Synthesis of Some New Heterocyclic Compounds Derived from 2-Chlorobenzoic Acid as Potential Biological Activity

Received: 06-Aug-2026, Manuscript No. DPC-26-193376; Editor assigned: 10-Aug-2026, Pre QC No. DPC-26-193376 (PQ); Reviewed: 24-Aug-2026, QC No. DPC-26-193376; Revised: 15-Aug-2026, Manuscript No. DPC-26-193376 (Q); Published: 22-Aug-2026, DOI: 10.4172/0975-413X.18.1.774-778

Introduction

1,3,4-Oxadiazole is a five-membered heterocyclic ring that contains two nitrogen atoms and one oxygen atom. It is one of the four isomeric forms of oxadiazole and has become an important structural unit in medicinal chemistry.

Several approved drugs already contain the oxadiazole ring—examples include: Furamizole (antibacterial), Butalamine (vasodilator), Oxolamine (cough suppressant), Pleconaril (anti-viral), Fasiplon (anxiolytic), and Raltegravir (antiretroviral). Over the past four decades, oxadiazole compounds have been widely studied and are known to show an impressive range of biological activities such as anti-cancer, anti-inflammatory, anti-fungal, anti-depressant, anti-angiogenic, analgesic, anti-insomnia, and anti-oedema effects. Among these, 1,3,4- oxadiazole derivatives are particularly important because they demonstrate numerous therapeutic properties, including anti-diabetic, antibacterial, anti-inflammatory, anti-fungal, anti-convulsant, and anti-HIV activities. Structurally, oxadiazoles resemble furans, but instead of two carbon atoms in the ring, they contain two Nitrogen atoms (–N=). This substitution gives oxadiazoles unique chemical behavior and biological relevance.

There are various methods for preparing 1,3,4-oxadiazoles. The most common approach involves reacting acid hydrazides (or hydrazine) with acid chlorides or carboxylic acids. Another widely used technique is the cyclization of diacylhydrazides using dehydrating agents like phosphorus oxychloride, thionyl chloride, or triflic acid. Because of their structural versatility and ease of modification, 1,3,4-oxadiazole derivatives have become a significant class of molecules in medicinal chemistry. They have been associated with a broad spectrum of biological activities, including anti-inflammatory, anti-HIV, antibacterial, anticonvulsant, antimalarial, herbicidal, antianxiety, insecticidal, anti-tubercular, anti-viral, anti-fungal, anti-HBV, anti-cancer, and analgesic properties.

In summary, substituted 1,3,4-oxadiazoles hold great importance in drug discovery due to their wide-reaching therapeutic potential and diverse biological effects [1-16].

Antifungal drugs generally classified in four groups. Fungal species like Aspergillus, blastomycosis, Cryptococcus, coccidiodo, Candida, histoplasma, sporotrichosis, yeasts, malassezia, trichophyton, epidermophyton etc. Fungal infections are most common on skin, nails, mouth, throat, lungs, urinary tract and many other parts of human body. Overcome this issue and help to the living human being, study on that direction and investigate some novel compound are required and this novel compounds studied against some known fungal species are essential [17].

Antifungal drug’s mechanism of action

Polyenes (like amphotericin B): These drugs attach themselves to ergosterol, a key component of fungal cell membranes. When they latch on, they poke holes in the membrane, causing important cell contents to leak out—eventually killing the fungus.

Azoles (like fluconazole) and allylamines (like terbinafine): Both of these drug classes stop the fungus from making ergosterol. Without ergosterol, the fungal cell membrane becomes weak and can’t function properly, so the fungus can’t grow or survive.

Flucytosine: Once inside the fungal cell, flucytosine is changed into a compound similar to one used to build RNA and DNA. This “fake” building block disrupts the fungus’s ability to make proper genetic material, stopping it from growing and reproducing.

Griseofulvin: This drug interferes with the fungus’s internal skeleton specifically its microtubules which are needed for cell division. Without functioning microtubules, the fungus can’t divide and spread.

Echinocandins (like caspofungin): These drugs block the production of β-glucan, an essential ingredient in the fungal cell wall. With a weak or incomplete cell wall, the fungal cell becomes unstable and eventually bursts [18].

