Discovery of 1-(phenylsulfonyl)-1H-indole-based multifunctional ligands targeting cholinesterases and 5-HT6 receptor with anti-aggregation properties against amyloid-beta and tau was written by Wichur, Tomasz;Pasieka, Anna;Godyn, Justyna;Panek, Dawid;Goral, Izabella;Latacz, Gniewomir;Honkisz-Orzechowska, Ewelina;Bucki, Adam;Siwek, Agata;Gluch-Lutwin, Monika;Knez, Damijan;Brazzolotto, Xavier;Gobec, Stanislav;Kolaczkowski, Marcin;Sabate, Raimon;Malawska, Barbara;Wieckowska, Anna. And the article was included in European Journal of Medicinal Chemistry in 2021.Safety of N-(5-Bromopentyl)phthalimide This article mentions the following:
Multifunctional ligands as an essential variant of polypharmacol. are promising candidates for the treatment of multi-factorial diseases like Alzheimer’s disease. Based on clin. evidence and following the paradigm of multifunctional ligands we have rationally designed and synthesized a series of compounds targeting processes involved in the development of the disease. The biol. evaluation led to the discovery of two compounds with favorable pharmacol. characteristics and ADMET profile. Compounds I [n = 1] and II [R = [ethyl(methyl)carbamoyl]oxidanyl, n =1] are 5-HT6R antagonists (Ki = 13 nM and Ki = 15 nM resp.) and cholinesterase inhibitors with distinct mechanisms of enzyme inhibition. Compound I [n = 1], a tacrine derivative is a reversible inhibitor of acetyl- and butyrylcholinesterase (IC50 = 8 nM and IC50 = 24 nM resp.), while compound II [R = [ethyl(methyl)carbamoyl]oxidanyl, n =1] with rivastigmine-derived Ph N-ethyl-N-methylcarbamate fragment is a selective, pseudo-irreversible inhibitor of butyrylcholinesterase (IC50 = 455 nM). Both compounds inhibit aggregation of amyloid β in vitro (75% for compound I [n = 1] and 68% for II [R = [ethyl(methyl)carbamoyl]oxidanyl, n =1] at 10μM) moreover, compound II [R = [ethyl(methyl)carbamoyl]oxidanyl, n =1] is a potent tau aggregation inhibitor in cellulo (79%). In ADMET in vitro studies both compounds showed acceptable metabolic stability on mouse liver microsomes (28% and 60% for compound I [n = 1] and II [R = [ethyl(methyl)carbamoyl]oxidanyl, n =1] resp.), no or little effect on CYP3A4 and 2D6 up to a concentration of 10μM and lack of toxicity on HepG2 cell line (IC50 values of 80 and 21μM, for I [n = 1] and II [R = [ethyl(methyl)carbamoyl]oxidanyl, n =1] resp.). Based on the pharmacol. characteristics and favorable pharmacokinetic properties, we propose compounds I [n = 1] and II [R = [ethyl(methyl)carbamoyl]oxidanyl, n =1] as an excellent starting point for further optimization and in-depth biol. studies. In the experiment, the researchers used many compounds, for example, N-(5-Bromopentyl)phthalimide (cas: 954-81-4Safety of N-(5-Bromopentyl)phthalimide).
N-(5-Bromopentyl)phthalimide (cas: 954-81-4) belongs to organobromine compounds. Bromine is more electronegative than carbon (2.9 vs 2.5). Consequently, the carbon in a carbon–bromine bond is electrophilic, i.e. alkyl bromides are alkylating agents. Many of the alkyl bromine derivatives are excellent alkylating agents since bromides are good leaving groups. Tribromides, like tetrabutylammonium tribromide, are used as a solid source of bromine. N-bromosuccimide (NBS) is used for the selective bromination of allylic bonds.Safety of N-(5-Bromopentyl)phthalimide
Referemce:
Bromide – Wikipedia,
bromide – Wiktionary