Primaquine and Chloroquine Fumardiamides as Promising Antiplasmodial Agents

Beus Beus,Zorc Zorc,Uzelac Uzelac,Prudêncio Prudêncio,Held Held,Kralj Kralj,Fontinha Fontinha,Rajić Rajić

doi:10.3390/molecules24152812

Beus Beus, Zorc Zorc + Show 6 more

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https://doi.org/10.3390/molecules24152812

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Abstract

This paper describes a continuation of our efforts in the pursuit of novel antiplasmodial agents with optimized properties. Following our previous discovery of biologically potent asymmetric primaquine (PQ) and halogenaniline fumardiamides (1–6), we now report their significant in vitro activity against the hepatic stages of Plasmodium parasites. Furthermore, we successfully prepared chloroquine (CQ) analogue derivatives (11–16) and evaluated their activity against both the hepatic and erythrocytic stages of Plasmodium. Our results have shown that PQ fumardiamides (1–6) exert both higher activity against P. berghei hepatic stages and lower toxicity against human hepatoma cells than the parent drug and CQ derivatives (11–16). The favourable cytotoxicity profile of the most active compounds, 5 and 6, was corroborated by assays performed on human cells (human breast adenocarcinoma (MCF-7) and non-tumour embryonic kidney cells (HEK293T)), even when glucose-6-phosphate dehydrogenase (G6PD) was inhibited. The activity of CQ fumardiamides on P. falciparum erythrocytic stages was higher than that of PQ derivatives, comparable to CQ against CQ-resistant strain PfDd2, but lower than CQ when tested on the CQ-sensitive strain Pf3D7. In addition, both sets of compounds showed favourable drug-like properties. Hence, quinoline fumardiamides could serve as a starting point towards the development of safer and more effective antiplasmodial agents.

Highlights

Despite enormous efforts made by the scientific community, malaria remains a deadly disease, especially among pregnant women and children
Here we evaluated the drug-likeness of CQ derivatives 11–16, by employing the Chemicalize.org software to calculate an array of physicochemical parameters, including the topological polar surface area (TPSA), the number of atoms, molecular weight (MW), the partition coefficient, the H-bond donor (HBD), the H-bond acceptor (HBA), and molecular refractivity (MR) (Table 3) [22]
Our results show that all hybrids 11–16 fall within the Lipinski’s and Gelovani’s rules for prospective small molecular drugs (MW ≤ 500, log P ≤ 5, number of H-bond donors ≤ 5, number of H-bond acceptors ≤ 10, TPSA < 140 Å2, MR within the range of 40 and 130 cm3 /mol, the number of atoms 20–70)

Summary

Introduction

Despite enormous efforts made by the scientific community, malaria remains a deadly disease, especially among pregnant women and children. According to the 2018 World Malaria Report, malaria is responsible for 266,000 deaths of children aged under five years worldwide [1]. In order to achieve the 2020 milestones of the WHO Global Technical Strategy for Malaria 2016–2030, which include a global reduction of at least 40% in malaria incidence and mortality rates, and disease elimination in at least 10 countries, substantial amounts of funding and research are required [2]. Malaria is caused by Plasmodium parasites, which infect their mammalian host upon the bite of an infected female Anopheles mosquito. Injected sporozoites travel to the liver, where they undergo an asymptomatic but obligatory phase of intra-hepatic replication.

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