Positive Charge in an Antimalarial Compound Unlocks Broad-Spectrum Antibacterial Activity.

Area of Science:

• Medicinal Chemistry
• Drug Discovery
• Antimicrobial Research

Background:

• Developing drugs against Gram-negative bacteria (GNB) is challenging due to difficulties in penetrating their cell envelope.
• The eNTRy rules (ionizable Nitrogen, low three-dimensionality, Rigidity) offer structural guidelines to enhance GNB accumulation.
• Existing antimalarial compounds can be modified to target bacterial pathogens.

Purpose of the Study:

• To synthesize and evaluate eNTRy-rule-compliant compounds for broad-spectrum antimicrobial activity.
• To investigate the impact of ionizable nitrogen introduction on antibacterial and antimalarial efficacy.
• To validate the eNTRy rules as a strategy for developing novel antibacterial agents.

Main Methods:

• Synthesized a library of pyrazole-amide derivatives incorporating amines and guanidines to comply with eNTRy rules.
• Conducted phenotypic screening against a panel of pathogens including Gram-negative bacteria, Gram-positive bacteria, *Mycobacterium tuberculosis*, and *Plasmodium falciparum*.
• Compared the activity of eNTRy-rule-compliant compounds with noncompliant analogs.

Main Results:

• eNTRy-rule-compliant compounds exhibited broad-spectrum activity against Gram-negative and Gram-positive bacteria, *M. tuberculosis*, and *P. falciparum*.
• Activity against *P. falciparum* was enhanced to the double-digit nanomolar range.
• Compliant compounds showed significant growth inhibition (micromolar range) of tested bacteria, while noncompliant compounds were inactive.
• The pyrazole-amide class demonstrated adherence to the eNTRy rules, supporting their utility.

Conclusions:

• The introduction of ionizable nitrogen atoms according to eNTRy rules is an effective strategy for developing broad-spectrum antibacterial agents.
• This approach enhances activity against challenging pathogens like Gram-negative bacteria and *M. tuberculosis*.
• The findings support and extend the applicability of the eNTRy rules in drug discovery for infectious diseases.