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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).

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A pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidin-5-amine antagonist of the A2A adenosine receptor (AR) was functionalized as amine congeners, fluorescent conjugates and a sulfonate, and the A2AAR binding modes were predicted computationally. The optimal n-butyl spacer was incorporated into the following A2AAR-selective (Ki, nM) conjugates: BODIPY630/650 derivative 11 (MRS7396, 24.6) and AlexaFluor488 derivative 12 (MRS7416, 30.3). Flow cytometry of 12 in hA2AAR-expressing HEK-293 cells displayed saturable binding (low nonspecific) and inhibition by known A2AAR antagonists. Water-soluble sulfonate 13 was a highly potent (Ki = 6.2 nM) and selective A2AAR antagonist based on binding and functional assays. Docking and molecular dynamics simulations predicted the regions of interaction of the distal portions of these chain-extended ligands with the A2AAR. The BODIPY630/650 fluorophore of 11 was buried in a hydrophobic interhelical (TM1/TM7) region, while AlexaFluor488 of 12 associated with the hydrophilic extracellular loops. In conclusion, we have identified novel high affinity antagonist probes for A2AAR drug discovery and characterization.