Enantioselective Synthesis and Profiling of Potent, Nonlinear Analogues of Antimalarial Tetraoxanes E209 and N205

Abstract

Synthetic endoperoxide antimalarials, such as 1,2,4-trioxolanes and 1,2,4,5-tetraoxanes, are promising successors for current front-line antimalarials, semisynthetic artemisinin derivatives. However, limited solubility of second-generation analogues in biological-relevant media represents a barrier in clinical development. We present methodology for the synthesis of nonlinear analogues of second-generation tetraoxane antimalarials E209 and N205 to investigate reduced molecular symmetry on in vitro antimalarial activity and physicochemical properties. While maintaining good antimalarial activity and metabolic stability, head-to-head comparison of linear and nonlinear counterparts showed up to 10-fold improvement in FaSSIF solubility for three of the four analogues studied. Pharmacokinetic studies in rats comparing a selected nonlinear analogue 14a and its parent N205 showed improvement on oral absorption and exposure in vivo with more than double the AUC and a significant increase in oral bioavailability (76% versus 41%). These findings provide support for further in vivo efficacy studies in preclinical animal species.

Synthesis, Structure and Antileishmanial Evaluation of Endoperoxide–Pyrazole Hybrids

“…Calculated intrinsic aqueous solubility (ClogS) values show similar values between trioxolanes (1.20–1.38) and tetraoxanes (1.18–1.21). However, the poor solubility of dispiro 4′’-substituted tetraoxanes may be associated to their structural symmetry [ 35 ]. A decrease in molecular symmetry has been correlated to better physicochemical properties, such as absorption and solubility, resulting in enhanced systemic exposure to a drug.…”

“…A decrease in molecular symmetry has been correlated to better physicochemical properties, such as absorption and solubility, resulting in enhanced systemic exposure to a drug. So it is anticipated that 3′’-substituted analogues could overcome this solubility issue [ 35 , 36 ]. Therefore, future optimization to 3”-substituted analogues should be considered.…”

Artefenomel Regioisomer RLA-3107 Is a Promising Lead for the Discovery of Next-Generation Endoperoxide Antimalarials

“…is typical) affording the desired cis -R 4 or trans -R 3 diastereomers in reactions of C4- or C3-substituted cyclohexanones, respectively . Full stereocontrol can thus be achieved by employing enantiomerically pure cyclohexanone substrates, as demonstrated in our enantioselective synthesis of arterolane-like trans -R 3 amide and carbamate analogs, and in O’Neill’s synthesis of desymmetrized tetraoxanes …”

“…More recently, O’Neill and co-workers described desymmetrized analogs of the tetraoxane antimalarials E209 and E205, which bear an artefenomel-like side chain. The desymmetrized analogs in general exhibited markedly lower melting points than the symmetrical progenitors, while an analog of E205 exhibited significantly improved solubility in simulated gastric fluid and an improved pharmacokinetic profile …”

“…The desymmetrized analogs in general exhibited markedly lower melting points than the symmetrical progenitors, while an analog of E205 exhibited significantly improved solubility in simulated gastric fluid and an improved pharmacokinetic profile. 12 Here we describe an efficient (4 steps, 50% overall yield) synthesis of RLA-3107 (2), a desymmetrized regioisomer of artefenomel. We compared 1 and 2 across in vitro ADME and antiplasmodial assays, and in the P. berghei mouse malaria model using 12 different oral dosing regimens.…”