Rhodanine Conjugate 2017

Antimicrobial Rhodanine-3-Acetic Acid Derivatives

Abstract

 

 

Twenty-four 2-(4-oxo-2-thioxothiazolidin-3-yl)acetic acid

 (rhodanine-3-acetic acid)-based amides, esters
and 5-arylalkylidene derivatives were synthesized,
characterized and evaluated as potential antimicrobial agents
against a panel of bacteria, mycobacteria and fungi.


All of the derivatives were active against mycobacteria.
N-(4-Chlorophenyl)-2-[5-(2-hydroxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl]acetamide
demonstrated the highest activity against Mycobacterium tuberculosis
with minimum inhibitory concentrations (MIC) of 8–16 μM.


Non-tuberculous mycobacteria were the most susceptible to 2-[5-(2-hydroxybenzylidene)-4-oxo-2-thioxothiazolidin-3-yl]
acetic acids (MIC values ⩾32 μM).


The highest antibacterial activity against Gram-positive bacteria
 including methicillin-resistant Staphylococcus aureus exhibited 4-(trifluoromethyl)phenyl 2-(4-oxo-2-thioxothiazolidin-3-yl)acetate (MIC ⩾ 15.62 μM).


Several structure-activity relationships were identified.


The activity against Gram-negative and fungal pathogens was marginal.

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Graphical abstract

Keywords

• Amides;
• Antibacterial activity;
• Antifungal activity;
• Antimycobacterial activity;
• Condensation;
• Esters;
• In vitro activity;
• 2-(4-Oxo-2-thioxothiazolidin-3-yl)acetic acid;
• Rhodanine

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Abstract

Hepatitis C virus (HCV) NS5B polymerase is a key target for anti-HCV therapeutics development.

Herein, we report the synthesis and in vitro evaluation of anti-NS5B polymerase activity of a molecular hybrid of our previously reported lead compounds 1 (IC₅₀ = 7.7 μM) and 2 (IC₅₀ = 10.6 μM) as represented by hybrid compound 27 (IC₅₀ = 6.7 μM).


We have explored the optimal substituents on the terminal phenyl ring of the 3-phenoxybenzylidene moiety in 27, by generating a set of six analogs. This resulted in the identification of compound 34 with an IC₅₀ of 2.6 μM.



To probe the role of stereochemistry towards the observed biological activity, we synthesized and evaluated the d-isomers 41 (IC₅₀ = 19.3 μM) and 45 (IC₅₀ = 5.4 μM) as enantiomers of the l-isomers 27 and 34, respectively.



The binding site of compounds 32 and 34 was mapped to palm pocket-I (PP-I) of NS5B. The docking models of 34 and 45 within the PP-I of NS5B were investigated to envisage the molecular mechanism of inhibition.

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Graphical abstract

Keywords

• l-Phenylalanine;
• d-Phenylalanine;
• Rhodanine;
• Knoevenagel condensation;
• Ullmann condensation;
• HCV NS5B polymerase

 

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