Design, Spectroscopy, and Assessment of Cholinesterase Inhibition and Antimicrobial Activities of Novel Coumarin-Thiadiazole Hybrids

Abstract

A novel series of coumarin-thiadiazole hybrids, derived from substituted coumarin-3-carboxylic acids was isolated and fully characterized with the use of a number of spectroscopic techniques and XRD crystallography. Several of the novel compounds showed intensive fluorescence in the visible region, comparable to that of known coumarin-based fluorescence standards. Moreover, the new compounds were tested as potential antineurodegenerative agents via their ability to act as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. Compared to the commercial standards, only a few compounds demonstrated moderate AChE and BuChE activities. Moreover, the novel derivatives were tested for their antimicrobial activity against a panel of pathogenic bacterial and fungal species. Their lack of activity and toxicity across a broad range of biochemical assays, together with the exceptional emission of some hybrid molecules, highlights the possible use of a number of the novel hybrids as potential fluorescence standards or fluorescence imaging agents.

Keywords: antimicrobial activity; cholinesterase inhibitors; coumarin; fluorescence imaging; hybrids; neurodegeneration; thiadiazole.

Figure 1

General structure of coumarin–thiadiazole hybrids 1-12 showing the numbering system of atoms and substituents present at the coumarin phenyl ring.

Figure 2

Synthetic pathway for the synthesis of coumarin–thiadiazole hybrids 1-12: (A) diethyl malonate, piperidine, 40 °C; (B) Meldrum’s acid, piperidine, acetic acid, ethanol, reflux; (C) Meldrum’s acid, H₂O, reflux; (D) POCl₃, thiosemicarbazide, 75 °C.

Figure 3

Formation of the coumarin–thiadiazole hybrids 1-12 from coumarin-3-carbonyl chloride intermediates.

Figure 4

Crystal structures of coumarin–thiadiazole hybrids 4 and 11 and their respective coumarin-3-carboxylic acid precursors 4′ and 11′.

Figure 5

Comparison of the IR(ATR) spectra of coumarin-3-carboxylic acid 4′ (top) and the corresponding coumarin–thiadiazole hybrid 4 (bottom).

Figure 6

Comparison of the ¹H-NMR (DMSO_d6) spectra of coumarin-3-carboxylic acid 1′ (top) and the corresponding coumarin–thiadiazole hybrid 1 (bottom). The most informative signals, namely the hydrogens H4 and H8, are marked in red. For better clarity, the residual solvent and water peaks were omitted.

Figure 7

Electronic absorption (left) and fluorescence emission spectra (right) of coumarin–thiadiazole hybrids 1-12 recorded in methanol. The absorption spectra were recorded at a concentration of 0.2 mM, except 1, which was recorded at 0.04 mM. The fluorescence spectra were recorded at λ_ex = 380 nm and a concentration of 0.01 mM, except 1, which was recorded at λ_ex = 420 nm and 0.002 mM, respectively.

Figure 8

Comparison of structures of highly fluorescent coumarin–thiadiazole hybrid 1 (left) and coumarin-derived fluorescence standard Coumarin 6 (Right).