Synthesis In Silico Estimation and Pharmacological Screening of Some Substituted Oxadiazole Derivatives

Abstract

Oxadiazole derivatives have emerged as a vital class of heterocyclic compounds in medicinal chemistry due to their diverse pharmacological activities and favorable drug-like properties. The present study focuses on the design, synthesis, in-silico analysis, and pharmacological evaluation of a series of novel substituted oxadiazole derivatives with the objective of identifying promising candidates for future therapeutic development. The structures of the synthesized derivatives were confirmed using spectral techniques such as FT-IR, ¹H-NMR, and mass spectrometry, ensuring purity and structural integrity. In-silico studies were performed to predict the biological behavior of the synthesized compounds, focusing on their molecular docking interactions with selected protein targets known to play key roles in microbial infection and inflammation. The docking results indicated strong binding affinities and stable interactions between several oxadiazole derivatives and the active sites of the target enzymes, suggesting potential for antimicrobial and anti-inflammatory activities.

Keywords

Introduction

In the present study, a series of substituted 1,3,4-oxadiazoles were synthesized using microwave-assisted methods and evaluated for their antibacterial and antifungal activities. Microwave synthesis proved to be highly efficient, offering significantly higher yields in a shorter time compared to conventional methods. The synthesized compounds were recrystallized using various solvents, including ethanol, petroleum ether, n-hexane, methanol, butanol, and acetone, through a slow evaporation technique. Among these solvents, ethanol and acetone produced the most well-defined crystal structures, typically forming needle-like, cross-shaped, and clustered crystals. This is particularly important, as polymorphism can greatly influence the bioavailability of drugs—especially those with poor water solubility. The structural integrity of the synthesized compounds was confirmed by satisfactory results from IR, ¹H NMR, and mass spectroscopic analyses.

1,3,4-oxadiazole- An important Heterocycle^16-19: -

The five-membered oxadiazole nucleus is present in heterocyclic compounds with a wide range of health benefits. Oxadiazoles are cyclic compounds that include one oxygen and two nitrogen atoms in a five-membered ring. Oxadiazole is considered to be created by replacing two of the methane (-CH=) groups with two of the nitrogen (-N=) groups of the pyridine type in furan. Compounds with the 1,3,4-oxadiazole nucleus exhibit unique anti-inflammatory, analgesic, antibacterial, anticancer, anticonvulsant, anthelmintic, herbicidal, anti-mycobacterial, antioxidant, and anti-hepatitis B virus properties. Oxadiazole is a heterocyclic aromatic compound with five components, including one oxygen and two nitrogen atoms. In medicinal chemistry, they have also been studied as bioisosteres for carboxylic acids, esters, and carboxamides. It comes in a variety of isomeric forms, including 1,2,3, 1,2,4, 1,2,5, and 1,3,4-oxadiazole.

 Reaction scheme:

Where,

Table No. 5.1.1 Physicochemical data of 5 substituted 1,3,4 oxadiazolidin -2 yl formamide by Conventional and microwave methods

Antibacterial Activity Docking Result

Compound code 4a             Standard (Ciprofloxacin)

Compound code 4a                                            Standard (Ciprofloxacin)

Table 6.2.4.2: Data for interaction of compound code 4a with amino acid

Amino acid	Atom of ligand	Distance	Interaction type
TYR279B	1C	3.991	AROMATIC_INTERACTION
ARG56A	956H	2.982	VDW_ INTERACTION
OH507C	17C	2.937	VDW_ INTERACTION
ARG56A	957H	2.534	HYDROGENBOND_ INTERACTION

Compound code 4a                                          Standard (Ciprofloxacin)

Anti-Fungal Activity Docking Result

Compound code 3a                                           Standard (Fluconazole)

Compound code 3a                                           Standard (Fluconazole)

Table 6.2.4.4: Data for interaction of compound code 3a with amino acid

Amino acid	Atom of ligand	Distance	Interaction type
TYR80A	9O	1.690	HYDROGENBOND_ INTERACTION
TYR80A	15N	3.750	VDW_ INTERACTION
HIS72A	8C	4.310	AROMATIC_ INTERACTION
LEU83A	17C	3.408	VDW_ INTERACTION

Compound code 3a                                            Standard (Ciprofloxacin)

