ChemMedChem

The cover picture shows a molecular model of the natural product analogue halofuginone and the life cycle of the malaria parasite that requires a mosquito vector, the sequential infection of mammalian liver cells, followed by the invasion of red blood cells. Halofuginone is a synthetic derivative of the plant alkaloid febrifugine, which constitutes the active component of “Chang Shan”—a traditional Chinese medicine prepared from the roots of the blue evergreen hydrangea Dichroa febrifuga. Both compounds have been widely recognized for their activity in the symptomatic blood stage of malaria. We have discovered that halofuginone also potently inhibits the early- and late-liver-stage processes, clearing parasites one day after liver cell infection, a feature that is uncommon for most antimalarial agents. This finding reveals that halofuginone has potential as a prophylactic that could prevent the progression of the disease to the life-threatening blood stage. For more details, see the Full Paper by Emily R. Derbyshire, Ralph Mazitschek and Jon Clardy on p. 844 ff.

The inside cover picture shows that replacement of the ester bond in cyclic lipodepsipeptide antibiotics with an amide bond affords equipotent analogues with improved serum stability. The amide derivatives show improved selectivity for bacterial over host cells, probably due to their lower overall hydrophobicity and amphiphilicity. For more details, see the Full Paper by Predrag Cudic et al. on p. 871 ff.

Follow my lead! NSC 670224, previously shown to be toxic to Saccharomyces cerevisiae at low micromolar concentrations, potentially acts via a mechanism of action related to that of tamoxifen (NSC 180973), breast cancer drug. The structure of NSC 670224, previously thought to be a 2,4-dichloro arene, was established as the 3,4-dichloro arene, and a focused library of analogues were synthesized and biologically evaluated.

Inspired by nature: Angelmarin is an anticancer natural product with potent antiausterity activity, that is, selective cytotoxicity towards nutrient-deprived, resistant cancer cells. Through structure–activity relationship studies, three analogues were identified as lead compounds for the develpoment of molecular probes for the investigation of the mode of action and biological targets of the antiausterity compounds.

Southern belles! Simplified analogues of tedanolide, a natural product with picomolar activity against a range of tumor cell lines, were synthesized and evaluated for potency in mammalian cancer cells. The truncated analogues were found to retain significant activity in vitro (23 μmol mL⁻¹ for the example shown) compared with the parent compound tedanolide (0.33 nmol mL⁻¹), and represent potential leads for the development of novel anticancer agents.

Modification of meisoindigo, an antileukemic drug, by replacing N-methyl with a solubilizing piperazinylethyl side chain significantly enhanced aqueous solubility, improved antiproliferative activity on cancer cell lines and gave rise to in vivo activity on tumor-induced xenografts in mice.

Click and you′re on Holliday! Click chemistry has been used to generate a small library of 9-aminoacridines. These novel analogues were evaluated for cytotoxicity, and duplex, quadruplex and Holliday junction (HJ) DNA binding. For some compounds, there was a direct correlation between activity and DNA binding, while for others a more complicated relationship exists. The acridine 3-carboxamides proved the most interesting, stabilising both quadruplex and HJ DNA.

Silver bullets: Silver–N-heterocyclic carbenes (NHCs) exhibit potent antiproliferative activity toward human cancer cell lines with IC₅₀ values in the nanomolar range. Silver–NHCs do not target DNA but likely mitochondria, decreasing the inner membrane potential (ΔΨ_m), causing the release of mitochondrial proteins and thus early apoptosis. This phenomenon is triggered by translocation of AIF and caspase-12 into the nucleus to promote DNA fragmentation and finally cell death.

Combating cancer resistance: The Amaryllidaceae alkaloid bulbispermine inhibits proliferation of glioblastoma cells through cytostatic effects that are possibly due to rigidification of the actin cytoskeleton. These findings argue that crinine-type alkaloids could be useful drug leads for the treatment of apoptosis-resistant cancers and glioblastoma in particular.

