Synthesis and biological evaluation of antiparasitic Cysteine protease inhibitors based on the Isatin Scaffold

Widespread drug resistance, loss of efficacy and toxicity has limited the full utilization of the current available drugs against malaria and other parasitic diseases. This necessitates the development of new drugs. Meanwhile, the cysteine protease family of enzymes has been identified as potential targets for new modes of chemotherapy due to the numerous critical roles they play in the disease-causing agents. In this project, a non-peptidic and low molecular weight isatin (indole-2, 3-dione) possessing a wide range of pharmacological properties was used as a scaffold to which different moeities were appended. Potential inhibitors of parasitic cysteine proteases and three strains of P. falciparum were identified from synthesized libraries of compounds. Various N-substituted isatin derivatives were synthesized by KF/Ah03-mediated reaction of isatins with an alkyl, acyl or sulfonyl halide. A series of isatin-3-thiosemicarbazones were prepared by condensation of isatin I substituted isatins with thiosemicarbazide, and also a series of isatin-based Schiff and Mannich bases were prepared by reacting selected isatin-3-thiosemicarbazones with formaldehyde and appropriate secondary amines. To compare the effects of replacing the Mannich bases, a similar series of aminoquinolineethylene isatin-based derivatives were then synthesized. The synthesis was accomplished by condensation of quinoline-ethylene ketone forms with thiosemicarbazide. All synthesized compound were obtained in reasonable to excellent yields and characterized by spectroscopic and analytical techniques.

Grantor dc:publisher.institution

Department of Chemistry

Year dc:date.issued

2004

Author dc:creator

• Chiyanzu, Idan

Advisor dc:contributor.advisor

• Chibale, Kelly

Language dc:language.iso

eng

Handle dc:identifier.uri

http://hdl.handle.net/11427/6300

OAI identifier oai:identifier

oai:open.uct.ac.za:11427/6300