Graph No.5.2.1: IR Spectrum of 3a 5-(2 -formyl-4-nitrobenzamido)-1,3,4-oxadiaazolidin-2-yl-4-nitrobenzoate

Table. No.5.2.1: IR Spectrum of 3a 5-(2 -formyl-4-nitrobenzamido)-1,3,4-oxadiaazolidin-2-yl-4-nitrobenzoate

Sr. No.	Assignment	Functional groups	Wavenumber (cm?¹)
1	C-H Stretching	Aromatic and alkyl C-H	3111-2924
2	C=O Stretching	Ester and amide carbonyls	1729-1702
3	C=C Aromatic stretching	Aromatic rings	1600-1500
4	NO2 Stretching	Nitro group	1350-1300
5	C-O Stretching	Ester or ether	1250-1000

Graph No.5.2.6: IR Spectrum of 4a 5 (5 -chloro-2-formylbenzamido)-1,3,4-oxadiazolidin-2-yl-4- chlorobenzoate

Table. No.5.2.6: IR Spectrum of 4a 5 (5 -chloro-2-formylbenzamido)-1,3,4-oxadiazolidin-2-yl-4- chlorobenzoate.

NMR Spectrum of 3a 5-(2 -formyl-4-nitrobenzamido)-1,3,4-oxadiaazolidin-2-yl-4-nitrobenzoate

Graph no 5.2.11: NMR Spectrum of compound 3a

Table no. 5.2.11: NMR Spectrum value of compound 3a

Graph no 5.2.12: NMR Spectrum of compound 4a

Table no.5.2.12: NMR Spectrum value of compound 4a

Graph no. 5.2.13: MASS Spectrum of compound 3a

MASS Spectrum of 4a 5 (5 -chloro-2-formylbenzamido)-1,3,4-oxadiazolidin-2-yl-4- chlorobenzoate

Graph no 5.2.14: MASS Spectrum of compound 4a

Antimicrobial Activity

Fig no.7.7.1: Antimicrobial properties of synthesized compound

Table.no. 7.7.1 Antibacterial screening of synthesized compound (3a-4e) measuring the zone of inhibition in millimeters.

RESULT AND DISCUSSION

Graph no. 8.3.1 Antibacterial activity on synthesized compound. (3a-4e).

Antifungal activity: To test the synthesized compound's antifungal qualities, the cup-plate method was employed. The test sample (3a–4e) has been seen to have strong activity and a comparable proportion of inhibition to the conventional medication.

Graph no. 8.3.2 Antifungal activity on synthesized compound. (3a-4e)

SUMMARY AND CONCLUSION

A set of ten synthesized compounds were subjected to molecular docking studies to evaluate their antibacterial and antifungal potential. Compound 4a showed strong binding affinity and significant activity against the E. coli receptor and E. coli GLMU (PDB ID: 4AA7), particularly when combined with an antibacterial inhibitor. Meanwhile, compound 3a demonstrated notable antifungal activity by targeting the receptor DNA gyrase, which contains five disulfide bridges (PDB ID: 1KZN). In the present study, a series of substituted 1,3,4-oxadiazoles were synthesized using microwave-assisted methods and evaluated for their antibacterial and antifungal activities. Microwave synthesis proved to be highly efficient, offering significantly higher yields in a shorter time compared to conventional methods. The synthesized compounds were recrystallized using various solvents, including ethanol, petroleum ether, n-hexane, methanol, butanol, and acetone, through a slow evaporation technique. Among these solvents, ethanol and acetone produced the most well-defined crystal structures, typically forming needle-like, cross-shaped, and clustered crystals. This is particularly important, as polymorphism can greatly influence the bioavailability of drugs—especially those with poor water solubility. The structural integrity of the synthesized compounds was confirmed by satisfactory results from IR, ¹H NMR, and mass spectroscopic analyses. In this study, a group of new oxadiazole compounds was made and tested using both computer-based methods and laboratory experiments. The in-silico (computer) studies showed that some of the compounds could strongly bind to proteins of harmful microbes, suggesting they might work as drugs. Laboratory tests confirmed that a few of these compounds had good antibacterial and antifungal activity.  In comparison to ciprofloxacin, compound 4a exhibits substantial antibacterial activity, and In comparison to Fluconazole, compound 3a exhibits similar antifungal activity. Overall, the results suggest that the synthesized oxadiazole derivatives have the potential to be developed into effective medicines for treating infections.

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