Naslov
In silico prediction how different funcionalities in N-alkyl quaternary quinuclidines affect their physicochemical properties and toxicity

Autori
Žunec, Suzana ; Vadlja, Donna ; Zandona, Antonio ; Ramić, Alma ; Primožič, Ines ; Katalinić, Maja

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, znanstveni

Izvornik
Abstract Book / - Beograd, 2023, 176-177

Skup
13. International Congress of the Serbian Society of Toxicology & 1. TOXSEE Regional Conference

Mjesto i datum
Beograd, Srbija, 10.05.2023. - 12.05.2023

Vrsta sudjelovanja
Poster

Vrsta recenzije
Međunarodna recenzija

Ključne riječi
New chemical entities ; Quinuclidine ; Prediction ; Drug-like profiles
(new chemical entities, quinuclidine, prediction, drug-like profiles)

Sažetak
Guided by an interest to develop new cholinesterase-acting drugs with better biological activity and bioavailability, we have synthesized 14 quaternary quinuclidine compounds with the variation in N-alkyl chain length and incorporation of alcohol or oxime headgroup at the position 3 of the quinuclidine ring. SwissADME interface was used to determine basic physicochemical properties and to evaluate whether tested compounds interact with selected enzymes of the cytochrome P450 system, which could affect their metabolism. Most of the tested quinuclidines complied with the Lipinski's rule-of-five ensuring their drug-likeness properties. Exceptions were noticed for bisquaternary 3-hydroxy and 3- hydroxyimino compounds with C8 and C10 alkyl chains which exceed the number of rotating bonds and topological polar surface area compared to the recommended values. Furthermore, it was estimated that all compounds except 3-hydroxyimino compound with C16 alkyl chain have an ability to cross the blood brain barrier and favorable properties for gastrointestinal absorption. However, all tested quinuclidines have either negative logP value or below 1.5, indicating low lipophilicity and therefore low potential to be passively transported across biological barriers. According to computer prediction quinuclidines with a long side alkyl chain (C12 and C14) inhibit CYP2D6 that may be one of the causes of pharmacokinetics- related drug-drug interactions leading to toxic or other unwanted adverse effects. Understanding how combination of different functionalities in a molecule affects its physicochemical properties represents a good starting point for further biological research of activity and toxicity.

Izvorni jezik
Engleski

Znanstvena područja
Kemija, Temeljne medicinske znanosti

POVEZANOST RADA