New thiophene–acridine compounds: Synthesis, antileishmanial activity, DNA binding, chemometric, and molecular docking studies

Abstract

In this study, we synthesized eight new compounds containing the 2-amino-cycloalkyl[b]thiophene and acridine moieties (ACT and ACS -ACS ). None tested compounds presented human erythrocyte cytotoxicity. The new compounds presented antipromastigote activity, where ACS and ACS derivatives presented significant antileishmanial activity, with better performance than the reference drugs (tri and pentavalent antimonials), with respective IC values of 9.60 ± 3.19 and 10.95 ± 3.96 μm. Additionally, these two derivatives were effective against antimony-resistant Leishmania (Leishmania) amazonensis strains. In addition, binding and fragmentation DNA assays were performed. It was observed that the antileishmanial activity of ACS is not associated with DNA fragmentation of the promastigote forms. However, it interacted with DNA with a binding constant of 10 m . In partial least-squares studies, it was observed that the most active compounds (ACS and ACS ) showed lower values of amphiphilic moment descriptor, but there was a correlation between the lipophilicity of the molecules and antileishmanial activity. Furthermore, the docking molecular studies showed interactions between thiophene-acridine derivatives and the active site of pyruvate kinase enzyme with the major contribution of asparagine 152 residue for the interaction with thiophene moiety. Thus, the results suggested that the new thiophene-acridine derivatives are promising molecules as potential drug candidates.

Bioprospecting of Nitrogenous Heterocyclic Scaffolds with Potential Action for Neglected Parasitosis: A Review

“…Based on the structure of mepacrine, two series of novel thiophene-acridine derivatives were Additionally, spectroscopic techniques revealed DNA intercalation as a mechanism of action executed by these molecules due to its binding constant of 10 4 M -1 . The results suggested these compounds are promising as potential drug candidates [193]. bearing bioactive scaffolds, in which the acridine nucleus was included.…”

“…The mechanism of action performed by acridine compounds with antiparasitic activity has been mostly related to their ability to intercalate between the bases of DNA [192][193][194]. This mechanism of action is well-known to acridine compounds with chemotherapeutic action, considering the structure of the nucleus, which characterized as polyaromatic and planar, with a positively charged heteroatom inserted into the ring system, which assists in relocating the molecule to the center of the DNA [195,196].…”

Advances in the Synthesis of Benzo‐Fused Spiro Nitrogen Heterocycles: New Approaches and Modification of Old Strategies

“…Benzo‐fused heterocycles with a structure of quinoline, quinoxaline, acridine or indenoquinoxaline are found in both synthetic and natural biologically active compounds, which are of great interest to a large number of researchers [268–272] …”

Toxicity and Antitumor Activity of a Thiophene–Acridine Hybrid

“…ACS03 was provided by Dr. Ricardo Olimpio de Moura from the Laboratory of Synthesis and Vectorization of Molecules (LSVM) of the State University of Paraíba (UEPB), João Pessoa, Brazil, and it was synthesized as described previously [16]. For in vitro assays, ACS03 was dissolved in 100% DMSO and added to the culture medium at a final concentration of 0.5%.…”

“…This compound showed antileishmanial activity and no cytotoxicity against erythrocytes. Additionally, other hybrid thiophene-acridine compounds have been characterized with the ability to interact with Leishmania DNA [16]. Then, considering the pharmacological potential of acridine and thiophene compounds, the present study aimed to investigate the toxicity and antitumor effect of the hybrid ACS03 on in vitro and in vivo models.…”