Synthesis and In Vitro Antiprotozoan Evaluation of 4-/8-Aminoquinoline-based Lactams and Tetrazoles

Matshawandile Tukulula,Stefan Louw,Kelly Chibale,Mathew Njoroge

doi:10.3390/molecules25245941

Abstract

A second generation of 4-aminoquinoline- and 8-aminoquinoline-based tetrazoles and lactams were synthesized via the Staudinger and Ugi multicomponent reactions. These compounds were subsequently evaluated in vitro for their potential antiplasmodium activity against a multidrug-resistant K1 strain and for their antitrypanosomal activity against a cultured T. b. rhodesiense STIB900 strain. Several of these compounds (4a–g) displayed good antiplasmodium activities (IC50 = 0.20–0.62 µM) that were comparable to the reference drugs, while their antitrypanosomal activity was moderate (<20 µM). Compound 4e was 2-fold more active than primaquine and was also the most active (IC50 = 7.01 µM) against T. b. rhodesiense and also exhibited excellent aqueous solubility (>200 µM) at pH 7.

Highlights

Neglected tropical and infectious diseases caused by protozoan organisms such as kinetoplastid and plasmodium parasites pose a great danger to human lives
Key among these protozoan infections are the human African trypanosomiasis (HAT), known as sleeping sickness, caused by two Trypanosoma brucei subspecies (i.e., Trypanosoma brucei rhodesiense (T. b. rhodesiense) and Trypanosoma brucie gambiense (T. brucie gambiense)) and malaria caused by five plasmodium species, with Plasmodium falciparum (P. falciparum) being the most virulent [1,2,3,4]
HAT is fatal if left untreated, and T. b. gambiense accounts for about 95–97% of all cases while T. b. rhodesiense accounts for only 3–5% [5]

Summary

Introduction

Neglected tropical and infectious diseases caused by protozoan organisms such as kinetoplastid and plasmodium parasites pose a great danger to human lives. Key among these protozoan infections are the human African trypanosomiasis (HAT), known as sleeping sickness, caused by two Trypanosoma brucei subspecies In 2018 HAT and malaria had over 229 million reported cases and 405,000 deaths, the majority being attributed to the latter [6,7]. The number of reported cases and deaths have been dropping significantly due, in part, to the World Health Organization (WHO) goals of eliminating both HAT and malaria [8,9].

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Conclusion