Synthesis and Antiplasmodial Activity of Novel Bioinspired Imidazolidinedione Derivatives

Abstract

Malaria is an enormous threat to public health, due to the emergence of Plasmodium falciparum resistance to widely-used antimalarials, such as chloroquine (CQ). Current antimalarial drugs are aromatic heterocyclic derivatives, most often containing a basic component with an added alkyl chain in their chemical structure. While these drugs are effective, they have many side effects. This paper presents the synthesis and preliminary physicochemical characterisation of novel bioinspired imidazolidinedione derivatives, where the imidazolidinedione core was linked via the alkylene chain and the basic piperazine component to the bicyclic system. These compounds were tested against the asexual stages of two strains of P. falciparum—the chloroquine-sensitive (D10) and chloroquine-resistant (W2) strains. In parallel, in vitro cytotoxicity was investigated on a human keratinocyte cell line, as well as their hemolytic activity. The results demonstrated that the antiplasmodial effects were stronger against the W2 strain (IC50 between 2424.15–5648.07 ng/mL (4.98–11.95 µM)), compared to the D10 strain (6202.00–9659.70 ng/mL (12.75–19.85 µM)). These molecules were also non-hemolytic to human erythrocytes at a concentration active towards the parasite, but with low toxicity to mammalian cell line. The synthetized derivatives, possessing enhanced antimalarial activity against the CQ-resistant strain of P. falciparum, appear to be interesting antimalarial drug candidates.

On the application of 3d metals for C–H activation toward bioactive compounds: The key step for the synthesis of silver bullets

“…Another biologically active structural motif that can be activated by this catalyst are thioethers, as was well described by Hou and co-workers in 2018 [39]. In this work, the presence of and several alkenes resulted in the successful scandium-C(sp 3 )-H alkylation of methyl thioethers (Scheme 4B), by which different activated internal thioethers were obtained in good yields (Scheme 4C). The transformation facilitates direct access to several sulfur-containing pharmacological compounds that present valuable biological activities, such as anti-HIV ( 9) [51], inhibition of snake venom enzymes (10) [52], or even anti-estrogenic effects (11) [53] (Scheme 4A).…”

“…With regard to C-H activation reactions, Doye's group has dedicated its research to the development of significant titanium-catalyzed amine-directed C-H activation [66,67]. Recently, a good example was reported, in which C(sp 3 )-H hydroaminoalkylation of N-alkylaniline derivatives was achieved [68]. For this process, the authors used a bulky titanium catalyst, by which a desirable regioselectivity could be achieved (Scheme 7B and C).…”

“…Homogeneous and heterogeneous vanadium-based catalysts have been employed to obtain alcohols and carbonyl compounds through oxidation, including VOSO 4 , Na(VO 3 ), VO(acac) 2 , VOX 3 , among others. Obtaining ketones and aldehydes from hydrocarbon compounds through vanadium-mediated activation of C(sp 3 )-H bonds in a benzylic position has been selectively feasible without activating a C(sp 2 )-H bond in the arene moiety. Verma and co-workers [91] have reported the use of VO(acac) 2 immobilized over graphitic carbon nitride (VO@gC 3 N 4 ) under visible light irradiation to perform a photocatalytic C-H activation of arene methides and derivatives.…”

“…The discovery of new biologically active substances represents not only an advance in the chemistry field but also offers innovative chances for pharmacological and biomedical sciences. Every year, several molecules are discovered and studied against different types of diseases, such as cancer [1,2], malaria [3,4], Chagas disease [5,6], HIV [7,8], depression [9,10], amnesia [11], Alzheimer [12], and maybe even in a more recent scenario, COVID-19 [13]. Even though many compounds are found to present activity against these diseases, only a few of them become approved, due to their toxicity or other issues Scheme 1: Schematic overview of transition metals studied in C-H activation processes.…”

Design, Synthesis, and In Vitro Antiproliferative Activity of Hydantoin and Purine Derivatives with the 4-Acetylphenylpiperazinylalkyl Moiety

“…Due to their prevalence in nature, as well as their structural and chemical diversity, hydantoins play an immensely important role in anti-cancer drug discovery. While derivatives of hydantoin are commonly used for clinical treatment of epilepsy and cardiac arrhythmias and were recently identified also as antiplasmodial agents [ 4 ], hydantoins have also been associated with antitumor activities [ 5 , 6 , 7 ]. By way of example, spiromustine ( Figure 1 ), a spirohydantoin mustard, penetrates the blood–brain barrier and localizes in brain tumors [ 5 ].…”