Design, synthesis and evaluation of the activity of 4-aminoquinoline derivatives as potential cruzain and rhodesin inhibitors
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Date
2023-10
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Kampala International University
Abstract
In this research work a series of aminoquinolines, potential inhibitors of cruzain was designed, studied in silico by molecular modeling docking methods, synthesized and evaluated in vitro assays. Chagas disease is a neglected disease called America Trypanosomiasis caused by Trypanosoma cruzi and about 8 million people are estimated to be infected worldwide. Trypanosoma cruzi is 70 percent related to Trypanosoma brucei responsible for Human Africa Trypanosomiasis, is a major health problem worldwide. Current drugs used in treatment of both diseases shows high toxicity and low efficacy at chronic stage of the disease. Cruzain (or cruzipain) and TbrCATL is a cathepsin L-like cysteine protease considered the dominant protease of the protozoan Trypanosoma cruzi and Trypanosoma brucei, respectively. These proteases are believed to be involved in the acquisition of nutrients, degradation of host proteins and evasion of the immune system, representing a promising target for developing trypanocidal drugs. A series of potential inhibitors of cruzain was planned based on 7-chloro-4-aminoquinolines 2 and 3 (IC50 = 13.2 μM and 25μM) respectively. The molecular modeling docking results of the studies suggest that designed compounds are possible to be potent. The synthesized series contains a 7-chloro-4-aminoquinolines motif and different side chain lengths were explored. QFF (3) inhibited more than 85% of the activity of both cruzain and TbrCATL, with IC50 value of 23 and 29 μM, respectively. The results of the enzymatic assays without pre-incubation suggest that the compounds are not time dependent inhibitors. However, additional assay is required to exclude the possibility of QFF acting as a promiscuous inhibitor through aggregation. The overall results showed that aminoquinolines is a promising class in further investigation of cruzain and rhodesain inhibition.
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A research project submitted to the School Of Pharmacy, Department of Pharmacology, Kampala International University, Uganda in partial Fulfillment of the Requirement for the Award of Master Of Science in Pharmacology