Photoreactivity of biologically active compounds. XIX: Excited states and free radicals from the antimalarial drug primaquine

The formation and reactivity of excited states and free radicals from primaquine, a drug used in the treatment of malaria, was studied in order to evaluate the primary photochemical reaction mechanisms. The excited primaquine triplet was not detected, but is likely to be formed with a short lifetime (<50 ns) and with a triplet energy <250 kJ/mol as the drug is an efficient quencher of the fenbufen triplet and the biphenyl triplet, and forms 1O21O2 by laser flash photolysis (PQΦΔ=0.025)(PQΦΔ=0.025). Primaquine (PQ) exists as the monocation (PQH+)(PQH+) in aqueous solution at physiological pH. PQH+PQH+ photoionises by a biphotonic process and also forms the monoprotonated cation radical (PQH2+)(PQH2+) by one electron oxidation by HOHO (kq = 6.6 × 109 M−1 s−1) and Br2- (kq = 4.7 × 109 M−1 s−1) at physiological pH, detected as a long-lived transient decaying essentially by a second order process (k2 = 7.4 × 108 M−1 s−1). PQH2+PQH2+ is scavenged by O2, although at a limited rate (kq = 1.0 × 106 M−1 s−1). The reduction potential (E  °) of PQH2+/PQH+PQH2+/PQH+ is < +1015 mV, as measured versus tryptophan (TRP/TRPHTRP/TRPH). Primaquine also forms PQH2+PQH2+ at pH 2.4, by one electron oxidation by Br2- and proton loss (kq = 2.7 × 109 M−1 s−1). The non-protonated cation radical (PQ+PQ+) is formed during one electron oxidation with Br2- at alkaline conditions (kq = 4.2 × 109 M−1 s−1 at pH 10.8). The estimated pKa-value of PQH2+/PQ+PQH2+/PQ+ is pKa ∼ 7–8. Primaquine is not a scavenger of O2- at physiological pH. Thus self-sensitization by O2- is eliminated as a degradation pathway in the photochemical reactions. Impurities in the raw material and photochemical degradation products initiate photosensitized degradation of primaquine in deuterium oxide, prevented by addition of the 1O21O2 quencher sodium azide. Photosensitized degradation by formation of 1O21O2 is thus important for the initial photochemical decomposition of primaquine, which also proceeds by free radical reactions. Formation of PQH2+PQH2+ is expected to play an essential part in the photochemical degradation process in a neutral, aqueous medium.