Cover image for Vol. 12 Issue 6

Editorial Board Chairs: Antonello Mai, Rainer Metternich. Assoc. Editors: David Peralta, Scott Williams (Sr)

Impact Factor: 2.98

ISI Journal Citation Reports © Ranking: 2015: 18/59 (Chemistry Medicinal); 77/255 (Pharmacology & Pharmacy)

Online ISSN: 1860-7187

Associated Title(s): Angewandte Chemie International Edition, Chemistry - A European Journal, Chemistry – An Asian Journal, ChemBioChem, Medicinal Research Reviews, Molecular Informatics

February 02, 2011

ChemMedChem 02/2011: Rare and Neglected Diseases

ChemMedChem 02/2011: Rare and Neglected Diseases

Generally speaking, rare and neglected diseases (RND) are those for which the costs of developing a drug treatment cannot be recovered; a given disease under the RND classification is therefore quite likely to go undertreated, or largely untreated altogether. Paying greater attention to RND is clearly important for humanitarian, social, and economic reasons. Many RND are anything but 'rare', as they affect millions worldwide, and an ideal goal would be to do away with the 'N' in RND. With that goal in mind, the February issue of ChemMedChem is dedicated to medicinal chemistry research into RND.

Two of ChemMedChem's Board members, Professors Maurizio Botta and Alan Kozikowski, introduce this issue with their Editorial on RND, outlining some of the important diseases such as HIV, trypanosomiasis, tuberculosis, Gaucher disease, and cystic fibrosis.

In their Review article, Laith Q. Al-Mawsawi and Nouri Neamati (University of Southern California, Los Angeles, USA) discuss HIV integrase inhibitors that bind outside this enzyme's catalytic site. Efrat Noy and Hanoch Senderowitz (Bar Ilan University, Ramat-Gan, Israel) review compounds that correct the folding, trafficking, and gating defects in cystic fibrosis transmembrane conductance regulator (CFTR), the main protein implicated in cystic fibrosis.

Hemaka Rajapakse and colleagues at Merck (West Point, USA) report a comprehensive structure–activity relationship study at the S2 subpocket of HIV protease for their lysinol compound series, enabling the discovery of potent HIV protease inhibitors with better pharmacokinetic properties. Fragment-based screening was used by David Chalmers and Martin Scanlon (Monash University, Parkville, Australia), Michael Parker (St. Vincent's Institute of Medical Research, Fitzroy, Australia), and co-workers to identify a new ligand binding site on HIV-1 integrase. Crystal structures of fragments bound at this site were used in the design of elaborated second-generation compounds that bind with higher affinity and good ligand efficiency.

Richard Payne (University of Sydney, Australia) and co-workers describe potent ene–yne-based inhibitors of type II dehydroquinase. Most of these compounds inhibit the type II dehydroquinases of Streptomyces coelicolor, Helicobacter pylori, and Mycobacterium tuberculosis at the nanomolar level, and also show moderate activity against the growth of M. tuberculosis in vitro. In their work with type II dehydroquinase, Concepción González-Bello (University of Santiago de Compostela, Spain) and collaborators report tetrahydrobenzothiophene-derived rigid mimics of the catalytic reaction intermediate. These inhibitors fix the interaction with the tyrosine residue that initiates the enzymatic reaction in an orientation unsuitable for catalysis.

Cysteine proteases are important in the life cycles of such parasites as Trypanosoma and Plasmodium spp. Structure-based design carried out by François Diederich (ETH Zürich, Switzerland) and collaborators afforded highly active triazine nitrile inhibitors of the protozoan cysteine proteases falcipain-2 and rhodesain. Optimizing the occupancy of the S1, S2, and S3 pockets of these enzymes produced inhibition constants in the low nanomolar range. In another paper, Diederich and co-workers used computer-based design in combination with various trypanothione reductase (TR) inhibitor motifs to yield selective and highly potent compounds, most of which have low cytotoxicity and IC50 values between 0.12 and 6.0 μM against the protozoa T. b. rhodesiense and P. falciparum.

