Professor Richard K. HAYNES (PhD, Univ. of Western Australia, 1970)
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E-mail: "haynes@ust.hk"

Url: Northwest University

Research Interests

Medicinal chemistry, drug design and optimization, synthesis of bioactive natural products, asymmetric catalysis.

1. The natural peroxide qinghaosu or artemisinin obtained from the Chinese traditional herb qīng hāo, «C¿t (Artemisia annua) and derivatives are now used routinely for treatment of multidrug resistant malaria.   We have designed new derivatives that are metabolically more stable, and possess superior pharmaco­kinetic profiles and efficacies to the current derivatives.  One such derivative, artemisone, in Phase II clinical trials against malaria has a curative dose one third that of artesunate, and is a new development candidate. Artemisinins are active against a number of other parasitic diseases, and in particular, are emerging as drugs for use in adjunct therapy in treatment of cancer.  A wide ranging programme involving uncovering of the intriguing chemistry associated with mechanism of action, evaluation of the intracellular mechanism of action, the design and evaluation of new selectively cytotoxic derivatives both in our laboratories and in collaboration with other groups  in Hong Kong, Singapore, Europe and the UK is underway.

Structure of artemisone and energy-minimized models of rabbit SERCA 1¡Vthapsigargin (TG) binding site (left) and corresponding region of  the Ca2+ transporter in malaria parasite PfATP6 + artemisone (right).

2. We have an interest in small molecules known to enhance endoplasmic reticulum (ER) stress, in particular inhibitors or excitants of Ca2+ pumps which transfer the ion to the intracellular ER storage site.  Reduction of ER calcium is associated with increased uptake of mitochondrial calcium that initiates cell apoptosis.  The natural products plakortones are strong stimulators of cardiac ER Ca2+ transporter. We are carrying out the synthesis of small-ring heterocyclic analogues, which are robust and have good drug properties.  The structural analogy of our target compounds with bacterial quorum sensing agents also has prompted the preparation of rational analogues which will be more amenable to blockading the receptors.  We are also preparing new thermally-robust and stable peroxides for the same purpose which engage new chemistry and methodologies.

3. Sugar transporters are an established target in the drug discovery field.  Parasitic organisms such as P. falciparum and P. vivax require host glucose to sustain their replication within red blood cells. The target to regulate glucose transport is the hexose transporter (HT), a saturable, Na+-independent transporter with high affinity for glucose.  Blockade of HT prevents sugar uptake by the organism. The differences in selectivity between mammalian hexose transporters and parasitic transporters in principle enable the design of selective inhibitors. However, most known structural analogues of hexoses fail as drugs, because of their chemical similarity to the sugars whose uptake they are meant to inhibit, and are too easily metabolized.  We are using rather different and more robust heterocycle-based templates to provide matching sugar analogues. 

4. The influenza neuraminidase (NA) controls the release of new influenza virus particles from infected cells. Inhibitors of influenza NA include zanamivir (Relenza) and oseltamivir ethyl ester (Tamiflu).  Although crystal structure information provided the basis for development of the foregoing compounds, the highly polar active site poses a formidable challenge in the design of drug-like small molecule inhibitors, and computed best-fit analyses has been rather sparse in providing lead structures.  Using the concept of polarizability in addressing the type of functionalites which are compatible both with binding within the active site, and with drug-design concepts, we are preparing heterocyclic analogues bearing polarizable bioisosteres of the essential carboxyl and amide groups.

Representative Publications

"The Fe2+-Mediated Decomposition, PfATP6-Binding and Antimalarial Activities of Artemisone and Other Artemisinins: The Unlikelihood of C-Centered Radicals as Bioactive Intermediates" ChemMedChem , 2, 1480-1497 (2007).

"Preparation of N-Sulfonyl and -Carbonyl-11-Azaartemisinins with Greatly Enhanced Thermal Stabilities: in vitro Antimalarial Activities" ChemMedChem., 2, 1464-1479 (2007).

"Antimalarial Efficacy and Drug Interactions of the Novel Semi-synthetic Endoperoxide Artemisone in vitro and in vivo" J. Antimicrob. Chemother., 59, 658 ¡V 665 (2007).

"From Artemisinin to New Artemisinin Antimalarials: Biosynthesis, Extraction, Old and New Derivatives, Stereochemistry and Medicinal Chemistry Requirements" Current Medicinal Chemistry, 13, 509-537 (2006).

"Artemisone - A Highly Active Antimalarial Drug of the Artemisinin Class" Angew. Chem., Internat. Edit., 45, 2082-2088 (2006).