In this chapter, we discuss the current patents concerning aryl/heteroaryl
thiosemicarbazone derivatives as regard to their activities and properties, including
coordination (chelation) properties. The mode of action of the aryl/heteroaryl
thiosemicarbazone derivatives involves metal coordination with proteins or biological
fluids that have metal ions in their structure. Additionally, these molecules can also
form multiple hydrogen bonds through their (thio) amide and N3 nitrogen that ensure a
strong interaction with the receptor. In some cases, strong π-π interactions can be
observed between the aryl/heteroaryl rings and the tyrosine or other aromatic amino
acids. Special attention is given to pyridyl, bis-pyridyl, benzoylpyridyl and isatin
thiosemicarbazone derivatives that exhibit significant anticancer, antiviral and other
activities in free and in metal complex forms. This key biological role is often related
with their capability to inhibit the enzyme ribonucleotide reductase, similar to what is
observed with potent anticancer drugs such as Triapine ((3-aminopyridine-2-
carboxaldehyde thiosemicarbazone) (3-AP)) and methisazone. Recent studies have
revealed that thiosemicarbazone can also inhibit topoisomerase IIα enzyme.
Thiosemicarbazone derivatives form coordination complex with various metals such as
Zn, Cu, Fe, Co, Ni, Pt, Pd, etc, and these complexes provide better activities than the
free thiosemicarbazones. Recent patents show that the controlled or sustained release
dosage form of the thiosemicarbazone derivatives along with ionizing radiations is used
for the treatment of proliferative diseases (US20110152281, US20110245304,
US20120172217, WO2012079128 and WO2013082661).
Keywords: Benzoylpyridyl, bis-pyridyl, cancer, chelation, copper(II), cytotoxicity,
DNA, hydrogen bonding, iron (II), isatin, MDR, metal complexes, Pglycoprotein,
proliferative diseases, pyridyl, redox, ribonucleotide reductase,
semicarbazone, thiosemicarbazones, topoisomerase, zinc (II).
