Rapid triaging of three series of related hits selected from the Tres Cantos Anti-Malarial Set (TCAMS) are described. A triazolopyrimidine series was deprioritized due to delayed inhibition of parasite growth. A lactic acid series has derivatives with IC50 < 500 nM in a standard Plasmodium falciparum in vitro whole cell assay (Pf assay) but shows half-lives of < 30 min in both human and murine microsomes. Compound 19, from a series of cyclopropyl carboxamides, is a highly potent in vitro inhibitor of P. falciparum (IC50 = 3 nM) and has an oral bioavailability of 55% in CD-1 mice and an ED90 of 20 mg/kg after oral dosing in a nonmyelo-depleted P. falciparum murine model.
Imines react with N-iodosuccinimide (NIS) to afford unexpected 1 : 1 complexes and the structure of one of these was determined by single-crystal X-ray diffraction; the reaction seems to be very general for substituted cyclic imines with solid stable complexes obtained in high yields; this is the first reported example of a halogen bonding interaction involving the CLN bond and NIS.As part of a project focussed on the preparation of a small library of derivatives of 1-phenyl-3,4-dihydropyrrolo[1,2-a]pyrazine 1a we needed to prepare either the 6-bromo or 6-iodo derivatives as appropriate substrates for the Stille and/or Suzuki reactions.1 The reaction with NBS afforded the expected halogenated product 3 (Scheme 1) but under the same conditions, the reaction of 1a with NIS gave a yellow solid compound, the structure of which incorporates the iodo atom and the full heterocyclic and succinimide moieties-as evidenced by NMR spectroscopy and elemental analysis. Further structural analysis allowed us to rule out the co-halogenation compound 2 and we therefore tried to confirm the structure of this apparently simple compound by X-ray analysis. However, all our initial attempts to obtain suitable crystals failed.It was shown that the iminic bond in 1a seems to be critical for the formation of the unexpected reaction product with NIS, since 1-phenyl-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazine either does not react, or affords the 6-iodo derivative in the presence of NIS. For this reason, we decided to test the reaction with other imines in the hope that we could obtain an appropriate crystal for X-ray diffraction analysis. Fortunately, this aim was achieved in the reaction of 6,7-dimethoxy-1-phenyl-3,4-dihydroisoquinoline (1h) with NIS, which allowed us to establish structure 2a for the reaction product between 1a and NIS. We report here further details on the scope of this unprecedented reaction (Scheme 2).First, substitution at the C-1 position of 3,4-dihydropyrrolo[1,2-a]pyrazine was explored with alkyl (methyl and n-propyl), aryl and heteroaryl substituents 3 (Table 1, entries 2-7). Other related bicyclic and tricyclic imines such as 1-substituted 3,4-dihydroisoquinolines (entries 8 and 9) and 2-substituted 3,4-dihydropyrazino[1,2-a]indoles (entries 10-12) were also employed as iminic substrates. 4 The results are summarised in Table 1 and show the reaction to be very general for all aryl (Table 1, entries 4-6, 8, 10 and 12) and heteroaryl (entries 7 and 13) substituted substrates, with complexes being formed in yields of up to 64% and reactions completed within 1 h. The behaviour of alkyl substituted substrates depends of the heterocyclic imine and the nature of the alkyl group. For example, the reaction of 1-methyl-6,7-dimethoxy-3,4-dihydroisoquinoline 1i (entry 9) and 2-methyl-3,4-dihydropyrazino[1,2-a]indole (1k) (entry 11) afforded the addition compounds 2i and 2k in excellent yields (86 and 89%, respectively). However, the methyl derivative 1b gave a complex mixture of products and the n-propyl derivative 1c was ex...
Abtra~ The structure of 3,4-dihydropyrrolo[ 1,2-a]pyrazine and its N-protonated form is studied by ab initio calculations. Examples of the re, activity of this poorly studied system are presented in which it is shown that the imino moiety does not react with dienes but does undergo inter-and intramolecular 1,3-dipolar cycloadditions by reaction of azomethine ylides of this bicyclic system with suitable dipolarophiles.
Abstract-The first intermolecular C-N bond-forming reactions between substituted 2-bromopyrroles and primary and cyclic secondary amines were performed using Pd 2 (dba) 3 as catalyst with BINAP as the ligand. The aminations proceeded in the presence of NaO t Bu at 80-100°C in 31-93% yields.
The search for new antimalarial drugs with unexplored mechanisms of action is currently one of the main objectives to combat the resistance already in the clinic. New drugs should target specific mechanisms that once initiated lead inevitably to the parasite’s death and clearance and cause minimal toxicity to the host. One such new mode of action recently characterized is to target the parasite’s calcium dynamics. Disruption of the calcium homeostasis is associated with compromised digestive vacuole membrane integrity and release of its contents, leading to programmed cell death-like features characterized by loss of mitochondrial membrane potential and DNA degradation. Intriguingly, chloroquine (CQ)-treated parasites were previously reported to exhibit such cellular features. Using a high-throughput phenotypic screen, we identified 158 physiological disruptors (hits) of parasite calcium distribution from a small subset of approximately 3000 compounds selected from the GSK TCAMS (Tres Cantos Anti-Malarial Set) compound library. These compounds were then extensively profiled for biological activity against various CQ- and artemisinin-resistant Plasmodium falciparum strains and stages. The hits were also examined for cytotoxicity, speed of antimalarial activity, and their possible inhibitory effects on heme crystallization. Overall, we identified three compounds, TCMDC-136230, -125431, and -125457, which were potent in inducing calcium redistribution but minimally inhibited heme crystallization. Molecular superimposition of the molecules by computational methods identified a common pharmacophore, with the best fit assigned to TCMDC-125457. There were low cytotoxicity or CQ cross-resistance issues for these three compounds. IC50 values of these three compounds were in the low micromolar range. In addition, TCMDC-125457 demonstrated high efficacy when pulsed in a single-dose combination with artesunate against tightly synchronized artemisinin-resistant ring-stage parasites. These results should add new drug options to the current armament of antimalarial drugs as well as provide promising starting points for development of drugs with non-classical modes of action.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.