As part of their ongoing research into the mechanism of action of artemisinins and related antimalarial drugs, Richard Haynes and Zhi-Hong Guo (Hong Kong University of Science and Technology, Hong Kong, P.R. China), Diego Monti (CNR-ISTM, Milan, Italy), and colleagues report that NADPH–E. coli flavin reductase (Fre) reduces FAD to FADH2, which in turn rapidly reduces artemisinins and antimalarial peroxides to deoxy or ketone products under physiological conditions. Antimalarial activity is therefore effected by perturbation of intraparasitic redox homeostasis by oxidation of FADH2 in critical flavoenzymes with consequent sequestration of NADPH.

Ian Gilbert and colleagues (University of Dundee, UK) report their optimization of inhibitor hits against T. brucei pteridine reductase 1 (PTR1). They were able to derive potent competitive inhibitors of PTR1 with relatively weak activities against the parasite, probably due to accumulation of the dihydrobiopterin substrate, which displaces the inhibitors from the PTR1 target. Malaria was the focus of another collaborative project led by Gilbert, who previously reported 5'-tritylated analogues of deoxyuridine as selective inhibitors of P. falciparum dUTPase, a potential drug target for the treatment of malaria. In their current paper, they report further structure–activity studies of the 5'-trityl group, the introduction of various substituents at the 3'-position of deoxyuridine, and modifications of the base.

Indatraline is a CNS-active inhibitor of trypanothione reductase (TryR) revealed in a previous high-throughput screen. For this study, Nicholas Westwood (University of St. Andrews, UK), Alan Fairlamb (University of Dundee, UK), and colleagues prepared indatraline analogues and tested their capacity to inhibit TryR and the proliferation of T. brucei cells; inhibitors with a mixed mode of inhibition and micromolar potency were identified. The antitrypanosomal activity of the natural antibiotic acivicin can be substantially increased on passing to its 3-bromo analogue, as reported by Paola Conti (University of Milan, Italy), Michael Barrett (University of Glasgow, UK), Terry Smith (University of St. Andrews, UK), and collaborators. 3-Bromoacivicin is threefold more potent than acivicin as an inhibitor of T. b. brucei CTP synthetase; this translates to a twelvefold increase in antitrypanosomal activity and a marked improvement in selectivity.

Using high-throughput screening, Alan Kozikowski (University of Illinois, Chicago, USA), William Bishai (Johns Hopkins School of Medicine, Baltimore, USA), and collaborators identified pyrido[1,2-a]benzimidazoles as potent antitubercular agents. Chemical modifications to the hit compound led to a more potent analogue with less toxicity. They found that this analogue maintains activity against two extensively drug-resistant strains and one multidrug-resistant strain of tuberculosis.

Maurizio Botta (University of Siena, Italy) and co-workers designed and synthesized three new series of salicylic acid derivatives to investigate their activity toward HIV-1 integrase. Some of these compounds were obtained by microwave-assisted procedures developed and optimized in Botta's research group, which allowed them to rapidly generate several final compounds in high purity.

In their research on iminoxylitol-based pharmacological chaperones for the treatment of Gaucher disease, Olivier Martin (University of Orléans, France), Philippe Compain (University of Strasbourg, France), and colleagues report that moving the alkyl chain from the pseudo-anomeric position to O2 in iminoxylitol derivatives maintains high inhibitory potency toward glucosylceramidase as well as chaperone activity at sub-inhibitory concentration (10 nM). Such structural simplification leads to shorter and more practical synthetic sequences. Finally, Eric Ballard (University of Virginia, Charlottesville, USA) et al. report their synthesis of a library of nitazoxanide-based analogues, which were analyzed for antibacterial efficacy against pyruvate–ferredoxin oxidoreductase (PFOR)-utilizing microorganisms. Derivatives were found to recapitulate and improve activity against these organisms, and select analogues were screened for activity against staphylococci, resulting in the identification of analogues capable of inhibiting both staphylococci and all PFOR organisms at low micromolar MIC values.

We hope you enjoy this special RND issue of ChemMedChem; browse it today!

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