Antimalarials: construction of chloroquine molecular hybrids

Antimalarials: construction of molecular hybrids based on chloroquine

Antimalarials: Construction of molecular hybrids of chloroquine

Summary

The resistance developed by the Plasmodium falciparum Before traditional drugs of type 4-amino-7-chloroquinolinic has led to the design and synthesis of dual inhibitors, such as chloroquine hybrids. In addition to the typical pharmacophore in this class of antimalarials, such hybrids incorporate a methylene spacer as part of a diaminic fragment, the purpose of which is to functionalize the amino terminal group in diverse heterocyclic systems with reported biological activities. This in order to avoid the rapid and limination of the molecule by the parasite, which is known as resistance. The design and synthesis of these molecular hybrids are discussed.

Keywords: malaria, chloroquine resistance, molecular hybrids, functionalization.

Abstract

The resistance developed by Plasmodium falciparum against traditional 4-amino-7-chloroquinolinic drugs has lead to the design and synthesis of dual inhibitors such as chloroquine hybrids. Besides the usual pharmacophore in this type of antimalarials, such hybrids incorporate a methylenic spacer as part of a diaminic fragment whose purpose is the functionalization of the terminal amino group in various heterocyclic systems having reported biological activities. The prime goal is to avoid the molecule rapid elimination by the parasite, which is known as resistance. The design and synthesis of these molecular hybrids are discussed.

Key words: malaria, chloroquine resistance, molecular hybrids, functionalization.

I summarize

A resistance developed by Plasmodium falciparum hair compared to traditional drugs of type 4-amino-7-chloroquinolinic tem levado ao desenho and synthese de inibidores duais, such as chloroquine hybrids. Além do pharmacóforo typical nesta classe de antimalaricos, tais hybrids incorporates a methylene spaçador as part of a diamond fragment, which purposely feared the functionalization of the amino terminal group in diverse heterocyclic systems with reported biological activities. This is the end of avoiding rapid elimination of the molecule by the parasite, or that it becomes resistance. He discussed or unraveled these molecular hybrids.

Palavras-Chave: malaria, resistance to chloroquine, molecular hybrids, functionalization.

Introduction

Design and synthesis of new antiparasitic agents using a natural product as a prototype are important tasks of medicinal chemistry. One of the most outstanding examples involves the South American indigenous people, who extracted the bark from the trees Cinchona, using the extract to combat chills and fever in the 17th century. In 1633 this herbal medicine was introduced in Europe, where it was given the same use and also against malaria. In 1820 the active component was isolated, later determining that it was quinine (1), the first compound to exhibit significant antimalarial activity. To eliminate its toxic effects, an attempt was made to maintain, synthetically, some of the chemical and structural characteristics of this alkaloid using it as a leading composite, thus producing the synthetic analog, chloroquine (CQ) (2), which was, initially, a excellent treatment for malaria (Figure 1) (Woster, 2001).

Malaria is a disease that can cause death in a few hours, so prevalent that in some areas practically all children have suffered from it during the first year of life. According to the World Health Organization, in its report on malaria in the world 2005, malaria is the cause of death of more than a million people annually and constitutes a risk for 3.2 billion people living in 107 countries and territories . Children under the age of 5 represent by far the majority of deaths. 14% of the population of the Americas lives at risk, but the death rate of this region in the world total is minimal. Colombia is one of the countries with a high incidence of the protozoan Plasmodium falciparum, with 160,000 cases reported in 2003 (World malaria report 2005; Carmona-Fonseca, 2007). Quinine and its simple prototype - CQ, are important and current drugs in the fight against malaria caused by protozoa of the genus Plasmodium (Wiesner et al., 2003). The resistance of this parasite against current antimalarial drugs (especially chloroquine) forces us to identify new alternative compounds and to design dual inhibitors (double drugs) or hybrids, which could inhibit the formation of hemozoin and another different target of this protozoan. Furthermore, new derivatives and hybrids based on the CQ skeleton (7-chloro-4-aminoquinolines) could combat protozoa of various genera, causing parasitic diseases leishmaniasis and American trypanosomiasis (Chagas disease), among others. Working for several years with quinolinic molecules, our laboratory (http://ciencias.uis.edu.co/labqobio) has generated new small libraries of different classes of quinolinic heterocycles, which have good antiparasitic activity (Kouznetsov et al., 2004; Kouznetsov, Rodríguez et al., 2004; Kouznetsov et al., 2006; Kouznetsov et al., 2007). Continuing this activity, in our laboratory the synthetic study towards new and own CQ hybrids began, whose interesting results force us to explore more this promising and important topic in the search for new antimalarial agents (Amado Torres, 2008; Vargas Méndez et al., 2007).

