Abstract:
Leishmaniasis is a widespread parasitic disease caused by protozoa of the genus
Leishmania. The control of leishmaniasis remains a problem and it is emerging as an
important opportunistic infection in immuno-compromised patients especially those
infected with HIV. The current treatment use pentavalent antimony as primary therapy,
which must be administered parenterally and requires long duration of therapy. It also
has toxic side effects and variable efficacy with treatment failures being reported in
India and Kenya. The most widely used secondary treatment is amphotericin B which is
highly active but has extensive toxicity complications with the newer formulations being
too expensive for use by the majority of endemic countries. A real need exists for
improved anti-leishmanials as the current chemotherapy is inadequate and expensive.
This study evaluated the physicochemical profiles comprising solubility, ionization
constant (pKa) and partition coefficient (Log P) of parvaquone, buparvaquone, 2-
Hydroxy-1, 4-Naphthoquinone (NQ) and 2-Hydroxy-3- (2-phenylbutyl)-1, 4-
Naphthoquinone (PNQ). Parvaquone and buparvaquone are hydroxynapthoquinones that
were developed for treatment of East coast fever (ECF) in cattle and being tested here
against leishmaniasis. The anti-leishmanial activity of these compounds was also
determined in cell free media and infected macrophages. Aqueous Solubility, pKa and
Log P measurements were done following literature methods of poorly soluble drugs.
Amphotericin B and Pentostam were used as standard drugs in in vitro evaluation of
anti-leishmania activity. The compounds under test exhibited low aqueous solubility as
all were below 65 μg/ml. According to literature most drugs that are orally active have
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aqueous solubility greater than 65 μg/ml but when the solubility is 20 μg/ml or less as
was the case here, the probability of useful oral activity is very low. In cell free and
macrophage assay, buparvaquone displayed the most potent activity while 2- hydroxy-1,
4-Naphthoquinone (NQ) had the least potency among the test drugs. The in vitro activity
of buparvaquone was comparable to standard drugs unlike parvaquone that exhibited
weak activity compared with the positive control. The results further showed that the
mode of action of the test drugs was not through nitric oxide production. In cytotoxicity
assays, buparvaquone had the lowest minimum inhibitory concentration (MIC) among
test drugs and a high selectivity index (SI). The test compound, 2-hydroxy-3- (2-
phenylbutyl)-1, 4- Naphthoquinone (PNQ) had the lowest SI. In conclusion,
buparvaquone exhibited the most favourable physico chemical parameters and in vitro
activity among the test drugs. However, the challenge for oral and topical formulation of
this drug is its poor aqueous solubility which will lead to low bioavailability.
