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Abstract <p><b>Objective:</b> The growing threat of bacterial resistance to antiseptics, along with the concerning toxicity profile of conventional quaternary ammonium compounds (QACs), underscores the critical need for new, safer antimicrobial agents. <b>Methods:</b> The compound design was based on the “soft drug” concept, where hydrophobic fragments are linked to the cationic center <i>via</i> biodegradable amide, ester, and acetal bonds. Antibacterial activity was evaluated <i>in vitro</i> against Gram-positive and Gram-negative bacteria, including clinical isolates. Cytotoxicity was assessed on normal human cells (MSC, CHL, HSF) and tumor (PC-3, MCF-7) cell lines. The <i>c</i>log<i>P</i> values, selectivity index (SI) for tumor cells, and acute toxicity (LD<sub>50</sub>) upon intragastric administration in mice were determined. <b>Results and Discussion:</b> Several of the synthesized methylpyridinium salts exhibited antibacterial activity comparable to commercial antiseptics (benzalkonium chloride, miramistin, and chlorhexidine) against both Gram-positive and Gram-negative bacterial strains, including clinical isolates. Methylpyridinium salts with an amide linker were found to be more active than ester derivatives. However, one ester-based compound exhibited antibacterial activity comparable to commercial antiseptics while possessing significantly lower cytotoxicity (with IC<sub>50</sub> values 15–20 times higher than those of chlorhexidine and miramistin). <i>In vivo</i> acute toxicity studies in mice (intragastric administration) confirmed its safety (LD<sub>50</sub> &gt;2000 mg/kg). The study of antitumor activity showed that some methylpyridinium salts were effective against PC-3 and MCF-7 tumor cell lines. However, the antitumor effect of most compounds was determined by high cytotoxicity. An exception was one amide derivative, which exhibited both potent antitumor activity and acceptable safety toward normal cells (selectivity index, SI = 7–15). <b>Conclusions:</b> These findings suggest that methylpyridinium salts derived from pyridoxine represent a promising platform for developing novel antiseptic agents with high antibacterial efficacy and low toxicity. The obtained results confirm the effectiveness of the “soft drug” concept in the design of safe antimicrobial agents.</p>

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Pyridoxine-Based Methylpyridinium Salts: Synthesis and Biological Activity

  • 期刊论文

  • 发表日期：

    2026年2月24日

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  • M. A. Belova,
  • A. D. Strelnik,
  • N. V. Shtyrlin,
  • S. V. Sapozhnikov,
  • S. A. Ivanov,
  • M. N. Agafonova,
  • D. V. Ivanova,
  • E. S. Bulatova,
  • D. Yu. Grishaev,
  • Yu. V. Badeev,
  • O. I. Gnezdilov,
  • O. V. Bondar,
  • O. S. Vasilieva,
  • M. N. Mansurova,
  • Yu. G. Shtyrlin

摘要

Abstract

Objective: The growing threat of bacterial resistance to antiseptics, along with the concerning toxicity profile of conventional quaternary ammonium compounds (QACs), underscores the critical need for new, safer antimicrobial agents. Methods: The compound design was based on the “soft drug” concept, where hydrophobic fragments are linked to the cationic center via biodegradable amide, ester, and acetal bonds. Antibacterial activity was evaluated in vitro against Gram-positive and Gram-negative bacteria, including clinical isolates. Cytotoxicity was assessed on normal human cells (MSC, CHL, HSF) and tumor (PC-3, MCF-7) cell lines. The clogP values, selectivity index (SI) for tumor cells, and acute toxicity (LD50) upon intragastric administration in mice were determined. Results and Discussion: Several of the synthesized methylpyridinium salts exhibited antibacterial activity comparable to commercial antiseptics (benzalkonium chloride, miramistin, and chlorhexidine) against both Gram-positive and Gram-negative bacterial strains, including clinical isolates. Methylpyridinium salts with an amide linker were found to be more active than ester derivatives. However, one ester-based compound exhibited antibacterial activity comparable to commercial antiseptics while possessing significantly lower cytotoxicity (with IC50 values 15–20 times higher than those of chlorhexidine and miramistin). In vivo acute toxicity studies in mice (intragastric administration) confirmed its safety (LD50 >2000 mg/kg). The study of antitumor activity showed that some methylpyridinium salts were effective against PC-3 and MCF-7 tumor cell lines. However, the antitumor effect of most compounds was determined by high cytotoxicity. An exception was one amide derivative, which exhibited both potent antitumor activity and acceptable safety toward normal cells (selectivity index, SI = 7–15). Conclusions: These findings suggest that methylpyridinium salts derived from pyridoxine represent a promising platform for developing novel antiseptic agents with high antibacterial efficacy and low toxicity. The obtained results confirm the effectiveness of the “soft drug” concept in the design of safe antimicrobial agents.