New hybrids of tacrine and indomethacin as multifunctional acetylcholinesterase inhibitors

Abstract

A new series of hybrid compounds were designed, consisting of anti-AChE and BuChE activity components with an antiinflammatory component. A series of 9-amino-1,2,3,4-tetrahydroacridine and indomethacin derivatives were synthesized. All compounds were created using alkyldiamine with different chain lengths as a linker. Various biological activities were evaluated, including inhibitory activity against AChE and BuChE. The tested compounds showed high inhibitory activities against cholinesterases. The IC 50 values for all compounds ranging from 10 nM to 7 µM. The potency of inhibition was much higher than well-known AChE and BuChE inhibitors (tacrine and donepezil). Compound 3h had the strongest inhibitory activity; kinetic studies showed it to have a mixed-type of acetylcholinesterase inhibition properties. The cytotoxicity of the newly-synthesized compounds against HepG2 (hepatocarcinoma cells) and EA.hy96 (human vein endothelial cells) cell lines was determined using the MTT and MTS tests. All investigated compounds presented similar cytotoxic activity against HepG2 and EA.hy926 cell line, ranged in micromolar values. Compounds with longer linkers showed higher antioxidant activity. The most active compound was 3h. Docking studies confirmed interactions with important regions of AChE and BuChE. Its multifunctional properties, i.e. high activity against AChE and BuChE, antioxidant activity and low cytotoxicity, highlight 3h as a promising agent for the treatment of AD.

In silico and in vitro Studies Confirm Ondansetron as a Novel Acetylcholinesterase and Butyrylcholinesterase Inhibitor

“…The IC 50 values thus obtained are 33 µM and 2.5 µM for AChE and BChE, respectively. This can be compared to the IC 50 values of the reference inhibitors: Rivastigmine was was reported to have an IC 50 value in AChE of 71µM [42] or 501 µM [43], whereas for Tacrine the values range between 0.2-0.45 µM [44,45]. Ondansetron is hence a more potent binder to AChE than Rivastigmine, but less so than Tacrine, which agrees perfectly with the MMGBSA data of Table 2.…”

In silico and in vitro studies confirm Ondansetron as a novel acetylcholinesterase and butyrylcholinesterase inhibitor

“…The IC 50 values thus obtained are 33 µM and 2.5 µM for AChE and BChE, respectively. This can be compared to the IC 50 values of the reference inhibitors: Rivastigmine was reported to have an IC 50 value in AChE of 71 μM 45 or 501 μM 46 , whereas for Tacrine the values range between 0.02 and 0.45 μM 46,47 .…”

Tacrine-Based Hybrids: Past, Present, and Future

“…Because the number of articles devoted to the development of analogues of THA is enormous, we structured the articles published in 2006–2022 [ 30 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 …”

“…In 2021, Zawada et al reported THA–indometacine hybrids 464 – 471 [ 77 ]. The IC 50 values for hybrids range from 10 to 260 nM.…”

“… THA–flurbiprofen hybrids 439 – 443 [ 74 ], THA–flurbiprofen–NO–donating hybrids 444 – 455 [ 75 ], 456 – 463 [ 76 ], THA–indometacine hybrids 464 – 471 [ 77 ], ROS–responsive ibuprofen–THA hybrids 472 – 475 [ 78 ]. …”