The Chemical Midas Touch – Combining Gold with Natural Products to Create Novel Antimalarial Drugs

by and | May 17, 2019 | School of Physical and Mathematical Sciences

Gold ferrocenyl phosphine targeting digestive vacuole function of the malaria parasite, Plasmodium falciparum

Malaria is one of the worst scourges ever known to mankind. The deadly disease, which is caused by plasmodium parasites transmitted by the female anopheles mosquito, remains a global public health threat despite concerted efforts to eradicate it. In 2016 alone, it infected 194 million people in Africa and caused 445,000 deaths. Worryingly, increasing numbers of malaria cases have been found to be resistant to common antimalarial drugs such as chloroquine. This trend, if left unchecked, could have disastrous consequences for humanity, so the race is on to develop new and effective antimalarial drugs that plasmodium parasites lack resistance to.

At the School of Physical and Mathematical Sciences (SPMS) in the Nanyang Technological University (NTU), Singapore, a team of chemists is developing a class of semi-synthetic antimalarial drugs by combining gold atoms with molecules derived from natural products (compounds produced by living organisms).

The team’s efforts are focused on one particular natural product, artemisinin, which is isolated from the sweet wormwood plant (artemisia annua), an herb used in traditional Chinese medicine. In the 1970s, the Chinese chemist Tu Youyou had isolated artemisinin and identified its antimalarial properties, for which she was awarded the 2015 Nobel Prize in Physiology or Medicine. Artemisinin and its derivatives are now widely used to treat malaria and other parasitic worm infections, often administered as a combination therapy with other drugs. Its advantages include rapid action, the ability to affect all life cycle stages of the parasite, and relatively minor side-effects. However, artemisinin also has several notable drawbacks, including a low rate of absorption by the human body and high manufacturing cost. To make matters worse, malaria parasites are beginning to develop resistance against artemisinin, especially in Southeast Asia.

The NTU team is led by Dr. Sumod A. Pullarkat, who had previously developed a set of compounds known as gold-complexed ferrocenyl phosphines, and had collaborated with NTU’s Lee Kong Chian School of Medicine (RSC Adv., 2018, 8, 28960) and the Singapore University of Technology and Design (SUTD)  to show that the compounds have antitumor and antimalarial effects (https://www.asianscientist.com/2018/12/in-the-lab/gold-ferrocenyl-phosphine-anti-malaria-drug/). Inspired by this previous work, the NTU team is currently developing new methods for synthesizing artemisinin derivatives using a specialized process known as organopalladium-catalyzed hydrophosphination. Each resulting molecule contains a gold atom that stabilizes the chemical and contributes to its pharmacological attributes. A variety of these “gold-complexed” artemisinin derivatives have now been developed, and the team is pursuing the next step of screening them for antimalarial activity, including tests with multi-drug resistant malarial parasites.

Besides artemisinin, another natural product that the team is investigating is curcumin, a bright yellow chemical extracted from turmeric (curcuma longa). Curcumin is commonly used as an herbal supplement, but numerous assessments in laboratory and clinical studies have thus far turned up no confirmed medicinal properties. The team has created chemical derivatives of curcumin using the process of organopalladium-catalyzed hydrophosphination and stabilization using a gold-based chemical groups. In future work, they hope to investigate the medicinal properties of these chemical compounds. If any are found, it would make curcumin a highly advantageous and cheaply-available natural source for drugs.

Like the mythical King Midas, who turned everything he touched into gold, this team of scientists is converting natural products into gold complexes. But whereas King Midas starved because he was unable to derive any benefit from the gold, the gold complexes have the potential to be eminently useful, as medicines targeting drug-resistant strains of malaria.

Ong Yew Jin and Tadayuki Kojima are undergraduate students from Chemistry and Biological Chemistry, NTU Singapore. Their article above won the Merit Prize in the SPMS Science-Writing Competition 2019.