Novel small molecule inhibitors targeting the “switch region” of bacterial RNAP: Structure-based optimization of a virtual screening hit

Sahner, J. Henning; Groh, Matthias F.; Negri, Matthias; Haupenthal, Jörg; Hartmann, Rolf W.

doi:10.1016/j.ejmech.2013.04.060

Cited by 30 publications

(74 citation statements)

References 32 publications

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“…For the synthesis of derivatives containing a carboxylic acid group in meta or para position to the amino group (39─42), the methyl esters (39b─42b) were gained by reaction of the starting compounds (39c─42c) with thionyl chloride and MeOH under reflux conditions. The other methyl or ethyl esters used were commercially available or were synthesized as described earlier [9]. A coupling reaction of 38b─49b with [1,1'-biphenyl]-4-carbonyl chloride and 50b with [1,1'-biphenyl]-4-sulfonyl chloride was performed in pyridine with catalytic amounts of DMAP at room temperature, in CH 2 Cl 2 with triethylamine at room temperature or in toluene under reflux conditions.…”

Section: Chemistrymentioning

confidence: 99%

Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections

Hinsberger

Jong

Groh

et al. 2014

European Journal of Medicinal Chemistry

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Targeting PqsD is a promising novel approach to disrupt bacterial cell-to-cell-communication in Pseudomonas aeruginosa. In search of selective PqsD inhibitors, two series of benzamidobenzoic acids  one published as RNAP inhibitors and the other as PqsD inhibitors  were investigated for inhibitory activity toward the respective other enzyme. Additionally, novel derivatives were synthesized and biologically evaluated. By this means, the structural features needed for benzamidobenzoic acids to be potent and, most notably, selective PqsD inhibitors were identified. The most interesting compound of this study was the 3-Cl substituted compound 5 which strongly inhibits PqsD (IC 50 6.2 µM) while exhibiting no inhibition of RNAP.

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Section: Chemistrymentioning

confidence: 99%

Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections

Hinsberger

Jong

Groh

et al. 2014

European Journal of Medicinal Chemistry

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“…This indicates that the introduction of an additional chlorine substituent in the 3-position of the phenyl ring leads to a dramatic increase in potency (4 vs 3), which is more pronounced than observed for RNAP inhibition. 21,22 Comparing class II compounds which are highly similar to compounds of class I (the only difference is the position of the S in the thiophene ring) and had shown similar RNAP inhibition, 22 strong differences regarding the inhibition of RT were observed, too. This finding can be attributed to the different binding sites and the slight differences in the molecular properties of the ligands.…”

Section: Chartmentioning

confidence: 99%

“…In the next step, we varied the substituents at the ureido motif of 4 (compounds 9-11, Table 2). While increasing bulkiness and lipophilicity at the ureido motif led to a potent RNAP inhibitory activity (10), 21,22 the RT inhibitory activities observed for compounds 9-11 were surprising. Exchange of the ethyl substituent by a hydrogen (9) as well as by a sterically demanding benzyl substituent (10) reduced activity drastically.…”

Section: Chartmentioning

confidence: 99%

“…Modification of the previous procedures that did not employ TEA in the coupling step 21,22 was necessary to enhance the reaction regioselectivity. Since the utilized anilines in this work are weak nucleophiles, the coupling reaction using p-anisidine for example in absence of TEA afforded a mixture of the amide 42 and the ureidocarboxylic acid 13 in nearly 1:1 ratio as indicated from the 1 H NMR spectrum ( Figure S3).…”

Section: Antiretroviral Activity In Nnrti Resistant Hiv-1 Strainsmentioning

confidence: 99%

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Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors

et al. 2016

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We are concerned with the development of novel anti-infectives with dual antibacterial and antiretroviral activities for MRSA/HIV-1 co-infection. To achieve this goal, we exploited for the first time the mechanistic function similarity between the bacterial RNA polymerase (RNAP) "switch region" and the viral non-nucleoside reverse transcriptase inhibitor (NNRTI) binding site. Starting from our previously discovered RNAP inhibitors, we managed to develop potent RT inhibitors effective against several resistant HIV-1 strains with maintained or enhanced RNAP inhibitory properties following a structure-based design approach. A quantitative structure−activity relationship (QSAR) analysis revealed distinct molecular features necessary for RT inhibition. Furthermore, mode of action (MoA) studies revealed that these compounds inhibit RT noncompetitively, through a new mechanism via closing of the RT clamp. In addition, the novel RNAP/RT inhibitors are characterized by a potent antibacterial activity against S. aureus and in cellulo antiretroviral activity against NNRTI-resistant strains. In HeLa and HEK 293 cells, the compounds showed only marginal cytotoxicity.

