ABSTRACT
A series of hydroxamates (4a-4l) were prepared from p-aminobenzoic acid to inhibit HDAC8. The idea is to substitute rigid aromatic ring in place of less rigid piperazine ring of hydroxamates reported earlier by our group. It is expected to increase potency retaining the selectivity. Result obtained suggested that the modifications carried out retained the selectivity towards HDAC8 isoform and increasing the potency in very few cases. Increase in potency is also associated with variation in cap aryl region. Two compounds (4f &4l) were found to inhibit HDAC8 at concentrations (IC50) less than 20µM.
Subject(s)
4-Aminobenzoic Acid/chemistry , 4-Aminobenzoic Acid/pharmacology , Histone Deacetylase Inhibitors/chemistry , Histone Deacetylase Inhibitors/pharmacology , Hydroxamic Acids/chemistry , Hydroxamic Acids/pharmacology , Repressor Proteins/antagonists & inhibitors , Crystallography, X-Ray , Drug Design , Histone Deacetylases/chemistry , Histone Deacetylases/metabolism , Humans , Molecular Docking Simulation , Protein Binding , Repressor Proteins/chemistry , Repressor Proteins/metabolism , Structure-Activity RelationshipABSTRACT
Thiosemicarbazones of p-aminobenzoic acid (PABA) were synthesized and tested for their antimicrobial and anticancer activity. Hydroxamate derivatives 4a-4l were found to have better antimicrobial and anticancer activity than their acid counterpart. Compound 4d was found to have good antimicrobial activity against Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, Vibrio cholerae, and Bacillus subtilis with IC(50) value of about 1 µM. Compound 4f showed potent antifungal activity against Candida albicans (IC(50) = 1.29 µM) and compound 4h showed potent anticancer activity (IC(50) = 0.07 µM).
