Synthesis, X-ray crystal structure and theoretical calculations of antileishmanial neolignan analogues

Abstract

A síntese e a estrutura cristalina por difração de raios-X de dois análogos de neolignanas, 2-(4-clorofenil)-1-feniletanona (20) e 2-[tio(4-clorofenil)]-1-(3,4-dimetoxifenil)propan-1-ona (12) são descritas. O composto 12 apresenta atividade intracelular contra Leishmania donovani e Leishmania amazonensis de amastigotas que causam a leishmaniose tegumentar e visceral. Além disso, a teoria do funcional de densidade (DFT) com o funcional híbrido B3LYP foi empregado para calcular um conjunto de descritores moleculares para dezenove análogos sintéticos de neolignanas com atividades antileishmaniose. Posteriormente, a análise discriminante stepwise foi realizada para investigar possíveis relações entre a estrutura molecular e atividades biológicas. Por meio dessa análise os compostos foram classificados em dois grupos ativos e inativos de acordo com seu grau de atividade biológica, e as propriedades mais importantes foram as cargas de alguns átomos, a afinidade eletrônica e o ClogP.The synthesis and X-ray crystal diffraction structure of two analogues of neolignans, 2-(4-chlorophenyl)-1-phenylethanone (20) and 2-[(4-chlorophenyl)thio]-1-(3,4-dimethoxyphenyl) propan-1-one (12) is described. The compound 12 presents activity against intracellular Leishmania donovani and Leishmania amazonensis amastigotes that cause cutaneous and visceral leishmaniasis. In addition, the density functional theory (DFT) with the B3LYP hybrid functional was employed to calculate a set of molecular descriptors for nineteen synthetic analogues of neolignans with antileishmanial activities. Afterwards, the stepwise discriminant analysis was performed to investigate possible relationship between the molecular descriptors and biological activities. Through this analysis the compounds were classified into two groups active and inactive according to their degree of biological activities, and the more important properties were charges on some key atoms, electronic affinity and ClogP.

Synthesis, antimalarial activity in vitro, and docking studies of novel neolignan derivatives

“…In previous work where active lignans were evaluated against a chloroquine‐resistant P. falciparum strain, the importance of the methoxy substituent for good antiparasitic activity was demonstrated. Most lignoids were not cytotoxic (MLD 50 > 1,500 μ m ) and are therefore good new antimalarial candidates as suggested previously . The selectivity index was above 100 μ m for two new compounds tested, the neolignan derivatives 9 and 10 .…”

“…The neolignans correspond to a kind of lignoids derived from the oxidative homo‐ or cross‐coupling of alylphenols and propenyl phenols . They are found in plants from the Miristicaceae family, and have demonstrated antibacterial, anti‐ Schistosoma, antifungal, trypanosomicidal, anti‐ Plasmodium , and leishmanicida activities. Neolignan derivatives are active against Plasmodium at nanomolar concentrations, and are considered the most active lignoids against malaria, thus promising antimalarial prototypes …”

Novel 3-chloro-6-nitro-1H-indazole derivatives as promising antileishmanial candidates: synthesis, biological activity, and molecular modelling studies

“…performed a DFT-B3LYP study on nineteen neolignan derivatives which could be categorised into two groups active and inactive according to their anti-leishmanial efficiencies. An assessment of the molecular electrostatic potentials (MEPs) of the nineteen compounds showed the active compounds have much more intense regions of negative electrostatic potentials than the inactive ones 62 . Similarly, Pinheiro and co-workers synthesised eleven 5-(4,5-dihydro-1 H -imidazol-2-yl)-4-(arylamino)thieno[2,3- b ]pyridine derivatives as new anti-leishmanial compounds.…”

Antileishmanial Activity and Structure-Activity Relationship of Triazolic Compounds Derived from the Neolignans Grandisin, Veraguensin, and Machilin G

“…The transport of a compound across membranes may be influenced by the molecular hydrophobicity described by the octanol/water partition coefficient (ClogP) [19]. According to Lipinski's Rule of Five [20][21][22], compounds with logP < 5 have better absorption and permeation in vivo.…”

“…The most active compound on intracellular amastigotes (19) came from methylenedioxy series (IC 50 = 4.4 µM). Compound 19 is a hybrid from machilin G 3 and grandisin 2 and was also quite selective (SI = 10.6) ( Table 1).…”