Materials and Methods

Synthesis of substituted 1,3,4-Oxadiazole derivatives

Reagents and conditions: (a) H₂SO₄, methanol, 65°C, 98% (1), yield 80%, (b) Hydrazine hydrate, isopropanol, 75-80°C, 5 h, yield 98% (2), (c) Aromatic acid/Aromatic aldehyde derivative, POC_l3, water, ethanol, 75-80°C, 5 h, yield 80-90%, (d) Chloroacetyl chloride, TEA, MDC, water, 0-30°C, yield 80%, (3), (e) Triethylamine (3 mmol), TsCl (1.5 mmol), Acetonitrile (5 vol.), 25-30°C, 4 h, yield 80% (4), (f) Potassium tert. Butoxide, DMSO, Amine derivatives, Water, 25-30°C, yield 70-80% (DMF): N,N-dimethylformamide, POC_l3: Phosphoryl Chloride, MDC: Methylene Dichloride, TsCl: P-Toluene sulfonyl Chloride, DMSO: Dimethyl Sulphoxide)

Synthesis of Methyl 2-chlorobenzoate (1) (Condition a)

Mixture of 2-chlorobenzoic acid (100 g, 1 mmol), sulfuric acid (93.4 g, 1.5 mmol) in methanol (1000 ml) was refluxed for 5 hrs at 60- 70°C, distilled out solvent under vacuum, add water (500 ml), cool to 25-30°C, extract in dichloromethane (500 ml) and distilled out organic layer atmospherically, get yellow colour oily product, Yield: 80%, ¹H NMR (DMSO-d6): δ 3.8 (s, CH3), 7.38 (m, CH), 7.41 (m, CH), 7.25 (m, CH), 7.91 (m, CH) ppm; ¹³C NMR (DMSO-d6): δ 51.5, 128.8, 134.5, 126.8, 131.3, 131.7, 134.7, 166 ppm; MS (EI): m/z calculated for C₈H₇C_lO₃ [M+H] +: 170.6; found 171.0

Synthesis of 2-chlorobenzohydrazide (2) (Condition b)

Mixture of methyl 2-chlorobenzoate (100 g, 1 mmol), hydrazine hydrate (59 g, 2 mmol) in isopropanol (1000 ml) was refluxed for 5 hrs at 70-75°C, distilled out solvent under vacuum, add toluene (200 ml), cool to 25-30°C, filter solid and dry in air oven, get white solid product, yield: 98%, ¹H NMR (DMSO-d6): δ 2.0 (bs, NH2), 8.0 (bs, NH), 7.38 (m, CH), 7.41 (m, CH), 7.32 (m, CH), 7.89 (m, CH) ppm; ¹³C NMR (DMSO-d6): δ 129.8, 133.5, 127.8, 128.3, 132.7, 133.7, 164 ppm; MS (EI): m/z calculated for C₇H₇C_lN₂O [M⁺H]⁺: 170.6; found 171.0

Synthesis of compound 3a to 3h (Condition c)

In an oven dried reaction flask, a solution of 2-chlorobenzohydrazide (10 g, 1 mmol), POCl₃ (5 vol.) Aromatic acid/Aldehyde derivative (1.5 mmol), stirred the reaction solution for 4-5 h, at 70-75°C, monitored reaction by TLC (Mobile phase: Hexane/Ethyl acetate 8:2) and quenched in to water (10 v), solid precipitated out. Filtration followed by recrystallization in ethanol afforded desired product, yield: 80-90%, ¹H NMR (CDCl₃): δ 7.33 (Aromatic–2XCH), 7.16 (Aromatic–2XCH), 7.20 (Aromatic–2XCH), 7.42 (Aromatic–2XCH) (Table 1).

Table 1: Synthesis and characterization of 1,3,4-oxadiazole derivatives (3a–3h).

