1,4-Dihydropyridine as a Promising Scaffold for Novel Antimicrobials Against Helicobacter pylori

Abstract

The increasing occurrence of multidrug-resistant strains of the gastric carcinogenic bacterium Helicobacter pylori threatens the efficacy of current eradication therapies. In a previous work, we found that several 1,4-dihydropyridine (DHP)-based antihypertensive drugs exhibited strong bactericidal activities against H. pylori by targeting the essential response regulator HsrA. To further evaluate the potential of 1,4-DHP as a scaffold for novel antimicrobials against H. pylori, we determined the antibacterial effects of 12 novel DHP derivatives that have previously failed to effectively block L- and T-type calcium channels. Six of these molecules exhibited potent antimicrobial activities (MIC ≤ 8 mg/L) against three different antibiotic-resistant strains of H. pylori, while at least one compound resulted as effective as metronidazole. Such antimicrobial actions appeared to be specific against Epsilonproteobacteria, since no deleterious effects were appreciated on Escherichia coli and Staphylococcus epidermidis. The new bactericidal DHP derivatives targeted the H. pylori regulator HsrA and inhibited its DNA binding activity according to both in vitro and in vivo analyses. Molecular docking predicted a potential druggable binding pocket in HsrA, which could open the door to structure-based design of novel anti-H. pylori drugs.

Design, synthesis, and biological evaluation of 1,4,7,8‐tetrahydro‐5H‐furo[3,4‐b]pyrazolo[4,3‐e]pyridin‐5‐one‐based azo dyes

“…As shown in Table 2, the anticipated products were obtained with a high yield and in a short reaction time (8-10 min). The structure of the prepared compounds was confirmed by Fourier transform infrared spectroscopy (FTIR), 1 H nuclear magnetic resonance (NMR), and 13 C NMR spectroscopy as well as high-resolution mass spectrometry (HRMS). Spectral data are described in the experimental section.…”

“…1,4‐DHPs includes drugs such as amlodipine [6], manidipine [7], and pranidipine [8] which are calcium channel blockers and are used to treat hypertension [9]. Some of the biological activities of 1,4‐DHPs include antiinflammatory [10], antituberculosis [11], antihypertensive [12], antimicrobial [13], cytotoxic [14], and AO [15] activities. Considering these important biological activities, many researchers have been encouraged to synthesize 1,4‐DHP and investigate their medicinal and medical applications.…”

Two-component regulatory systems in Helicobacter pylori and Campylobacter jejuni: Attractive targets for novel antibacterial drugs

“…To date, some investigations have been carried out in order to validate HsrA and ArsR as effective therapeutic targets against H. pylori infection as well as discovering low-molecular weight inhibitors of these RRs exhibiting strong bactericidal activities against antibiotic-resistant strains of this pathogen ( González et al., 2019a ; González et al., 2019b ; González et al., 2020 ; Antoniciello et al., 2022 ; González et al., 2022 ). Notably, some of the novel antibacterial candidates evaluated in these studies, including natural flavonoids and 1,4-dihydropiridines, have shown in vitro antimicrobial activities in the range of those observed with first-line conventional antibiotics ( González et al., 2021 ; González et al., 2022 ).…”

“…To date, some investigations have been carried out in order to validate HsrA and ArsR as effective therapeutic targets against H. pylori infection as well as discovering low-molecular weight inhibitors of these RRs exhibiting strong bactericidal activities against antibiotic-resistant strains of this pathogen ( González et al., 2019a ; González et al., 2019b ; González et al., 2020 ; Antoniciello et al., 2022 ; González et al., 2022 ). Notably, some of the novel antibacterial candidates evaluated in these studies, including natural flavonoids and 1,4-dihydropiridines, have shown in vitro antimicrobial activities in the range of those observed with first-line conventional antibiotics ( González et al., 2021 ; González et al., 2022 ). In some cases, these novel antimicrobial candidates exhibited synergistic effects in combination with conventional antibiotics, leading to reversion of drug-resistant phenotypes ( González et al., 2019b ), but also showed minor antimicrobial actions on representative members of human normal microbiota ( González et al., 2022 ).…”

“…Notably, some of the novel antibacterial candidates evaluated in these studies, including natural flavonoids and 1,4-dihydropiridines, have shown in vitro antimicrobial activities in the range of those observed with first-line conventional antibiotics ( González et al., 2021 ; González et al., 2022 ). In some cases, these novel antimicrobial candidates exhibited synergistic effects in combination with conventional antibiotics, leading to reversion of drug-resistant phenotypes ( González et al., 2019b ), but also showed minor antimicrobial actions on representative members of human normal microbiota ( González et al., 2022 ).…”