Synthesis, Antimicrobial Activities, and Model of Action of Indolyl Derivatives Containing Amino-Guanidinium Moieties
The objectives of the study were to design, synthesize, and evaluate the antibacterial activity of a series of novel aminoguanidine-indole derivatives. Thirty-seven new compounds were effectively synthesized through nucleophilic substitution reaction and guanidinylation reaction. Chemical structures...
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| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-02-01
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| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/4/887 |
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| Summary: | The objectives of the study were to design, synthesize, and evaluate the antibacterial activity of a series of novel aminoguanidine-indole derivatives. Thirty-seven new compounds were effectively synthesized through nucleophilic substitution reaction and guanidinylation reaction. Chemical structures of all the desired compounds were identified by NMR and HR-MS spectroscopy. Most of the synthesized compounds showed significant antibacterial activity against ESKAPE pathogens and clinical resistant <i>Klebsiella pneumoniae</i> (<i>K. pneumoniae</i>) isolates. <i>K. pneumoniae</i> is an important opportunistic pathogen that often threatens the health of immunocompromised people such as the elderly, children, and ICU patients. The most active compound <b>4P</b> showed rapid bactericidal activity against resistant <i>K. pneumoniae</i> 2108 with MIC and MBC values that were 4 and 8 µg/mL, respectively. The hemolytic activity of <b>4P</b> was low, with an HC<sub>50</sub> value of 123.6 µg/mL. Compound <b>4P</b> induced the depolarization of the bacterial membrane and disrupted bacterial membrane integrity and was not prone to antibiotic resistance. The dihydrofolate reductase (DHFR) activity was also notably inhibited by <b>4P</b> in vitro. Molecular docking revealed that the aminoguanidine moiety and indole structure of <b>4P</b> played an important role in binding to the target site of the <i>K. pneumoniae</i> dihydrofolate reductase (DHFR) receptor. In the mouse pneumonia model caused by <i>K. pneumoniae</i>, <b>4P</b> improved the survival rate of mice, reduced bacterial loads, and alleviated tissues’ pathological injuries at a dosage of 4 mg/kg. Therefore, compound <b>4P</b> may be a promising lead compound or drug candidate for antibacterial purposes against <i>K. pneumoniae</i>. |
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| ISSN: | 1420-3049 |