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

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,

R=

1. 4-Nitrobenzoic acid
2. 3 Chlorobenzoic acid

R1=

(a)- Benzaldehyde

(b)Formaldehyde

(c) 4 Choro benzaldehyde

(d) 4 Dimethyl amine benzaldehyde

(e) 3 Nitrobenzaldehyde

Synthesis:

Synthesis by conventional method:

When compared to other compounds, compounds 3a through 4e and compound 4a had the lowest dock scores (-62.60). When we compared the results of the molecule to the literature, this docking score indicated that the suggested compounds had a good binding affinity for hinding to receptors (PDB Code-4AA7). In the binding pocket, the suggested compounds all take on a very similar conformation, displaying van der Waals interactions with the ASP5SA, ARG56A, and TYR67A amino acids as well as hydrogen bond interactions with the ARG56A amino acid. A 2D image is used to depict it (figno.6.2.4.2). 4a chemical and receptor overlay in the figure. It was discovered that the popular drug ciprofloxacin had a dock score of -65.60.

Compound code 4a             Standard (Ciprofloxacin)

Fig. no. 6.2.4.1 Docking poses of compound code 4a and standard drug

Compound code 4a                                            Standard (Ciprofloxacin)

Fig. no. 6.2.4.2: 2D representation of Docking poses of compound code 4a and standard drug

Compound code 4a                                          Standard (Ciprofloxacin)

Fig. no. 6.2.4.3:  Superimpose image representation of Docking poses of compound code 4a and standard drug

Compounds 3a through 4e have dock scores ranging from - 48.121, with compound 3a having the minimum dock value compared to the remaining compounds. This docking score showed that the developed compounds have a strong binding affinity for binding to the receptor (PDB Code-1kZN) when we compared the results of compound 3a to the literature. The optimal position derived from the docking findings is shown in figure no.6.2.4.4. At the binding pocket, every proposed molecule takes on a fairly similar shape. This includes hydrogen bonding with the amino acid of TYR80A, vanderwal interaction binding LEU83A, hydrophobic interaction binding LEU83A, and aromatic interaction showing with the amino acid of HIS72A. This is depicted in the 2D representation diagram (fig. 6.2.4.5). Superimpose the 3a compound picture with the receptor depicted in the diagram (fig. 6.2.4.6).

Compound code 3a                                           Standard (Fluconazole)

Fig. no. 6.2.4.4:  Docking poses of compound code 3a and standard drug

Compound code 3a                                           Standard (Fluconazole)

Fig. no. 6.2.4.5: 2D representation of Docking poses of compound code 3a and standard drug

Compound code 3a                                            Standard (Ciprofloxacin)

Fig. no. 6.2.4.6:  Superimpose image representation of Docking poses of compound code 3a and standard drug

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

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

Graph no 5.2.11: NMR Spectrum of compound 3a

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

Graph no 5.2.12: NMR Spectrum of compound 4a

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

Graph no. 5.2.13: MASS Spectrum of compound 3a