7-Amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes]: Synthesis and cholinesterase inhibitory activity of structurally modified tacrines.

Five new examples of 9,10-chloro(bromo)-7-amine-spiro[chromeno[4,3-b]quinoline-6,1'-cycloalkanes] - in which cycloalkanes = cyclopentane, cyclohexane, and cycloheptane - were synthesized at yields of 42-56%, using a sequential one-pot two-step cyclocondensation reaction of three different scaffolds of 2-aminobenzonitriles and the respective spiro[chroman-2,1'-cycloalkan]-4-ones, and using AlCl3 as the catalyst in a solvent-free method. Subsequently, the five new spirochromeno-quinolines and nine quinolines previously published by us (14 modified tacrine scaffolds) were subjected to AChE and BChE inhibitory activity evaluation. The molecule containing a spirocyclopentane derivative had the highest AChE and BChE inhibitory activity (IC50 = 3.60 and 4.40 µM, respectively), and in general, the non-halogenated compounds were better inhibitors of AChE and BChE than the halogenated molecules. However, the inhibitory potency of compounds 3a-n was weaker than that of tacrine. By molecular docking simulations, it was found that the size of the spirocarbocyclic moieties is inversely proportional to the inhibitory activity of the cholinesterases, probably because an increase in the size of the spirocyclic component sterically hindered the interaction of tacrine derivatives with the active site of tested cholinesterases. The findings obtained here may help in the design and development of new anticholinesterase drugs.

High level of methylmercury exposure causes persisted toxicity in Nauphoeta cinerea.

Methylmercury (MeHg+) is a neurotoxicant abundantly present in the environment. The long-term effects of MeHg+ have been investigated in rodents, yet data on the long-term or persisted toxicity of MeHg+ in invertebrates is scanty. Here, we examined the acute, intermediate, and chronic effects upon dietary administration of MeHg+ in nymphs of Nauphoeta cinerea. Besides, the potential reversibility of the toxic effects of MeHg+ after a detoxification period was evaluated. Nymphs were exposed to diets containing 0 (control), 2.5, 25, and 100 µg MeHg+/g of diet for 10, 30, and 90 days. Additional groups of nymphs were fed with the same dose of MeHg+ for 30 days and then were subjected to a detoxification period for 60 days. The nymphs exposed to 100 µg MeHg+/g succumbed to a high mortality rate, along with multiple biochemical (increase of reactive oxygen species production and glutathione S-transferase activity, as well as decrease in the acetylcholinesterase activity) and behavioral alterations. We observed delayed mortality rate and behavioral alterations in nymphs exposed to 100 µg MeHg+/g for 30 days and subsequently subjected to 60 days of detoxification. However, the biochemical alterations did not persist throughout the detoxification period. In conclusion, our results established the persistent toxic effect of MeHg+ even after a prolonged detoxification period and evidenced the use of N. cinerea as an alternative model to study the toxicity of MeHg+.