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