, solubility water. 1H NMR(deltappm) : 6.36 (2CH), 6.21 (CH), 4.0(2NH), 5.0(OH), MASS Spectroscopy (m\z):212. 1H NMR(DMSO-d6, 300 MHz) d: 2.70(s, 2H, CH2), 4.64(s, 1H, NH aromatic), 5.70(s, 1H, NH benzimidazole), 6.9-7.72(m, 8H), 4.75(s, 2H, SO2NH2);
While considerable emphasis has been placed herein on the specific features of the preferred embodiment, it will be appreciated that many additional features can be added and that many changes can be made in the preferred embodiment without departing from the principles of the disclosure. These and other changes in the preferred embodiment of the disclosure will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the disclosure and not as a limitation.
, Claims:1. A method for synthesizing benzimidazole derivatives with potent antifungal activity, comprising the steps of:
(a) reacting o-phenylenediamine with an organic acid selected from 3,5-dinitrosalicylic acid or adipic acid in the presence of an acidic medium, specifically 4n hcl, under reflux conditions for a duration of 2 hours to facilitate cyclization;
(b) monitoring the completion of the reaction using thin-layer chromatography (tlc) to confirm the formation of the desired product;
(c) allowing the reaction mixture to cool to room temperature and subsequently evaporating the solvent to obtain a crude solid;
(d) recrystallizing the crude solid with ethanol or a suitable solvent to purify the product and enhance its crystallinity;
(e) optionally introducing a catalytic amount of potassium ferrocyanide to the reaction mixture to improve reaction efficiency and product yield;
2. The antifungal compound as claimed in claim 1, wherein the derivative is specifically 4-(2,3-dihydro-1H-benzo[d]imidazole-2-yl)-2,5-dinitrophenol, with a molecular formula C13H10N4O5, molecular weight 302 g/mol, and a melting point of 240°C, exhibiting solubility in ethanol and spectral properties confirmed by IR and 1H NMR data.
3. The antifungal compound as claimed in claim 1, wherein the derivative is specifically 3-(2,3-dihydro-1H-benzo[d]imidazole-2-yl)phenol, with a molecular formula C13H12N2O, molecular weight 212 g/mol, and a melting point of 220°C, exhibiting solubility in water and spectral properties confirmed by IR, 1H NMR, and mass spectroscopy.

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