Anthranilamides with quinoline and β-carboline scaffolds: design, synthesis, and biological activity

Abstract

Graphical abstract In the present study, we report the design and synthesis of novel amide-type hybrid molecules based on anthranilic acid and quinoline or β-carboline heterocyclic scaffolds. Three types of biological screenings were performed: (i) in vitro antiproliferative screening against a panel of solid tumor and leukemia cell lines, (ii) antiviral screening against several RNA viruses, and (iii) anti-quorum sensing screening using gram-negative Chromobacterium violaceum as the reporter strain. Antiproliferative screening revealed a high activity of several compounds. Anthranilamides 12 and 13 with chloroquine core and halogenated anthranilic acid were the most active agents toward diverse cancer cell lines such as glioblastoma, pancreatic adenocarcinoma, colorectal carcinoma, lung carcinoma, acute lymphoblastic, acute myeloid, chronic myeloid leukemia, and non-Hodgkin lymphoma, but also against noncancerous cell lines. Boc-protected analogs 2 and 3 showed moderate activities against the tested cancer cells without toxic effects against noncancerous cells. A nonhalogenated quinoline derivative 10 with N -benzylanthranilic acid residue was equally active as 12 and 13 and selective toward tumor cells. Chloroquine and quinoline anthranilamides 10 – 13 exerted pronounced antiviral effect against human coronaviruses 229E and OC43, whereas 12 and 13 against coronavirus OC43 (EC 50 values in low micromolar range; selectivity indices from 4.6 to > 10.4). Anthranilamides 14 and 16 with PQ core inhibited HIV-1 with EC 50 values of 9.3 and 14.1 µM, respectively. Compound 13 displayed significant anti-quorum/biofilm effect against the quorum sensing reporter strain (IC 50 of 3.7 μM) with no apparent bactericidal effect. Supplementary Information The online version contains supplementary material available at 10.1007/s11030-021-10347-8.

Synthesis and Biological Evaluation of New Quinoline and Anthranilic Acid Derivatives as Potential Quorum Sensing Inhibitors

“…The present study is a continuation of our work on anti-QS agents against Gramnegative biofilm-forming pathogens [24]. Here, we report a set of new series of hybrid molecules incorporating the quinoline and anthranilic acid scaffolds (Figure 1).…”

“…Also, the concept of hybridization has been previously employed by various research groups within the subject area [32][33][34]. In this study, the generated hybrid compounds were first pre-screened for their anti-QS/biofilm and bactericidal activities using a Gram-negative Chromobacterium violaceum-based microscale screening platform, which allows compounds with genuine anti-QS activity to be distinguished from those with bactericidal activity in one single experiment [24,[35][36][37][38][39]. C. violaceum is also an opportunistic pathogen capable of causing severe and potentially fatal manifestations in both immunocompromised and non-compromised hosts [40], and, therefore, serves as a suitable reporter for screening therapeutic agents.…”

Food-Grade Bacteria Combat Pathogens by Blocking AHL-Mediated Quorum Sensing and Biofilm Formation

“…Gram-negative Chromobacterium violaceum has shown high promise to screen anti-QS activities that could be used to prevent the biofilm formation of Gram-negative bacterial pathogens harboring an AHL-mediated QS system [17,[25][26][27][28][29][30][31][32][33][34][35]. Interruption of the QS signaling in Gram-negative bacteria can be achieved by (i) preventing the synthesis of AHL molecules or the expression of QS regulon genes by QS inhibitors (QSIs) or by (ii) quorum quenching (QQ) that occurs by inactivating the AHL molecules by hydrolytic enzymes [25,26].…”