1.1. Life cycle of the malaria parasite Plasmodium falciparum

With the bite of a mosquito Anopheles infected female, sporozoites are transferred to the human blood stream (A) (Figure 2). Sporozoites invade liver cells and begin their asexual division, resulting in the production of several thousand merozoites (B). Merozoites are released from liver cells to infect erythrocytes in the blood stream (C). Once inside erythrocytes, asexual reproduction occurs in 48-hour (D) cycles (Vickerman, 2005). Parasites develop in annular stages, tropozoites, and then in schizons. In the segmentation stage, each schizon is typically divided into 16 erythrocytic merozoites, which are released by erythrocyte lysis and immediately invade new erythrocytes.

Despite its low efficacy and tolerability, quinine still plays an important role in the treatment of multidrug-resistant malaria due to its high solubility and because it can be given intravenously in patients who can no longer tolerate oral medication. The Pamaquina (3) (Figure 3), synthesized in 1925, is an 8-aminoquinoline and one of the first synthetic antimalarials that turned out to be more potent than quinine by eradicating the liver stages of the parasite in humans and the resurgence of malaria by Plasmodium vivax. Mepacrine (4) developed in 1932 (Figure 3), which is active against the blood stages of P. falciparumIt is also known as atebrine or quinacrine and remembered from World War II for the yellow pigmentation it produced on the skin of soldiers (Foley and Tilley, 1998).

1.3. Other antimalarial compounds

Among the most effective active compounds today is sesquiterpene artemisinin (12) (Figure 4), a 1,2,4, -trioxane, the powerful antimalarial component of the ancestral Artemisia annua, used as an herbal remedy in China for fever and more recently for the treatment of P. falciparum multi-resistant. However, its therapeutic value decreases due to its poor solubility; as a consequence several derivatives have been developed. By reduction of artemisinin, dihydroartemisinin (13) is obtained, from which a series of first-generation semi-synthetic derivatives is reached: artemeter (14) and arteter (15) (Figure 4), compounds more powerful than artemisinin but more toxic to the CNS and with a shorter plasma life time, rapidly excreted in the urine (Biagini et al., 2003).

As a new alternative, sodium artesunate (16) and sodium artelinate (17) develop, with less CNS toxicity. These types of molecules represent a new class of antimalarial compounds that are not based on the quinoline structure and that are also active against multi-resistant strains, without any resistance emerging so far, rapidly becoming the drug of choice in most malaria cases in countries where it occurs and becoming the most important antimalarial class currently available (Krishna et al., 2004). It has been established that the peroxide unit of these trioxanes is essential for its potency as an antimalarial. Understanding the mechanism of action and metabolism of artemisinin (12) and semi-synthetic endoperoxides (13-17) (Figure 4) is an essential objective for the development of new antimalarial trioxanes (Posner and O'Neill, 2004).

1.4. Chloroquine analogues

Since the 1940s, CQ analogues (2) have been prepared in the same way and seeking the same goal: to improve antimalarial activity (Carmack et al., 1946). For this purpose, innumerable compound libraries have been developed that have served to enrich knowledge about the factors that affect the biological activity of this type of molecule (Singh et al., 1969. Singh et al., 1971). Also during the course of this new century, synthetic organic chemicals continue to work with CQ analogues (18-21), incorporating novel characteristics in the amino terminal group, in the spacer carbon chain or even, looking for unique alternatives that include the 7-chloroquinolinic nucleus. These variations include analogues that replace diethylamine function with shorter chains with amino groups (Figure 5).