Synthesis of 2-chloro-N'-(2-chloroacetyl)benzohydrazide (4) (Condition d)

In an oven dried reaction flask, a solution of 2-chlorobenzohydrazide (100 g, 1 mmol), Triethylamine (130.6g, 2.2 mmol) and Chloroacetyl chloride (99.3 g, 1.5 mmol) in Dichloromethane (1000 ml) at 0-5°C, followed by stirred the reaction solution for 2 h at 25-30°C, monitored reaction by TLC (Mobile phase: Methanol/Chloroform 0.5:9.5), and quenched in to water (500 ml), stop stirring and separate lower Dichloromethane layer and upper aqueous layer, Dichloromethane layer distilled out atmospherically at 40-45°C, to get 2-chloro-N'-(2-chloroacetyl)benzohydrazide, Yield: 80%. ¹H NMR (DMSO-d6): δ 4.27 (s, CH2), 8.0 (bs, 2XNH), 7.45 (m, 2XCH), 7.32 (m, CH), 7.89 (m, CH) ppm; ¹³C NMR (DMSO-d6): δ 44.9, 129.5, 133.8, 127.3, 128.7, 132.7, 164, 166 ppm; MS (EI): m/z calculated for C₉H₈Cl₂N₂O₂ [M+H] +: 247.08; found 248.0.

Synthesis of 2-(chloromethyl)-5-(2-chlorophenyl)-1,3,4-oxadiazole (5) (Condition e)

In an oven dried reaction flask, a solution of 2-chloro-N'-(2-chloroacetyl)benzohydrazide (100 g, 1 mmol), Triethylamine (61.4 g, 1.5 mmol) Tosyl chloride (85 g, 1.1 mmol) in Acetonitrile (500 ml). Stirred the reaction solution for 4-5 h, at 25-30°C, monitored reaction by TLC (Mobile phase: Hexane/Ethyl acetate 8:2) and quenched in to water (10 v), solid precipitated out. Filtration followed by recrystallization in ethanol afforded desired product, Yield: 80%, ¹H NMR (DMSO-d6): δ 4.64 (s, CH2), 7.42 (m, CH), 7.20 (m, CH), 7.16 (m, CH), 7.33 (m, CH) ppm; ¹³C NMR (DMSO-d6): δ 45, 128.5, 127.8, 130.3, 129.7, 132.7, 136.2, 164, 166 ppm; MS (EI): m/z calculated for C₉H₆Cl₂N₂O [M+H] +: 229.06; found 230.0.

Synthesis of compound 6a to 6h (Condition f)

In an oven dried reaction flask, a solution of 2-(chloromethyl)-5-(2-chlorophenyl)-1, 3, 4-oxadiazole (10.0 g, 1 mmol), Amine derivatives (1.5 mmol), Potassium tert. Butoxide (1.2 mmol) and DMSO (2.0 vol.) at 5-10°C followed by stirred the reaction solution for 4-5 hrs at 25-30°C. Monitored reaction by TLC (Mobile phase: Methanol/Chloroform 0.5:9.5), quenched in to water (10 v), solid precipitated out. Filtration followed by recrystallization in ethanol afforded desired product, yield 70-80% (Table 2).

Table 2: Synthesis and characterization of oxadiazole derivatives (6a–6h).

Results and Discussion

The MIC values (Minimal Inhibitory Concentration) for newly synthesized compounds were determined by using micro dilution broth method (Table 3). The results obtained from antimicrobial and antifungal susceptibility testing are depicted in tabular form in terms of Minimum Inhibitory Concentration (MIC).

Table 3: MIC values of synthesized compounds against selected bacterial and fungal strains.

Conclusion

In this study discuss the series of 1,3,4-Oxadiazole derivatives. All compounds subjected to tested against antifungal agents like Ketoconazole, clotrimazole and antibacterial agents like ampicillin. Species used for the testing purposes are two-gram positive bacterial species like Staphylococcus aureus, Streptococcus pyogenes, two-gram negative bacterial species like Escherichia coli, Pseudomonas aeruginosa and two fungal species like Candida albicans, Aspergillus niger etc. Product 4e, shows comparable activity against bacterial strain and product 4b, 6d shows comparable activity against fungal strain.

Conflict of Interest

The authors declare that there is no conflict of interest.

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