Hybrid Quinolinyl Phosphonates as Heterocyclic Carboxylate Isosteres: Synthesis and Biological Evaluation against Topoisomerase 1B (TOP1B)

Abstract

This work describes, for the first time, the synthesis of dialkyl (2-arylquinolin-8-yl)phosphonate derivatives. The preparation was carried out through a direct and simple process as a multicomponent Povarov reaction of aminophenylphosphonates, aldehydes, and styrenes and subsequent oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or, alternatively, by a cycloaddition reaction between phosphonate aldimines and acetylenes. Based on phosphonate group structural characteristics, considered as phosphorous isosteres of carboxylic heterocycles, they may present interesting biological properties related to cell proliferation. In the current report, a new series of dialkyl (2-arylquinolin-8-yl)phosphonates have been synthesized and their antiproliferative effect evaluated on different human cancer and embryonic cells, as well as on Leishmania infantum parasites, a eukaryotic protist responsible for visceral leishmaniasis. Thereby, the antitumor effect was assessed in human lung adenocarcinoma cells (A549), human ovarian carcinoma cells (SKOV3), and human embryonic kidney cells (HEK293) versus the non-cancerous lung fibroblasts cell line (MRC5). On the other hand, the antileishmanial activity was tested against both stages of L. infantum cell cycle, namely free-living promastigotes and intramacrophage amastigotes, using a primary culture of Balb/c splenocytes to calculate the selectivity index. Besides the antiproliferative and antileishmanial capacities, their behavior as topoisomerase 1B inhibitors has been evaluated as a possible mechanism of action.

Gel-Free Tools for Quick and Simple Screening of Anti-Topoisomerase 1 Compounds

“…To demonstrate that the TB-EAD assay can be used as a drug screening tool for MsTOP1-targeting compounds, the activity of purified MsTOP1 was tested (see Supplementary Figure S2C for protein purification) in the presence of increasing concentrations of novel synthesized compounds, as indicated in Figure 5 A. In the design of methods for the detection and quantification of this enzymatic inhibition, some heterocyclic compounds are key species due to their behavior against this target [ 52 ], as previously published [ 53 , 54 , 55 , 56 ]. Incidentally, it is important to mention that the recently optimized Povarov reaction [ 57 , 58 ] is a very suitable strategy, whose multicomponent version gives access to different families of heterocycles in a simple and fast manner.…”

Miltefosine and Nifuratel Combination: A Promising Therapy for the Treatment of Leishmania donovani Visceral Leishmaniasis

“…To assess the antileishmanial effect of drugs and drug combinations on axenic amastigotes, 40 μL of a suspension containing 3–10 4 iRFP- L. donovani parasites per well were incubated with another 40 μL of serial dilutions (one-half or one-third dilutions) of the drug or drug combinations in the amastigote culture medium. Incubations were performed in 384-well black microtiter plates with an optical bottom at 26 °C for 72 h. A 0.1% ( v / v ) DMSO and 10 μM AMB solution were used as negative and positive controls, respectively [ 68 ].…”

Efficient AntiMycolata Agents by Increasing the Lipophilicity of Known Antibiotics through Multicomponent Reactions

“…Thus, we planned and executed these MCRs, widely used in medicinal chemistry [32], involving the aniline moiety present in both drugs. In particular, we promoted Ugi MCRs with carbonyls (aldehydes and ketones), isocyanides and carboxylic acid partners [33], Povarov MCRs with aldehydes and electron rich olefins [34][35][36], or acetylenes (Figure 1B) [37].…”