Synthesis of designed new 1,3,4-oxadiazole functionalized pyrano [2,3-f] chromene derivatives and their antimicrobial activities

Abstract

Diethyl 2-(((4-methyl-2-oxo-2H-chromen-7-yl)oxy)methylene)malonate (2) was synthesized from coumarin 1 and diethyl ethoxymethylene malonate in ethanol, followed by cyclization in diphenyl ether to give chromene-9-carboxylate (3). Sugar hydrazones 5a-c were formed by reacting hydrazide 4 with D-galactose, D-mannose, and D-xylose, then acetylated to per-O-acetyl derivatives 6a-c. Heating 5a-c with acetic anhydride at 100 °C gave oxadiazolines 7a-c. Compound 8, obtained by refluxing 4 with carbon disulfide, was alkylated to 9 or reacted to give 10. Further reactions yielded acetoxy derivative 13 and hydroxy derivative 14. Compounds 17a-e and 18a-e were synthesized using thiomorpholinophenyl ureido/thioureido-s-triazine. These compounds were characterized and evaluated for antibacterial activity against Gram (+ve) bacteria (B. subtilis, S. aureus) and Gram (-ve) bacteria (E. coli, P. aeruginosa) in addition to yeast-like fungi (C. albicans). Compounds 11, 13, 15, 16, 17c-e, and 18a-e showed the highest antibacterial activity. Molecular docking was performed to study their binding with transpeptidases.

Keywords: 1,3,4-Oxadiazole; Antimicrobial activities; Molecular docking; Pyrano[2,3-f]chromene; Sugars; Transpeptidases.

Graphical abstract

Fig. 1

Some drugs containing 1,3,4-oxadiazole moiety.

Scheme 1

Synthesis of compounds 5a-c, 6a-c and 7a-c.

Scheme 2

Synthesis of compounds 8-14.

Scheme 3

Synthesis of compounds 15-18.

Fig. 2

a): The 3D orientation of original ligand AI8 of transpeptidases enzyme (elemental colored), the re-docked ligand (green), b): The 3D orientation of the re-docked ligand (green), 11 (dark blue); 13; (orang); 15 (faint purple); 16 (pink); 17c (yellow); 17d (maroon); 17e (silver metallic); 18a (pink metallic); 18b (greenish brown); 18c (blue); 18d (dark red); 18e (blue sky) inside the binding pocket of transpeptidases enzyme (PDB: 5TW8).

Fig. 3

a-l. The 2D interaction of compounds 11, 13, 15, 16, 17c-e, and 18a-e inside the binding pocket of transpeptidase enzyme, PDB: 5TW8, illustrating the formed hydrogen bonds, attractive charge, pi-pi bond, and pi-alkyl.

Fig. 4

a-l. The 3D configurations of compounds 11, 13, 15, 16, 17c-e, and 18a-e inside the binding pocket of transpeptidase enzyme (PDB: 5TW8).

Fig. 5

a), b) The 2D interactions of AI8 and 18e inside the binding pocket of transpeptidase enzyme (PDB: 5TW8), c) and d) clarifying the 3D configurations of AI8 and 18e inside the binding pocket of transpeptidase enzyme (PDB: 5TW8).