Identification and Profiling of a Novel Diazaspiro[3.4]octane Chemical Series Active against Multiple Stages of the Human Malaria Parasite Plasmodium falciparum and Optimization Efforts

Abstract

A novel diazaspiro [3.4]octane series was identified from a Plasmodium falciparum whole-cell high-throughput screening campaign. Hits displayed activity against multiple stages of the parasite lifecycle, which together with a novel sp 3 -rich scaffold provided an attractive starting point for a hit-to-lead medicinal chemistry optimization and biological profiling program. Structure−activity-relationship studies led to the identification of compounds that showed low nanomolar asexual blood-stage activity (<50 nM) together with strong gametocyte sterilizing properties that translated to transmission-blocking activity in the standard membrane feeding assay. Mechanistic studies through resistance selection with one of the analogues followed by wholegenome sequencing implicated the P. falciparum cyclic amine resistance locus in the mode of resistance.

Potent Antiplasmodial Derivatives of Dextromethorphan Reveal the Ent-Morphinan Pharmacophore of Tazopsine-Type Alkaloids

“…1 H NMR (CDCl3, 600 MHz): δ 7.02 (d, 1H, J = 8.3); 6.80 (d, 1H, J = 2.4); 6.69 (dd, 1H, J = 2.4, 8.3); 3.79 (s, 3H); 3.78-3.95 (m, 2H); 2.61 (dd, 1H, J = 4.9, 17.9); 2.55 (d, 1H, J = 9.5); 2.51-2.45 (m, 2H); 2.34 (d, 1H, J = 13.3); 2.06 (t, 1H, J = 11); 1.86 (d, 1H, J = 10); 1.77 (t, 1H, J = 10.7); 1.63 (d, 1H, J = 12.1); 1.55-1.50 (m, 3H); 1.42-1.25 (m, 5H); 1.13 (qd, 1H, J = 3.5, 12.6); 0.93-0.90 (t, 3H, J = 7.2). 13 Cpd. 16b, (9α,13α,14α)-17-n-butyl-3-methoxymorphinan, C21H31NO.…”

“…1 H NMR (CDCl3, 300 MHz): δ 7.02 (d, 1H, J = 9.0); 6.80 (d, 1H, J = 3.0); 6.69 (dd, 1H, J = 3.0, 9.0); 3.78 (s, 3H); 2.96-2.90 (m, 2H); 2.64-2.45 (m, 4H); 2.35-2.32 (m, 1H); 2.08-2.00 (td, 1H, J =3.0, 9.0); 1.87-1.72 (m, 2H); 1.64-1.61 (m, 1H); 1.54-1.45 (m, 3H); 1.44-1.27 (m, 7H); 1.13-1.08 (m, 1H); 0.94-0.90 (t, 3H, J = 6.0). 13 Cpd. 16c, (9α,13α,14α)-17-n-pentyl-3-methoxymorphinan, C22H33NO.…”

“…1 H NMR (CDCl3, 400 MHz): δ 7.00 (d, 1H, J = 8.3); 6.80 (d, 1H, J = 2.6); 6.69 (dd, 1H, J = 2.6, 8.3); 3.78 (s, 3H); 2.96-2.89 (m, 2H); 2.61 (d, 1H, J = 5.5); 2.56-2.44 (m, 3H); 2.33 (d, 1H, J = 12.3); 2.04-2.01 (m, 1H); 1.84 (d, 1H, J = 12.4); 1.76 (m, 1H); 1.63 (m, 1H); 1.54-1.47 (m, 3H); 1.41-1.26 (m, 9H); 1.13-1.09 (qd, 1H J = 2.8, 11.8); 0.89 (t, 3H, J = 6.8). 13 C NMR (CDCl3, 100 MHz): δ Cpd. 16j, (9α,13α,14α)-17-(N-methyl-2′-pyrrolylmethyl)-3-methoxymorphinan, C23H30N2O.…”

“…1 H NMR (CDCl3, 600 MHz): δ 7.06 (d, 1H, J = 8.3); 6.81 (d, 1H, J = 1.9); 6.72 (dd, 1H J = 1.9, 8.3); 6.60 (s, 1H); 6.02 (s, 1H); 5.97 (s, 1H); 3.78 (s, 3H); 3.68-3.54 (m, 5H); 3.99 (d, 1H, J = 18.0); 2.79-2.76 (m, 1H); 2.62-2.57 (m, 1H); 2.46-2.43 (m, 1H); 2.36-2.33 (m, 1H); 2.09-2.04 (m, 1H); 1.76-1.73 (m, 1H); 1.65-1.62 (m, 2H); 1.52-1.50 (m, 1H); 1.39-1.29 (m, 5H); 1.18-1.07 (m, 1H). 13 Cpd. 17, (9α,13α,14α)-17-cyclopropylcarbonyl-3-methoxymorphinan, C21H27NO2.…”

“…On the other hand, the initial asymptomatic hepatic phase of parasite development features lower parasitemia and consequently lower mutation events, thus being considered an attractive target for malaria chemoprophylaxis. Drugs possessing novel chemical scaffolds active against parasite hepatic stages, either selectively [11] or as part of a pan-active mode of action [12,13], are therefore strongly pursued in drug discovery programs.…”