Further structure-activity relationship (SAR) studies on the recently identified pyrido[1,2-a]benzimidazole (PBI) antimalarials have led to the identification of potent, metabolically stable compounds with improved in vivo oral efficacy in the P. berghei mouse model and additional activity against parasite liver and gametocyte stages, making them potential candidates for preclinical development. Inhibition of hemozoin formation possibly contributes to the mechanism of action.

As artemisinin combination therapies (ACTs) are compromised by resistance, we are evaluating triple combination therapies (TACTs) comprising an amino-artemisinin, a redox drug and third drug with different mode of action. Thus, here we briefly review efficacy data on artemisone, artemiside, other amino-artemisinins and 11-aza-artemisinin, and conduct ADME profiling in vitro and PK profiling in vivo via iv and po administration to mice. The sulfamide derivative has a notably long murine microsomal half-life ( t 1/2 >150 min), low intrinsic liver clearance and total plasma clearance rates ( CL int 189.4, CL tot 32.2 mL/min/kg), and high relative bioavailability (F 59%). Kinetics are somewhat similar for 11-aza-artemisinin ( t 1/2 >150 min, CL int 576.9, CL tot 75.0 mL/min/kg), although bioavailability is lower (F 14%). In contrast, artemether is rapidly metabolized to DHA ( t 1/2 17.4 min) and eliminated ( CL int 855.0, CL tot 119.7 mL/min/kg), and has low oral bioavailability F of 2%. Whilst artemisone displays low t 1/2 of <10 min and high CL int of 302.1, it displays a low CL tot of 42.3 mL/min/kg, and moderate bioavailability F of 32%. Its active metabolite M1 displays a much improved t 1/2 of >150 min and a reduced CL int of 37.4 mL/min/kg. Artemiside has t 1/2 12.4 min and CL int 673.9 and CL tot 129.7 mL/kg/min, likely a reflection of its surprisingly rapid metabolism to artemisone, reported here for the first time. DHA is not formed from any amino-artemisinin. Overall, the efficacy and PK data strongly support the development of selected amino-artemisinins as components of new TACTs.

The emergence of Plasmodium falciparum (Pf) parasite strains tolerant of the artemisinin component and resistant to the other drug component in artemisinin combination therapies (ACTs) used for treatment now markedly complicates malaria control. Thus, development of new combination therapies are urgently required. For the non-artemisinin component, the quinolone ester decoquinate (DQ) that possesses potent activities against blood stage Pf and acts on a distinct target, namely the Pf cytochrome bc1 complex, was first considered. However, DQ has poor drug properties including high lipophilicity and exceedingly poor aqueous solubility (0.06 μg/ml), rendering it difficult to administer. Thus, DQ was chemically modified to provide the secondary amide derivative RMB005 and the quinoline O-carbamate derivatives RMB059 and RMB060. The last possesses sub-nanomolar activities against multidrug resistant blood stages of Pf, and P. berghei sporozoite liver stages. Here we present the results of ADME analyses in vitro and pharmacokinetic analyses using C57BL/6 mice. The amide RMB005 had a maximum mean whole blood concentration of 0.49 ± 0.02 µM following oral administration; however, the area under the curve (AUC), elimination half-life (t1/2) and bioavailability (BA) were not significantly better than those of DQ. Surprisingly, the quinoline O-carbamates which can be recrystallized without decomposition were rapidly converted into DQ in human plasma and blood samples. The maximum concentrations of DQ reached after oral administration of RMB059 and RMB060 were 0.23 ± 0.05 and 0.11 ± 0.01 µM, the DQ elimination half-lives were 4.79 ± 1.66 and 4.66 ± 1.16 h, and the DQ clearance were 19.40 ± 3.14 and 21.50 ± 3.38 respectively. Under these assay conditions, the BA of DQ could not be calculated Overall although RMB059 and -060 are labile in physiological medium with respect to the DQ parent, the potential to apply these as prodrugs is apparent from the current data coupled with their ease of preparation.

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