Synthesis and in vitro study of new coumarin derivatives linked to nicotinonitrile moieties as potential acetylcholinesterase inhibitors

Abstract

The appropriate pyridine-2(1H)-thiones were reacted with an equivalent amount of 5-(chloromethyl)-2-hydroxybenzaldehyde in ethanol in the presence of potassium hydroxide to give the corresponding 2-hydroxybenzaldehyde derivatives in excellent yields. The latter derivatives were taken as key synthons for the preparation of the target hybrids. Therefore, 2-hydroxybenzaldehydes were reacted with benzoylglycine in acetic anhydride in the presence of fused sodium acetate at 100 C for 6 hours to afford a new series of nicotinonitrile-coumarin hybrids. The in vitro acetylcholinesterase inhibitory activities were estimated for the new coumarins. The results were expressed as the inhibition percentage of the tested hybrids at concentration of 25 nM, compared to donepezil as a reference (inhibition percentage of 70.5). Coumarin hybrids linked to 6-(4-nitrophenyl) or 6-(4-chlorophenyl)-4-phenylnicotinonitrile exhibited more effective inhibitory activities than donepezil with inhibition percentages of 94.1 and 72.3, respectively. The new coumarins were tested for their free radical-scavenging capabilities against DPPH. Furthermore, some new coumarins were tested for in vitro cytotoxic activity against each MCF-10A, MCF-7, Caco2, and HEPG2. The new hybrids showed cytotoxicity in micromolar range (IC 50 of 3.5-13.9 μM) against all tested cell lines. These results clearly demonstrated that the hybrids being tested are not cytotoxic at the concentration required to inhibit acetylcholinesterase effectively.

Pyridine‐2(1H)‐thiones: Versatile precursors for one‐pot synthesis of new nicotinonitrile‐thiazole hybrids

“…NMR spectra were recorded on a Bruker Avance III 400 spectrometer (400 MHz for 1 H-NMR and 100 MHz for 13 C-NMR) using TMS as an internal standard and DMSO-d 6 as a solvent and chemical shifts were expressed as δ ppm units. Elemental analyses were carried out on a EuroVector instrument C, H, N analyzer EA3000 Series" [40]. A mixture of each of 2-((3-formyl-4-hydroxybenzyl) thio)nicotinonitriles 3a,b (5 mmol), thiosemicarbazide (5 mmol), and the appropriate of hydrazonyl chlorides 6ae, 9a-e, or the appropriate of halogen containing reagents namely chloroacetone 11, 2-bromo-1-(4-chlorophenyl) ethan-1-one 14 and ethyl chloroacetate 16 (5 mmol) in dioxane (30 ml) in the presence of TEA (1 ml, 10 mmol) was heated at 100 C for 5 h. The reaction mixture was cooled, filtered off, washed with cold ethanol, and then the product was recrystallized from the proper solvent.…”

“…In addition, they can be used in the treatment of multiple sclerosis by inhibition of sphingosine 1-phosphate lyase enzyme [38]. They also act as potent inhibitors of dipeptidyl peptidase-IV [34], acetylcholinesterase [39,40], and COX-2 enzymes [24]. Some biologically active hybrids linked to nicotinonitrile units are presented in Figure 2 [24,[40][41][42].…”

Ultrasound‐Mediated Synthesis of New (Piperazine‐Chromene)‐Linked Bis(thieno[2,3‐b]pyridine) Hybrids as Potential Anti‐acetylcholinesterase

“…The new bis(thieno[2,3-b]pyridines) 8(10) were tested for their ability to quench DPPH free radicals. [52] The inhibition percentage of the new hybrids at a concentration of 25 μg/mL using ascorbic acid as a reference is 88.7 (see Figure 5). The chromene-linked hybrids 10 a, 10 d, and 10 e, which are attached to 6-H, 6-Me, and 6-OMe units, respectively, showed the highest antioxidant activity, with inhibition percentages exceeding 50 %.…”

3‐Aminothieno[2,3‐b]pyridine‐2‐carboxylate: Effective precursor for microwave‐assisted three components synthesis of new pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4(3H)‐one hybrids

“…In connection with our previous efforts in the multicomponent synthesis of biologically promising heterocyclic hybrids [48–55], we reported herein an efficient procedure for the synthesis of pyrimidine hybrids with related thieno[2,3‐ b ]pyridine moiety.…”