Synthesis and Antimicrobial Evaluation of New 1,2,4-Triazolo[1,5-a]pyrimidine-Based Derivatives as Dual Inhibitors of Bacterial DNA Gyrase and DHFR DOI Creative Commons

Lamya H. Al-Wahaibi,

Safwat M. Rabea,

Mohamed A. Mahmoud

et al.

ACS Omega, Journal Year: 2024, Volume and Issue: 9(47), P. 47261 - 47273

Published: Nov. 11, 2024

A series of 1,2,4-triazolo[1,5-a]pyrimidine-based derivatives were developed and prepared by reacting chalcones 8a–p with 3-phenyl-1,2,4-triazole-5-amine (5). The novel compounds analyzed using several spectroscopic techniques, their antimicrobial efficacies against six pathogens (Gram-negative, Gram-positive, fungi) tested. Most the tested exhibited significant activity compared to ciprofloxacin fluconazole. Four (9d, 9n, 9o, 9p) showed promising results. Their minimal inhibitory concentration (MIC) values between 16 102 μM, similar ciprofloxacin's 10–90 μM values. MIC fungal species 15.50 26.30 higher than fluconazole's 11.50–17.50 Compounds 9n in particular, excellent bactericidal activity. most effective antibacterial agents, further evaluated for effects on bacterial DNA gyrase DHFR enzymes as possible molecular targets. results indicated that 9o demonstrated a level when reference drugs trimethoprim. We conducted docking investigate binding mechanism evaluate reactivity intriguing compounds. favorable interactions essential amino acids necessary inhibition E. coli enzymes.

Language: Английский

Small molecule-mediated targeted protein degradation of voltage-gated sodium channels involved in pain DOI Creative Commons
Alexander Chamessian,

Maria A. Payne,

Isabelle R. Gordon

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 22, 2025

The voltage-gated sodium channels (VGSC) NaV1.8 and NaV1.7 (NaVs) have emerged as promising high-value targets for the development of novel, non-addictive analgesics to combat chronic pain epidemic. In recent years, many small molecule inhibitors against these been developed. successful clinical trial VX-548, a NaV1.8-selective inhibitor, has spurred much interest in expanding arsenal subtype-selective channel therapeutics. Toward that end, we sought determine whether NaVs are amenable targeted protein degradation with degraders, namely proteolysis-targeting chimeras (PROTACs) molecular glues. Here, report degron-tagged potently rapidly degraded by degraders harnessing E3 ubiquitin ligases cereblon (CRBN) Von Hippel Lindau (VHL). Using LC/MS analysis, demonstrate PROTAC-mediated proximity between CRBN results ubiquitination on 2 nd intracellular loop, pointing toward potential mechanism action demonstrating ability recognize VGSC neosubstrate. Our foundational findings an important first step realizing immense NaV-targeting degrader pain.

Language: Английский

Citations

1
The Peptide PROTAC Modality: A New Strategy for Drug Discovery DOI Creative Commons
Youmin Zhu, Yu Dai,

Yun-Cai Tian

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(4)

Published: March 24, 2025

ABSTRACT In recent years, proteolysis targeting chimera (PROTAC) technology has made significant progress in the field of drug development. Traditional drugs mainly focus on inhibiting or activating specific proteins, while PROTAC provides new ideas for treating various diseases by inducing degradation target proteins. Especially peptide PROTACs, due to their unique structural and functional characteristics, they have become a hot research topic. This review detailed description key components, mechanisms, design principles elaborates applications skin‐related diseases, oncology, other potential therapeutic fields, analyzes advantages challenges, looks forward future development prospects. The not only opens up paths development, but also solving resistance safety issues faced traditional small‐molecule drugs. Compared with PROTACs such as multitargeting, biodegradability, low toxicity, flexibility design. With deepening continuous maturity technology, are expected one important strategies discovery, providing hope treatment more intractable diseases. Peptide ushering era precision medicine.

Language: Английский

Citations

0
The next frontier in drug discovery: Unveiling the pharmacological potential of proximity inducers DOI

Natalie Holmberg‐Douglas,

Katherine E. Near,

Felix González-López de Turiso

et al.

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Synthesis and Antimicrobial Evaluation of New 1,2,4-Triazolo[1,5-a]pyrimidine-Based Derivatives as Dual Inhibitors of Bacterial DNA Gyrase and DHFR DOI Creative Commons

Lamya H. Al-Wahaibi,

Safwat M. Rabea,

Mohamed A. Mahmoud

et al.

ACS Omega, Journal Year: 2024, Volume and Issue: 9(47), P. 47261 - 47273

Published: Nov. 11, 2024

A series of 1,2,4-triazolo[1,5-a]pyrimidine-based derivatives were developed and prepared by reacting chalcones 8a–p with 3-phenyl-1,2,4-triazole-5-amine (5). The novel compounds analyzed using several spectroscopic techniques, their antimicrobial efficacies against six pathogens (Gram-negative, Gram-positive, fungi) tested. Most the tested exhibited significant activity compared to ciprofloxacin fluconazole. Four (9d, 9n, 9o, 9p) showed promising results. Their minimal inhibitory concentration (MIC) values between 16 102 μM, similar ciprofloxacin's 10–90 μM values. MIC fungal species 15.50 26.30 higher than fluconazole's 11.50–17.50 Compounds 9n in particular, excellent bactericidal activity. most effective antibacterial agents, further evaluated for effects on bacterial DNA gyrase DHFR enzymes as possible molecular targets. results indicated that 9o demonstrated a level when reference drugs trimethoprim. We conducted docking investigate binding mechanism evaluate reactivity intriguing compounds. favorable interactions essential amino acids necessary inhibition E. coli enzymes.

Language: Английский

Citations

0