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“…Consequently, there is a need to focus on novel promising inhibitors. Recently, interesting peptidic and peptidomimetic (10)(11)(12) as well as nonpeptidic (13)(14)(15)(16)(17)(18) small-molecule RNAP inhibitors have been described. Another example is CBR703 (Fig.…”

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New Insights into the Bacterial RNA Polymerase Inhibitor CBR703 as a Starting Point for Optimization as an Anti-Infective Agent

Zhu

Haupenthal

Groh

et al. 2014

Antimicrob Agents Chemother

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c CBR703 was reported to inhibit bacterial RNA polymerase (RNAP) and biofilm formation, considering it to be a good candidate for further optimization. While synthesized derivatives of CBR703 did not result in more-active RNAP inhibitors, we observed promising antibacterial activities. These again correlated with a significant cytotoxicity toward mammalian cells. Furthermore, we suspect the promising effects on biofilm formation to be artifacts. Consequently, this class of compounds can be considered unattractive as antibacterial agents. Bacterial RNA polymerase (RNAP) is essential for bacterial growth and survival and is thus an attractive target for drug development (1, 2). Along with the recently FDA-approved fidaxomycin (3), the rifamycins, applied as first-line antituberculosis drugs, are the only RNAP inhibitors that are in clinical use (2). However, similarly to other anti-infectives, the use of rifamycins resulted in the occurrence of resistant bacterial strains (1, 4-7), which represents a remarkable threat to public health (8, 9). Consequently, there is a need to focus on novel promising inhibitors. Recently, interesting peptidic and peptidomimetic (10-12) as well as nonpeptidic (13-18) small-molecule RNAP inhibitors have been described. Another example is CBR703 (Fig. 1), whose mechanism of action is reported to be different from that of the rifamycins (19,20). This compound has been identified in a highthroughput screening searching for small-molecule inhibitors of RNAP (19). Two more-potent analogs in that report reveal the potential of optimizing CBR703 by structural enlargement. Furthermore, pursuing the hypothesis that RNAP is of particular importance for bacterial survival in biofilms, Villain-Guillot et al. showed CBR703 to significantly reduce Staphylococcus epidermidis biofilm mass (21). We therefore considered CBR703 to be a promising starting point for drug development. Consequently, we focused on CBR703 to perform systematic modifications on its core structure, aiming to obtain a more appropriate starting point for further structural optimization.Detailed information concerning the materials and methods used in synthesis and biology can be found in the supplemental material.In total, 30 final compounds and 24 intermediates were obtained and tested for Escherichia coli RNAP inhibition and their ability to inhibit the growth of E. coli TolC (see Table S1 to S3 in the supplemental material). According to their structures, the synthesized derivatives can be divided into three groups with modifications in part A, B, or C (Fig. 1). Compounds 1 to 25 (see Scheme S1 in the supplemental material) with introduction of substituents into the aromatic moieties (part A or B) were prepared by condensation of an intermediate amide with hydroxylamine (22, 23). In order to ensure an appropriate coverage of lipophilic and electronic properties, the substituents were chosen rationally from all quadrants of a Craig plot (e.g., Hansch-Fujita versus constant) (24). The results (see Table S1) showed that compound...

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Novel small molecule inhibitors targeting the “switch region” of bacterial RNAP: Structure-based optimization of a virtual screening hit

Cited by 30 publications

References 32 publications

Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections

Benzamidobenzoic acids as potent PqsD inhibitors for the treatment of Pseudomonas aeruginosa infections

Discovery and Structure-Based Optimization of 2-Ureidothiophene-3-carboxylic Acids as Dual Bacterial RNA Polymerase and Viral Reverse Transcriptase Inhibitors

New Insights into the Bacterial RNA Polymerase Inhibitor CBR703 as a Starting Point for Optimization as an Anti-Infective Agent

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