3-Hydroxypropanamidines: from antiplasmodial leads to a novel antibacterial scaffold
- 1Ruhr University Bochum, Germany
Abstract
Arylamino alcohols constitute an established class of antimalarial agents. While this class is best known for its potent antiplasmodial activity, selected members, most notably mefloquine, have also been reported to exhibit antibacterial activity. Structurally related 3-hydroxypropanamidines were developed as highly potent antimalarial agents. Here, we explored the antibacterial activity of three 3-hydroxypropanamidines (4 (BLK278), 5 (BLK280), and 6 (TKK088)) against clinically relevant Gram-positive and Gram-negative bacteria and investigated their cytotoxicity, in vitro pharmacokinetic properties, and proteome-based bacterial response to treatment. We observed good antibacterial activity against Staphylococcus aureus, with 6 (TKK088) displaying the highest activity against multidrug-resistant MRSA and VISA strains. 5 (BLK280) demonstrated the greatest spectrum of activity acting also against clinically relevant Gram-negative strains of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella aerogenes, and Shigella sonnei. In cytotoxicity assays with HUVEC and HAOSMC cells, 4 (BLK278) and the previously reported 7 (TKK129) showed the most favourable overall profiles among the investigated 3-hydroxypropanamidines. The selectivity indices for S. aureus were below 2.5 with clear cell-type-dependent differences for all compounds including mefloquine, suggesting that improving antibacterial selectivity is an important objective for further optimization. In vitro pharmacokinetics showed high plasma protein binding and good human microsomal and plasma stability for all three 3-hydroxypropanamidines. Gel-based proteomic responses revealed a strong impact on the bacterial cell envelope. The observed acute proteomic responses reflect pleiotropic effects and are consistent with earlier reports implicating F0F1-ATPase as a potential molecular target of mefloquine in Streptococcus pneumoniae.
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BibTeX
@misc{kaufmann20263hydroxypropanamidines,
title = {{3-Hydroxypropanamidines: from antiplasmodial leads to a novel antibacterial scaffold}},
author = {L.-S. Kaufmann and A. Schultz and N. Wladarz and T. Gangnus and B. Lungerich and T. C. Knaab and A. Haase and L. Joswig and F. Dressler and P. Dietze and R. Benndorf and B. B. Burckhardt and T. Kurz and J. E. Bandow},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.20.752996},
url = {https://www.biorxiv.org/content/10.64898/2026.09.20.752996v1},
note = {CC BY-ND},
}
RIS
TY - UNPB
TI - 3-Hydroxypropanamidines: from antiplasmodial leads to a novel antibacterial scaffold
AU - L.-S. Kaufmann
AU - A. Schultz
AU - N. Wladarz
AU - T. Gangnus
AU - B. Lungerich
AU - T. C. Knaab
AU - A. Haase
AU - L. Joswig
AU - F. Dressler
AU - P. Dietze
AU - R. Benndorf
AU - B. B. Burckhardt
AU - T. Kurz
AU - J. E. Bandow
PY - 2026
DA - 2026/09/20
PB - bioRxiv
DO - 10.64898/2026.09.20.752996
UR - https://www.biorxiv.org/content/10.64898/2026.09.20.752996v1
AB - Arylamino alcohols constitute an established class of antimalarial agents. While this class is best known for its potent antiplasmodial activity, selected members, most notably mefloquine, have also been reported to exhibit antibacterial activity. Structurally related 3-hydroxypropanamidines were developed as highly potent antimalarial agents. Here, we explored the antibacterial activity of three 3-hydroxypropanamidines (4 (BLK278), 5 (BLK280), and 6 (TKK088)) against clinically relevant Gram-positive and Gram-negative bacteria and investigated their cytotoxicity, in vitro pharmacokinetic properties, and proteome-based bacterial response to treatment. We observed good antibacterial activity against Staphylococcus aureus, with 6 (TKK088) displaying the highest activity against multidrug-resistant MRSA and VISA strains. 5 (BLK280) demonstrated the greatest spectrum of activity acting also against clinically relevant Gram-negative strains of Escherichia coli, Acinetobacter baumannii, Klebsiella pneumoniae, Klebsiella aerogenes, and Shigella sonnei. In cytotoxicity assays with HUVEC and HAOSMC cells, 4 (BLK278) and the previously reported 7 (TKK129) showed the most favourable overall profiles among the investigated 3-hydroxypropanamidines. The selectivity indices for S. aureus were below 2.5 with clear cell-type-dependent differences for all compounds including mefloquine, suggesting that improving antibacterial selectivity is an important objective for further optimization. In vitro pharmacokinetics showed high plasma protein binding and good human microsomal and plasma stability for all three 3-hydroxypropanamidines. Gel-based proteomic responses revealed a strong impact on the bacterial cell envelope. The observed acute proteomic responses reflect pleiotropic effects and are consistent with earlier reports implicating F0F1-ATPase as a potential molecular target of mefloquine in Streptococcus pneumoniae.
ER -