**9. Polycyclic antimalarial drugs**

Three antimalarial drugs have polycyclic ring structures in common (**Figure 13**). Doxycycline, a popular tetracycline antibiotic, is the first. The second is halofantrine, and the third is quinacrine [76], a discontinued agent that was used in the South Pacific.

#### **9.1 Halofantrine**

The Walter Reed Army Institute of Research [77] developed halofantrine in the 1960s and 1970s. It is a phenanthrene-type compound that is structurally distinct from all other antimalarial drugs. The trifluromethyl moiety [78] is an excellent example of drug design that integrates bioisosteric concepts. Halofantrine is a synthetic antimalarial that functions as a blood schizonticide but has no effect on

**Figure 12.** *Structures of ART derivatives.*

the sporozoite, gametocyte, or hepatic stages of the parasite. It works against *P. falciparum* malaria that is immune to several drugs (including mefloquine).

The mechanism of action of halfantrine against the parasite is unknown. It tends to prevent heme molecules from polymerising (by the parasite enzyme "heme polymerase"), allowing the parasite to become infected by its own waste. CYP3A4 converts halofantrine to N-desbutyl-halofantrine, which is excreted primarily in the *Molecular Approaches for Malaria Therapy DOI: http://dx.doi.org/10.5772/intechopen.98396*

**Figure 13.**

faeces; both the parent compound and the N-desbutyl metabolite are involved in vitro.

Halofantrine is usually well tolerated, but consistent absorption requires that it be taken with a fatty meal. Halofantrine has been shown to block open and inactivated HERG channels preferentially, disrupting nerve conduction in cardiac tissue and inducing cardiotoxicity. Cardiac arrhythmias are the most dangerous side effect: halofantrine induces severe QT prolongation [79], which is seen even at normal doses.

#### **9.2 Doxycycline**

Doxycycline is a tetracycline derived from oxytetracycline that inhibits pathogen protein synthesis by reversibly inhibiting the 30S ribosomal subunit, preventing the 50s and 30s units from bonding. Since the ribosomal subunits of bacteria and Plasmodium differ significantly from mammalian ribosomes, this class of antibiotics does not readily bind to mammalian ribosomes and therefore has good selective toxicity [80].

Antimalarial doxycycline is mainly used for prophylaxis against *P. falciparum* strains immune to chloroquine and sulfadoxine–pyrimethamine. During malaria exposure, 100 mg (adult dose) of doxycycline should be given every day as prophylactic therapy. It can also be used in conjunction with quinine to treat resistant *P. falciparum* infections, although it has a slow onset of action in acute malaria and should not be used alone [81]. When treating acute cases, 100 mg of doxycycline per day for seven days should be given in accordance with quinine.

Doxycycline is well absorbed when taken orally (90–100% when fasting; decreased by 20% when taken with food or milk) and excreted partially in the faeces and partially in the urine. Since tetracyclines chelate calcium, they can

*Structures of some representative polycyclic antimalarial compounds.*

interfere with the growth of permanent teeth in children. Doxycycline should only be used in children for a limited period. Tetracycline also increased photosensitivity, which is important because areas where malaria is endemic also have the most sunlight [82].
