Synthesis and anti-tubercular activity of N²-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides

Abstract

Tuberculosis has remained a challenge for medicinal chemists worldwide. In the framework of a collaborative program to identify and evaluate novel antitubercular candidate compounds, the biological properties of benzo[g]isoquinoline-5,10-diones have been found to be very promising. In this paper we have further expanded the library by incorporation of an amidinium moiety into the benzo[g]isoquinoline-5,10-dione scaffold. The presence of this functional group also increased the solubility of the quinones in polar solvents. To this purpose N(2)-arylbenzo[g]isoquinoline-5,10-dione-3-iminium bromides were synthesized in a straightforward way by means of a reaction of anilines with 2-(bromomethyl)-3-(cyanomethyl)-1,4-dimethoxynaphthalene. Following the biological evaluation, N(2)-(4-chlorophenyl)-5,10-dioxobenzo[g]isoquinoline-3(2H)-iminium bromide (MIC = 1.16 μM, CC50 = 28.51 μM, SI = 24.58) was selected as the most promising representative. Apart from the nano-molar anti-mycobacterial activity, the compound was able to target intracellular residing Mycobacterium tuberculosis and the susceptibility of a multi-drug-resistant strain towards the compound was confirmed.

Synthesis and antitubercular activity of 1- and 3-substituted benzo[g]isoquinoline-5,10-diones

“…As shown in antitubercular activity in comparison to their structural analogs 4. 8 In case of the diarylated analogs 30a and 30b, antitubercular activity again abolished completely (MIC > 64 µM). Finally, possible genotoxicity of the analogs and their potential metabolites was investigated using a Vitotox TM assay.…”

“…It is believed that the "out of plane" nature of these compounds contribute to a lower cytotoxity than their corresponding unsaturated analogs 7 . In our last publication 8 we have explored the effects of incorporating an amidine functional group into the C-ring (Figure 1) of the benzo[g]isoquinoline-5,10-dione core on solubility in polar solvents and the activity against Mtb. Improved solubility and nano-molar anti-mycobacterial activity of these compounds 4 proves the merit of core structure 5 as a template towards new antibiotics, notably for antitubercular compounds.…”

Antimalarial Properties of Isoquinoline Derivative fromStreptomyces hygroscopicussubsp. Hygroscopicus: An In Silico Approach

“…Cellular location of isoquinoline is in the cytoplasm [46]. Isoquinoline and its derivatives have been widely used as therapeutic agents for atherosclerosis therapy [47] and antibacterial [48], antituberculosis [49], anticancer [50], and antimalarial [51,52] agents, and others.…”

Quinoline Derivatives with Potential Activity Against Multidrug‐resistant Tuberculosis

“…From the biological evaluation, it can be concluded that the N 2 ‐arylbenzo [ g ]isoquinoline‐5,10‐dione‐3‐iminium bromides 9a – j (Fig. ) were much more active against MTB H37Rv than their dimethoxylated precursors 10a – j , and some of them were selected for further evaluation for their susceptibility against MDR‐TB and intracellular replicating MTB strains . The SAR revealed that derivatives bearing a halogen substituent on the phenyl ring showed an improved selectivity index compared with the derivatives with alternative substituents.…”