Short chains with alkyl amine groups, secondary and tertiary terminals instead of the isopentylene chain in chloroquine, give it greater elasticity for metabolic purposes. In fact, in rehearsals in vitroThese analogues turned out to be substantially more potent than the drug itself and even inhibited the growth of resistant strains in the nanomolar range, which is a consequence of replacing the diethylamine group with a metabolically inert basic group such as t-butyl, N-piperidinyl or N-pirrolidinyl, showing better results of the compound with t-butyl (18) and a significant reduction in activity, that of the N-morfolinil group (21). The previous analogues (18-21) are synthesized in a single step from materials arranged for this reaction (Figure 6) (Ward et al2002).

Synthetic methods that allow access to substituted amino groups are of great interest for medicinal chemistry, since alkylamine side chains are found in various drugs. A synthetic method has been developed that allows the introduction of two different diversity points in the amino lateral group by indirect and sequential reductive aminations. With commercially available aldehydes and the synthetic route of the figure 7 libraries of 300,000 possible theoretical products can be produced that when "filtered", to remove candidates that have non-organic atoms or reactive substructures or compounds that do not obey Lipinski's "Rule of Five", that is, molecules that are too large or heavy for drug standards, around 850 products are obtained whose retro-synthetic analysis leads to aldehypenders et al., 2004).

In the search for compounds that evade the resistance mechanism used by the parasite, whatever it may be, but that maintain antiplasmodium activity, the existing analogues of CQ (2) such as amodiaquine (5) have been transformed, a base of Mannich, in order to establish the structural characteristics that these antimalarials must have. Mannich-based derivatives replace amodiaquine diethylamine function (5) with an N-t-butylamine group to prevent lateral chain compounds from being metabolized by increasing cross resistance. The synthetic route to reach these replaced rented Mannich bases is diagrammed in the figure 8 begins with the alkylation of a phenol (22) via the formation of compounds (23) and (24), whose hydrolysis and treatment with commercial 4.7-dichloroquinoline, in ethanol, produces molecules (25) with yields of 50 %, with good inhibition results in vitro against CQ resistant strains (Ward et al., 1999).

However, these derivatives, having a hydroxyl in position with respect to the amine group, undergo oxidation by cytochrome P-450 and transform into quinonymines, more chemically reactive molecules. Amodiaquine and its 4'-hydroxylated derivatives oxidize to this class of metabolites (figure 9A), whose in vivo formation and its subsequent link to cellular macromolecules could affect cellular function directly or by immunological mechanisms, producing hepatotoxicity or agranulocytosis. The presence of the hydroxyl group at position 4 'has been shown to impart great antimalarial activity against resistant parasites, compared to their dehydroxylated analogues. The exchange between the hydroxyl group and the Mannich side chain provides a way to prevent oxidation to toxic metabolites, while retaining the interactions of possible important bonds with aromatic hydroxyl (figure 9B) (O'Neill et al., 2003). The isoquine prototype (26), is an amodiaquine regioisomer (5) that cannot form toxic metabolites by simple oxidation and that continues to be active against resistant parasites in vitro.

One of the most promising and successful strategies in the fight against malaria is combination chemotherapy, which uses an artemisinin derivative (12) (figure 4) together with a conventional antimalarial (4-aminoquinoline). Its purpose is to improve efficiency and delay the emergence of resistance. In light of the above observations, together with the resistance generated by analog compounds with dialkylamine-alkyl side chains and metabolically more stable analog compounds, with increased antimalarial activity (product of having lateral chains with basic nitrogen atoms in a piperidine or pyrolidine ring) are synthesized and study 4-aminoquinoline derivatives characterized by the presence of strongly basic and lipophilic (27) (figure 10), such as the quinolizidine ring, which is assumed to be difficult to metabolize (Sparatore et al., 2005). These compounds are prepared by reaction between 4,7-dichloroquinoline with 1-aminoquinolicidine in the presence of phenol (figure 10) and show activity between 5 and 10 times higher than that of CQ in some strains. The characteristic bulky and basic fragment turns out to be interesting.

