Structure-Based Design, Synthesis and Biological Evaluation of Bis-Tetrahydropyran Furan Acetogenin Mimics Targeting the Trypanosomatid F1 Component of ATP Synthase

Abstract

The protozoan parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp. are responsible for the severely debilitating neglected Tropical diseases of African sleeping sickness, Chagas disease and leishmaniasis, respectively. As part of our ongoing programme exploring the potential of simplified analogues of the acetogenin chamuvarinin we identified the T. brucei FoF1-ATP synthase as a target of our earlier triazole analogue series. Using computational docking studies, we hypothesised that the central triazole heterocyclic spacer could be substituted for a central 2,5-substituted furan moiety, thus diversifying the chemical framework for the generation of compounds with greater potency and/or selectivity. Here we report the design, docking, synthesis and biological evaluation of new series of trypanocidal compounds and demonstrate their on-target inhibitory effects. Furthermore, the synthesis of furans by the modular coupling of alkyne- and aldehyde-THPs to bis-THP 1,4-alkyne diols followed by ruthenium/xantphos-catalysed heterocyclisation described here represents the most complex use of this method of heterocyclisation to date.

Keywords: Biological activity; Drug design; FoF1‐ATP synthase; Homogeneous catalysis; Trypanosomatid.

Figure 1

Trypanocidal chamuvarinin, simplified heterocyclic analogues and structure of DB75.

Figure 2

Docked positions of compounds within the T. brucei F1 catalytic site. (A) Position of bound ADP coordinated with ions in the crystal structure. (B) Docked position of ADP in the absence of coordinating ions. The phosphates occupy a slightly different position, but the ribose and adenine occupy the same positions as in the crystal structure. C‐L colour scheme yellow, syn‐syn; green, syn‐anti; cyan, anti‐syn; magenta, anti‐anti. (C‐D) Docking of lead triazole 4 with Et at R¹ and OH at R² and furan analogue 5. The R² OH forms interactions with the phosphate‐binding pocket. (E‐H) Furan 6–9 with OBn at R¹ and OH at R². The additional R¹ OBn allows π‐stacking in the adenine‐bonding pocket. (I‐K) Bis‐OBn furans 10–12. Substitution of the R² OH for OBn results in the loss of all H‐bonds and potential destabilisation of bound compound. (L) Furan 13, with the OBn at R¹, flips orientation indicating the phenyl is preferable in the adenine pocket.

Scheme 1

Bis‐tetrahydropyran 2,5‐furan retrosynthesis.

Scheme 2

Synthesis of THP‐alkynes 20 and 21: a) (COCl)₂, DMSO, CH₂Cl₂, –78 °C, 1 h; then Et₃N –78 °C to r.t., 2 h; b) TMSCCH, Zn(OTf)₂, (+)‐N‐methylephedrine, Et₃N, PhMe, 70 °C, 16 h; c) (i) K₂CO₃, MeOH, r.t. 5 h; (ii) TBSCl, ImH, DMAP, CH₂Cl₂, r.t., 16 h. TBSCl = tert‐butyldimethylsilyl chloride, ImH = imidazole, DMAP = 4‐dimethylaminopyridine.

Scheme 3

Alkyne coupling and ruthenium/xantphos‐catalysed heterocyclisation to furans: a) (i) alkyne, nBuLi, MTBE, –78 °C, 10 min; aldehyde, –78 to r.t., 1 h; (ii) (±)‐CSA, MeOH/CH₂Cl₂ (1:1), r.t., 15 h; (b) Ru(PPh₃)₃(CO)H₂ (6 mol‐%), xantphos (6 mol‐%), PhCO₂H, PhMe, 120 °C, sealed tube, 15 h. ^aInitially co‐isolated with aldehyde by‐product, upon reduction with NaBH₄ in MeOH furan 7 was isolated in 11 % yield over two steps; ^b 32 was isolated in 49 % yield after two cycles of (±)‐CSA in MeOH/CH₂Cl₂ (1:1), see supporting information. MTBE = methyl tert‐butyltether, (±)‐CSA = camphorsulfonic acid, xantphos = 4,5‐bis(diphenylphosphanyl)‐9,9‐dimethylxanthene.