Abstract The synthesis of novel 8-chloro12H- 5,14- di hydro- quinoxalino [2,3, a] – penta cyclic phenothiazine (16) and its anilino derivatives (18 a-h) are reported. The preparation followed the water-mediated catalyst pre-activation method as reported by Buchwald and co-workers. Structures were established by analytical and spectral data. The compounds (18 a-h) were evaluated for inhibitory potency against Acetylcholineesterase (AChE) and Butyrylchlolinesterase (BChE). The tested pentacyclic phenothiazines showed IC50 values for both AChE and BChE in the range of 1.26 nM to 84.69 nM. Compound 18c exhibited the most persuasive inhibitor of AChE, having an IC50 value of 1.26 nM, while (18h) gave the least potent inhibitor at IC50 = 52.11 nM. The inhibitory values of the tested compounds for repression of BChE showed concentration range of 4.38-84.69 nM. The presence of substituent groups in the aromatic ring was noted to have influenced the inhibitory potency of the eight phenothiazine systems and as such demonstrating Structure Activity Relationship (SAR among the compounds. The results were compared with Rivastigmine and Galantamine, which are well known human cholinesterase inhibitors. All the tested phenothiazine systems showed excellent inhibition of AChE than Rivastigmine. Galanthamine was more potent on AChE than the tested compounds, except (18 a, 18c, 18f and 18g). Only five compounds exhibited inhibition of BChE than Galantamine.
Keywords 8-anilino-12H-5,14-dihydroquinoxalino-[2,3-a] penta cyclic phenothiazine, acetylcholinesterase, butyryl cholinesterase, inhibition, substituent groups.