It has been noted that several analogues containing an intramolecular hydrogen bond in one of its constituent fragments were active against P. falciparum multi-resistant, which has led to the exploration of how important this feature is. For this purpose, a series of 116 compounds were synthesized with four different alkyl groups and several aromatic substituents, with the ability to form hydrogen bonds (figure 11).

CQ is active only against the erythrocytic stages of Plasmodium and certainly only against those stages in which the parasite is actively degrading hemoglobin. Furthermore, it has also been assumed that chloroquine could interfere, in some way, with the parasite's feeding process, leading to its death by starvation. 4-aminoquinolines accumulate in high concentrations within the acidic compartments of the parasite, which is essential for the ability to inhibit its growth. CQ is a weak diprotic base (pKa_one=8.1; pKa₂=10.2), in its non-protoned form, it can cross the membranes of invaded erythrocytes and move with the pH gradient to accumulate in the vacuole (pH ∼ 5.5) of the invader (figure 12), where 4-aminoquinolines are believed to exert their antimalarial action. However, the precise mechanism could not be established but several widely accepted hypotheses could be established (Foley and Tilley, 1997).

CQ accumulates down the pH gradient, such that its accumulation in the parasite is 10,000 times greater than in the red blood cell. As the parasite matures within the invaded erythrocyte, it digests a large amount of hemoglobin (between 25% and 85% of the cell). The hemoglobin (Hb) ingested is transported to the vacuole of the parasite. Once inside it, digestion begins to provide essential nutrients to the invader. Aspartic hemoglobin I initiates hemoglobin degradation while aspartic hemoglobin II binds to denatured hemoglobin, due to the acid medium, giving ferriprotoporphyrin IX (FPIX) and globin. The third enzyme involved is a cysteinprotease (falcipaine) that does not recognize Hb or FPIX, but quickly binds to denatured globin,releasing a number of small peptides and amino acids that are essential for the growth of the parasite. The Plasmodium is unable to continue degrading free FPIX and whatever the reason for its disability, it is clear that non-degraded FPIX is toxic to the parasite, so it has developed a mechanism for its detoxification. For this purpose, it polymerizes free FPIX, forming a crystalline and insoluble substance known as hemozoin (β-hematin) or malarial pigment, a non-covalent coordination complex with the iron of one FPIX coordinating with the carboxyl of another FPIX (O'Neill et al., 1998). Since both amino acid release and detoxification by the FPIX group by polymerization are essential for parasite survival, both processes could be targets for 4-aminoquinoline medications. FPIX is also capable of coordinating with nitrogen bases such as pyridines and quinolines. So 4-aminoquinolines could form complexes with free FPIX by preventing the parasite from polymerizing it to detoxify, in fact, the affinity of chloroquine for the parasite is similar to the affinity of FPIX for chloroquine. This hypothesis was strengthened by verifying that the chloroquine-FPIX complex is even more toxic to the Plasmodiumthan free FPIX. This, added to the high concentration that chloroquine reaches within vacuole, thousands of times higher, compared to its concentration in erythrocytic cells, make the 4-aminoquinolines interesting compounds to explore the reasons that have led to resistance to the chloroquine medication. Several studies have shown that the structure of the complex formed between quinoline and FPIX is given by π interactions and that such structure consists of one quinoline molecule and two FPIX molecules, which are approximated as a sandwich. The toxic fragments of FPIX, by-product in the degradation of Hb, are polymerized in insoluble hemozoin. CQ accumulates within vacuole and is believed to directly inhibit polymerization of the heme group by trapping it,which leads to parasite poisoning given its inability to get rid of FPIX by another method (O'Neill et al., 1998; Foley and Tilley, 1998). If the FPIX group were allowed to accumulate within the vacuole, its concentration would reach 300-500 mM. This group is very toxic because it can generate reactive oxygenated species and induce oxidative stress, leading the parasite to death (figure 13).

