Development of Potent 3-Br-isoxazoline-Based Antimalarial and Antileishmanial Compounds

Abstract

Starting from the structure of previously reported 3-Br-isoxazoline-based covalent inhibitors of P. falciparum glyceraldehyde 3-phosphate dehydrogenase, and with the intent to improve their metabolic stability and antimalarial activity, we designed and synthesized a series of simplified analogues that are characterized by the insertion of the oxadiazole ring as a bioisosteric replacement for the metabolically labile ester/amide function. We then further replaced the oxadiazole ring with a series of five-membered heterocycles and finally combined the most promising structural features. All the new derivatives were tested in vitro for antimalarial as well as antileishmanial activity. We identified two very promising new lead compounds, endowed with submicromolar antileishmanial activity and nanomolar antiplasmodial activity, respectively, and a very high selectivity index with respect to mammalian cells.

Discovery of 1,3,4-Oxadiazole Derivatives as Broad-Spectrum Antiparasitic Agents

“…The N -acylated derivatives were submitted to a cyclization reaction using hexachloroethane, N,N -diisopropylethylamine, and triphenylphosphine in acetonitrile at room temperature to afford 2,5-disubstituted 1,3,4-oxadiazoles 62 – 71 . These intermediates are characterized by the presence of a vinyl substituent in the 2 position, which represents a good dipolarophile for the subsequent 1,3-dipolar reaction that was used to build the 3-bromo-4,5-dihydroisoxazole (BDHI) nucleus . Indeed, alkenes 62 – 71 reacted with bromonitrile oxide, generated in situ from its stable precursor dibromoformaldoxime (DBF) in the presence of solid NaHCO 3 as a heterogeneous base and ethyl acetate as an organic solvent, to give final compounds 20 – 29 in good to quantitative yields (57%-quantitative).…”

“…Thus, two synthons 74 and 76 were separately prepared and then coupled using standard conditions (EDC•HCl, HOBT, and TEA), leading to intermediate 77. Finally, 77 was cyclized by treatment with hexacloroethane, N,N-diisopropylethylamine, and triphenylphosphine in acetonitrile to yield the desired probe (30) in a 74% yield (Scheme 2). Carboxylic acid 74 was obtained in two steps and 80% yield from the commercially available ethyl acrylate, which was submitted to 1,3-dipolar cycloaddition with DBF, followed by ester hydrolysis with a 1 M aqueous solution of NaOH and dioxane.…”

“…Herein, we report the results of a medicinal chemistry campaign aimed at identifying novel broad-spectrum antiparasitic agents. The initial chemical starting point was identified following a phenotypic screening that made use of an in-house compound library of known antimalarial and antileishmanial agents 30 toward T. brucei parasite and led to the identification of the 1,3,4-oxadiazole derivative (19) as an anti-T. brucei hit compound (Figure 1B). When considering the impact of T. brucei on the CNS, a multiparameter optimization (CNS MPO) desirability tool was exploited to predict blood−brain barrier (BBB) permeability, and the resulting CNS MPO score was used to prioritize hit selection.…”

Emerging and Re-emerging Warheads for Targeted Covalent Inhibitors: An Update

“…3-Halo-4,5-dihydroisoxazoles (3-halo­isooxazolines) such as the natural product acivicin ( 123 ) and its more active synthetic 3-bromo-4,5-dihydro­isoxazole (BDHI) derivative 124 (Figure A) are well known for their ability to covalently inhibit cysteine-dependent enzymes like human trans­glutaminase 2 and for their activity on parasitic enzymes. − Such compounds have been subject to early reactivity/​promiscuity analyses which showed that the reaction proceeds through an addition–elimination mechanism, displacing the halogen at the electrophilic 3-position, which has been hypothesized to be favored in protease-like enzymes by stabilization of the tetrahedral intermediate via the oxyanion hole . With respect to human target proteins, Pinto et al recently showed by MS and X-ray crystallography (PDB code: 6FFM) that the BDHI 125 (Figure A) covalently binds to Cys151 of the KEAP1 protein, allowing the modulation of the antioxidant system NRF2/HO-1.…”

3-[N,N-Bis(sulfonyl)amino]isoxazolines with Spiro-Annulated or 1,2-Annulated Cyclooctane Rings Inhibit Reproduction of Tick-Borne Encephalitis, Yellow Fever, and West Nile Viruses

“…Successful efforts to obtain the compounds containing medium rings, in most cases with heteroatoms, have been recently reported, illustrating the arising interest in such structures and the need for synthetic methods for them [15][16][17]. Isoxazoles and isoxazolines reveal a broad range of biological activities, including antitumor, antibacterial, antimalarial, antisclerotic, antidiabetic, and others (Figure 1), and a number of examples exist of how the insertion of an isoxazoline moiety increases the potency of the bioactive compounds [18][19][20][21][22][23]. The most general approach to isoxazoline derivatives is 1,3-dipolar cycloaddition, though other methods, taking advantage of metal-mediated and radical processes, are constantly gaining more significance [24,25].…”