Structure–Activity Relationship Studies of 9-Alkylamino-1,2,3,4-tetrahydroacridines against Leishmania (Leishmania) infantum Promastigotes

Abstract

Leishmaniasis is one of the most neglected diseases in modern times, mainly affecting people from developing countries of the tropics, subtropics and the Mediterranean basin, with approximately 350 million people considered at risk of developing this disease. The incidence of human leishmaniasis has increased over the past decades due to failing prevention and therapeutic measures—there are no vaccines and chemotherapy, which is problematic. Acridine derivatives constitute an interesting group of nitrogen-containing heterocyclic compounds associated with numerous bioactivities, with emphasis to their antileishmanial potential. The present work builds on computational studies focusing on a specific enzyme of the parasite, S-adenosylmethionine decarboxylase (AdoMet DC), with several 1,2,3,4-tetrahydro-acridines emerging as potential inhibitors, evidencing this scaffold as a promising building block for novel antileishmanial pharmaceuticals. Thus, several 1,2,3,4-tetrahydroacridine derivatives have been synthesized, their activity against Leishmania (Leishmania) infantum promastigotes evaluated and a structure–activity relationship (SAR) study was developed based on the results obtained. Even though the majority of the 1,2,3,4-tetrahydroacridines evaluated presented high levels of toxicity, the structural information gathered in this work allowed its application with another scaffold (quinoline), leading to the obtention of N1,N12-bis(7-chloroquinolin-4-yl)dodecane-1,12-diamine (12) as a promising novel antileishmanial agent (IC50 = 0.60 ± 0.11 μM, EC50 = 11.69 ± 3.96 μM and TI = 19.48).

Evolution of the Quinoline Scaffold for the Treatment of Leishmaniasis: A Structural Perspective

“…This fact confirms the anti-folate mechanism of this type of molecules through the inhibition of DHFR-TS and PTR1. In the beginning of 2023, Silva et al developed a series of 1,2,3,4-tetrahydroacridines, based on a virtual screening performed against the enzyme S-adenosylmethionine decarboxylase, and evaluated them against L. infantum promastigotes [68]. From their results, a SAR study was structured and it was possible to verify that the length of the alkyl chain has a significant effect on the compounds' antileishmanial activity, especially in the case of dimers.…”

Drug Discovery Based on Oxygen and Nitrogen (Non-)Heterocyclic Compounds Developed @LAQV–REQUIMTE/Aveiro

“…Leishmaniosis is a major health problem, mainly affecting people from developing countries from the tropics, subtropics, and the Mediterranean basin, with an estimated world prevalence of 12 million cases [86]. Recently, our research group extended its medicinal chemistry efforts to the development of antileishmanial agents based on the 1,2,3,4-tetrahydroacridine scaffold [87]. The approach started with a virtual screening (VS) campaign of natural compounds (99 K) against a specific enzyme of the parasite, the S-adenosylmethionine decarboxylase (AdoMet DC).…”

“…dicinal chemistry efforts to the development of antileishmanial agents based on the 1,2,3,4-tetrahydroacridine scaffold [87]. The approach started with a virtual screening (VS) campaign of natural compounds (99 K) against a specific enzyme of the parasite, the Sadenosylmethionine decarboxylase (AdoMet DC).…”

“…The approach started with a virtual screening (VS) campaign of natural compounds (99 K) against a specific enzyme of the parasite, the Sadenosylmethionine decarboxylase (AdoMet DC). A large number of hit compounds were obtained, and upon the retrosynthetic analysis of their complexity, two tetrahydroacridine templates 71 and 72 were selected for the further preparation of analogues (Figure 40) [87]. A library of forty compounds was screened for its antileishmanial activity against L. infantum promastigotes.…”

“…However, compound 73 showed a high level of cytotoxicity (99.7% at 10 µM), while the quinoline analogue 74 was much less toxic (EC50 = 11.69 ± 3.96 µM), presenting a therapeutic index (TI) of 19.48. This means that the replacement of the tetrahydroacridine for a chloroquinoline surrogate resulted in much lower toxicity levels, not compromising the antileishmanial activity [87]. Bacterial infections are recognized by WHO as one of the top 10 global public health threats due to ever-increasing anti-microbial resistance.…”