Stereoselective Formation of Quaternary Stereogenic Centers via Alkylation of α‑Substituted Malonate-Imidazolidinones

A new stereoselective alkylation methodology is presented for formation of chiral, nonracemic quaternary centers via a chiral auxiliary protocol involving α-alkylated malonate imidazolidinones. Based on two X-ray structures of quaternized products, the diastereoselectivity observed may be rationalized via a transition-state involving an s-<i>trans</i>_C–N conformation of the C–N bond of the auxiliary, with the metal cation (K⁺) chelated into the malonate six-membered hole as a <i>Z</i>-enolate. A deprotection protocol involving ethanethiolate exchange of the imide to the corresponding thioester, followed by a standard Fukuyama reduction and a borohydride reduction, furnishes α,α′-quaternized β-hydroxypropionates in high ee overall

Identification and Mechanistic Evaluation of Hemozoin-Inhibiting Triarylimidazoles Active against <i>Plasmodium falciparum</i>

In a previous study, target based screening was carried out for inhibitors of β-hematin (synthetic hemozoin) formation, and a series of triarylimidazoles were identified as active against <i>Plasmodium falciparum</i>. Here, we report the subsequent synthesis and testing of derivatives with varying substituents on the three phenyl rings for this series. The results indicated that a 2-hydroxy-1,3-dimethoxy substitution pattern on ring A is required for submicromolar parasite activity. In addition, cell-fractionation studies revealed uncommonly large, dose-dependent increases of <i>P. falciparum</i> intracellular exchangeable (free) heme, correlating with decreased parasite survival for β-hematin inhibiting derivatives

Identification and SAR Evaluation of Hemozoin-Inhibiting Benzamides Active against <i>Plasmodium falciparum</i>

Quinoline antimalarials target hemozoin formation causing a cytotoxic accumulation of ferriprotoporphyrin IX (Fe­(III)­PPIX). Well-developed SAR models exist for β-hematin inhibition, parasite activity, and cellular mechanisms for this compound class, but no comparably detailed investigations exist for other hemozoin inhibiting chemotypes. Here, benzamide analogues based on previous HTS hits have been purchased or synthesized. Only derivatives containing an electron deficient aromatic ring and capable of adopting flat conformations, optimal for π–π interactions with Fe­(III)­PPIX, inhibited β-hematin formation. The two most potent analogues showed nanomolar parasite activity, with little CQ cross-resistance, low cytotoxicity, and high in vitro microsomal stability. Selected analogues inhibited hemozoin formation in <i>Plasmodium falciparum</i> causing high levels of free heme. In contrast to quinolines, introduction of amine side chains did not lead to benzamide accumulation in the parasite. These data reveal complex relationships between heme binding, free heme levels, cellular accumulation, and in vitro activity of potential novel antimalarials

Quaternized α,α′-Amino Acids via Curtius Rearrangement of Substituted Malonate–Imidazolidinones

An efficient synthesis protocol is presented for accessing quaternized α-amino acids in chiral, nonracemic form via diastereoselective malonate alkylation followed by C- to N-transposition. The key stereodifferentiating step involves a diastereoselective alkylation of an α-monosubstituted malonate–imidazolidinone, which is followed first by a chemoselective malonate PMB ester removal and then a Curtius rearrangement to provide the transposition. The method demonstrates a high product ee (89–99% for eight cases) for quaternizing a range of proteinogenic α-amino acids. The stereogenicity in targets <b>5a</b>–<b>i</b> supports previous conclusions that the diastereoselective alkylation step proceeds via an α-substituted malonate–imidazolidinone enolate in its <i>Z</i>-configuration, with the auxiliary in an <i>s</i>-<i>trans</i>_C–N conformation

4‑Aminoquinoline Antimalarials Containing a Benzyl­methyl­pyridyl­methyl­amine Group Are Active against Drug Resistant <i>Plasmodium falciparum</i> and Exhibit Oral Activity in Mice

Emergence of drug resistant <i>Plasmodium falciparum</i> including artemisinin-tolerant parasites highlights the need for new antimalarials. We have previously shown that dibemequines, 4-amino-7-chloroquinolines with dibenzylmethyl­amine (dibemethin) side chains, are efficacious. In this study, analogues in which the terminal phenyl group of the dibemethin was replaced with a 2-pyridyl group and in which the 4-amino-7-chloroquinoline was either maintained or replaced with a 4-aminoquinoline-7-carbonitrile were synthesized in an effort to improve druglikeness. These compounds exhibited significantly improved solubility and decreased lipophilicity and were potent against chloroquine-sensitive (NF54) and -resistant (Dd2 and 7G8) <i>P. falciparum</i> strains with 5/6 having IC₅₀ < 100 nM against the NF54 strain. All inhibited both β-hematin (synthetic hemozoin) formation and hemozoin formation in the parasite. Parasitemia was reduced by over 90% in <i>P. berghei</i> infected mice in 3/6 derivatives following oral dosing at 4 × 30 mg/kg, with microsomal metabolic stability data suggesting that this could be attributed to highly active metabolites

Bifunctional Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase: Mechanism and Proof-of-Concept as a Novel Therapeutic Design Strategy

Human immunodeficiency virus type 1 reverse transcriptase (HIV-1 RT) is a major target for currently approved anti-HIV drugs. These drugs are divided into two classes: nucleoside and non-nucleoside reverse transcriptase inhibitors (NRTIs and NNRTIs). This study illustrates the synthesis and biochemical evaluation of a novel bifunctional RT inhibitor utilizing d4T (NRTI) and a TMC-derivative (a diarylpyrimidine NNRTI) linked via a poly­(ethylene glycol) (PEG) linker. HIV-1 RT successfully incorporates the triphosphate of d4T-4PEG-TMC bifunctional inhibitor in a base-specific manner. Moreover, this inhibitor demonstrates low nanomolar potency that has 4.3-fold and 4300-fold enhancement of polymerization inhibition in vitro relative to the parent TMC-derivative and d4T, respectively. This study serves as a proof-of-concept for the development and optimization of bifunctional RT inhibitors as potent inhibitors of HIV-1 viral replication