ARIs for diabetes: We developed a novel method for the synthesis of 3-chloroquinoxalin-2(1H)-one derivatives and thereby successfully generated a new class of aldose reductase inhibitors (ARIs) based on the quinoxalinone scaffold. Most of the compounds, with an N1-acetic acid head group and a substituted C3-phenoxy side chain, proved to be potent and selective. Their IC₅₀ values ranged from 11.4 to 74.8 nM.

An elusive binding pose: The results of receptor-based, quantitative structure–activity relationship studies lend further support to one of the proposed binding modes for epothilones to β-tubulin and help interpret previously acquired experimental binding enthalpies.

Battling a silent killer: Before malaria symptoms even appear several parasites have silently invaded and propagated within the liver. We developed cell-based assays amenable to high-throughput screening to evaluate compounds for their ability to decrease parasite load in liver cells and to inhibit parasite traversal. These assays helped to identify halofuginone (shown) as a low-nanomolar inhibitor of liver-stage malaria parasites.

Inbuilt pyrophosphate mimic: A β-N-hydroxy-γ-ketocarboxamide pharmacophore was integrated into a quinazolinone scaffold to yield inhibitors of hepatitis C virus (HCV) NS5B polymerase. N-phenylpropyl carboxamide 9 k (IC₅₀=8.8 μM) possesses selective cytotoxicity in favor of HCV1b replicon Ava.5 cells (EC₅₀=17.5 μM) over parent Huh-7 cells (CC₅₀=187.5 μM).

Old target, new goal: A series of 4,5-dioxo-1,4,5,6-tetrahydropyrimido[4,5-c]pyridazines with modifications of both the side chain length at C6 and the substituent at N8 were designed and synthesized as potential inhibitors of the antibacterial target, dihydropteroate synthase (DHPS). Structural analyses of DHPS in complex with these inhibitors helped map this active site for future drug design.

Improving bioactivity: Ester-to-amide substitution in naturally occurring depsipeptide antimicrobials affords equally potent analogues with improved stability and greatly decreased cytotoxicity. Lower overall hydrophobicity and amphiphilicity of amide analogues relative to their parent depsipeptides may explain this dissociation of antibacterial activity from human cell cytotoxicity.

Keeping a good profile: A new series of S-DABO/N-DABO derivatives were synthesized to gather additional SAR information on the C2-position and in particular to improve ADME properties while maintaining a good activity profile against HIV-1 RT. The most interesting compounds were experimentally evaluated for their in vitro ADME properties (PAMPA permeation, water solubility, and metabolic stability) to get a reliable indication of their plasma levels after oral administration.

Heme oxygenase inhibition: We synthesized α-(1H-Imidazol-1-yl)-ω-phenylalkanes and analogues containing one heteroatom in the alkyl linker and evaluated them as novel inhibitors of heme oxygenases 1 (HO-1) and 2 (HO-2). Compounds with a five-atom linker between the α-(imidazol-1-yl) and ω-phenyl moieties are more potent HO-1 and HO-2 inhibitors, yet compounds with a four-atom linker are the most selective for HO-1. This study provides potentially useful imidazole-based HO inhibitors for pharmacological and therapeutic applications.

Gallant pain relief:D-Gal(7-Ahp)-B2 is an analgesic peptide that incorporates a central truncation of the galanin neuropeptide, the addition of a backbone spacer, and the introduction of D-amino acids. Oral administration of this galanin-based peptide demonstrates analgesic activity in the formalin model of acute and inflammatory pain in mice.

Aβ blockers: A diverse library of compounds with the same binding moiety was generated, and the general structural features that characterize inhibitors of β-amyloid oligomer and fibril formation were observed. The ultimate goal of this project was to identify lead structures for further focused inhibitor design.

Less psycho more active! Cannabinoid receptor type 2 (CB2)-selective agonists have potential as therapeutics for the treatment of pain, however, poor selectivity over CB1 has hampered the development. Here, the modulation of physicochemical properties of CB2 ligands through a simple bioisosteric approach was performed without significant loss of receptor affinity in an attempt to obtain potent leads with desirable drug-like properties.