The evidences allow us to propose a detailed structure-activity relationship model for CQ as follows: the nucleus of 4-aminoquinoline provides, by itself, a complexing structure of the heme group, but not enough for the inhibition of hemozoin formation; chlorine at position 7 is responsible for inhibition in hemozoin formation but probably has little influence on the strength of association with heme; the aminoalkyl side chain is a requirement for strong antiplasmodic activity, probably helps with accumulation in vacuole and also appears to increase the strength of association with heme in some cases (figure 14) (Egan et al2000).

The hybridization strategy is also used to try to counter resistance in parasites. With it chimerical or hybrid compounds are created that bring together the best of the properties of at least two different molecules, in the case of chloroquine hybrids, it is the 7-chloro-4-aminoquinoline fragment, recognized as crucial for the π-π interactions with the hemo group FPIX within the Plasmodium vacuole, that is, is the pharmacophore of this type of molecule. The other fragment, generally heterocyclic, must also possess some kind of biological activity. In the case of CQ hybrids, the activity is related to counteracting the rapid spread of 4-aminoquinolines since vacuole and, therefore, the decrease in their accumulation within the parasite. Today,synthetic works with this approach intensify. Compound synthesis (29) is an example of them (figure 15) (Chibale et al., 2004).

These amide a-acylamine aminoquinolines are active against strains of P. falciparum sensitive to CQ and against some resistant to CQ. This approach is analogous to conventional combination therapy in which two or more antimalarial drugs (cocktails) are supplied. The same synthetic tactic can be designed in such a way that the final product is focused on multiple targets within the parasite. Thus introducing cyclical variables such as γ- and δ-lactams and trying to decrease the flexibility levels associated with amides (29) as well as their bioavailability (Veber et al2002). The multi-component reaction of diamines, with levulinic acids (m = 1) or 4-acetylbutyric (m = 2) (30) and isonitrils (31) t-butylnitrile or cyclohexylonitrile in methanol generates lactams (32) (figure 16) (Chibale et al., 2006).

Hybrids are also called dual inhibitors or "double drugs," because of their potential to act on multiple targets within the same organism or cell causing the disease. The design and synthesis of hybrids derived from isatin (Chauhan et al., 2005), a privileged natural product on which molecules of greater potential can be built, including 4-aminoquinolines. In these hybrids, ketone and thiosemicarbazone introduced to provide reactive sites (imina, carbothiol), serve as electrophilic warheads and also already have reports of their antiplasmodium activity (Chibale et al., 2005). The hybrids (33) and (34) were prepared as in the figure 17. Thiosemicarbazones (34) showed better activities against three strains of P. falciparum and the potential to inhibit falcipain-2.

For this purpose, 4-aminoquinolin-semicarbazones have turned out to be excellent falcipaine-2 inhibitors when structurally combined with Mannich bases. In the figure 18 these hybrids (36) are prepared from the N^one- (7- chloroquinolin-4-il) -1,2-diaminoethane (Chibale et al2007).

Resistance in parasites has recently been discovered P. falciparum CQ is strongly associated with mutations in a membrane protein in vacuole and as a result of this mutation excessive CQ transport occurs from the site of action in the vacuola out of it. Protein is PfCRT (P. falciparum chloroquine resistance carrier), or CQ resistance transporter of the P. falciparum. Several molecular structures, called reversal agents, are known to inhibit PfCRT. It was proposed that linking a fragment such as CQ to one of these investment agents, to block the removal of CQ from vacuole, could result in a highly effective hybrid against malaria (Figure 19) (Peyton et al., 2006). Investment agents include the antidepressant imipramine, one of the most studied against PfCRT and its derivative, des-N-methylimipramine (37).

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