Sithabile Mokoena

When we think of medicine, we picture pills and syrups – not the chemistry behind them. But every drug begins in a lab, where researchers explore new compounds in the hope of discovering tomorrow’s treatments. One fascinating area of research involves tiny, ring-shaped molecules called triazolotriazines. These tongue-twister compounds may not be household names, but scientists around the world are excited about them because they show promise in treating a range of diseases.

My name is Sithabile Mokoena, and I am a PhD student within the Synthetic and Medicinal Chemistry Research Group (SMCRG) and a Principal Technician in Pharmaceutics at the University of KwaZulu-Natal. Over the past several years, my team and I have focused on triazolotriazines. So, what exactly are triazolotriazines? In simple terms, they’re made up of two nitrogen-rich rings fused together. This unique structure gives them the power to tackle both drug‑resistant bacteria and aggressive cancers. 

Why Triazolotriazines Matter

Traditional antibiotics usually hit a single bacterial target, say, the cell wall or protein machinery, making it easy for microbes to evolve resistance. Triazolotriazines use multiple modes of attack, binding DNA, disrupting essential enzymes, and compromising cell membranes. In one of our recent studies, we showed that a series of 1,2,4‑triazolo[1,5‑a] [1,3,5] triazine derivatives inhibited E. coli DNA gyrase, halting bacterial replication even in strains resistant to conventional drugs. These findings highlight how a multifaceted mechanism can outsmart microbial defences.

Our Antimicrobial Breakthroughs

In our lab, we designed and synthesised a small library of triazolotriazine compounds, systematically tweaking substituents to boost potency and selectivity. We recently demonstrated that adding electron‑withdrawing groups (a group or atom that has the ability to draw electron density toward itself and away from other adjacent atoms) at specific ring positions dramatically increased activity against E. coli and MRSA. Beyond standalone use, we’re exploring synergy with existing antibiotics, finding that combining our compounds with older drugs can resensitize resistant strains. This approach could extend the clinical life of antibiotics that are losing effectiveness worldwide.

Venturing into Cancer Research

While our primary focus is infections, we quickly discovered that triazolotriazines can also target cancer cells. Some of our older derivatives slowed the proliferation of cell lines such as MV4‑11 (acute myeloid leukaemia), G361 (melanoma), and HCC827 (lung adenocarcinoma). Early data suggest these molecules trigger DNA damage or disrupt energy production in cancer cells, resulting in cancer cell death. Although we’re still unravelling the precise mechanisms, these results open a promising new chapter, one where a single scaffold addresses two major health threats.

How We Work: From Design to Discovery

What excites me most is that we’re not just guessing, we’re using both lab experiments and computer simulations to understand what’s happening at a deeper level. It’s a mix of creativity and precision, which is one of the things I love most about science. Combining creativity and precision, we employ high‑yielding modular chemistry to generate diverse triazolotriazine libraries. Each design iteration is guided by computer simulations and lab assays, allowing us to predict and confirm how structural changes affect biological activity. This iterative cycle-design, synthesise, test, refine- helps us home in quickly on lead candidates. At the same time, we assess pharmacokinetics (absorption, distribution, metabolism, excretion) to ensure future compounds can be safely and effectively delivered in the body.

Challenges and the Road Ahead

Despite these advances, triazolotriazines remain in early stages. Our next priorities are toxicity profiling, animal studies, and scale‑up synthesis to support preclinical trials. We’re actively seeking collaborations with formulation experts to optimise delivery and with clinical partners to plan first‑in‑human studies. The complexity of these molecules demands rigorous evaluation, but the potential payoff, in terms of new therapies for resistant infections and hard‑to‑treat cancers, is enormous.

A Personal Note

Through this blog, I hope to give a glimpse into how researchers like me are working behind the scenes to turn promising molecules into tomorrow’s medicines. And with each experiment, we get a little closer. This work isn’t just about molecules, it’s about hope. I entered science driven by the desire to solve real‑world problems, and every promising result in the lab reaffirms that drive. We recently showed that thoughtful molecular design can yield compounds with genuine clinical potential. Yet the journey from bench to bedside is long, and progress depends on teamwork across disciplines. If you’re a fellow researcher, clinician, funder, or policymaker passionate about drug discovery, let’s connect. Together, we can transform triazolotriazines from chemical curiosities into life‑saving medicines.

Pamela Esterhuysen

In September 2024, reporter Chris Ndaliso wrote an article for The Witness, titled “Concern over condition of KZN Botanical Gardens’ Kingfisher Lake”. In this article, he wrote that the lake had been taken over by alien plants, was highly silted and that the bird diversity had declined, with only some Egyptian geese spotted. There was no sign of the water birds such as moorhens, cormorants, as well as herons and kingfishers. The water birds and other water animals, such as turtles and fish, require good quality water as they swim around to feed. The weeds and silting of the lake make normal feeding impossible as the food availability declines. Clearly, the lake was in terrible shape, with implications for the plant and animal species that rely on it. Cleaning this lake would be no easy or quick task…unless the public gets involved!

Ever heard of  Citizen Science? Citizen science is a form of public participation in scientific investigations, using an inquiry-based methodology, to collect and analyse data and contribute to solving the issue at hand. In this case, clean water! Clean water is safe water! Unfortunately, 13% of water nationally is not safe for human consumption. Given the extent of the issue, we need mass public participation! Indeed, there is a great need for local communities to get stuck in, with gumboots, gloves and heavy-duty plastic bags, and to help clean up the mess in our cities’ rivers.

A number of South African organisations have web-based platforms on which the concept of Citizen Science may be promoted, using a variety of tools which include crowd sourcing or observation-based biomonitoring. Results are evaluated and verified by an expert panel. Two Action Groups that use online mapping to provide a visual representation of the state of South Africa’s rivers through citizen science are, MiniSASS and WaterCAN. MiniSASS uses biomonitoring as a tool to assess the health of a freshwater system by looking at macroinvertebrates to arrive at a score for a particular site. The different groups of organisms are identified. Each group on the MiniSASS score card has a value. The sum of the values is divided by the number of groups to provide a score (refer to Image 1).

Image 1. How to score using MiniSASS.

The WaterCAN testing kit allows for the chemical testing of the water at that site, measuring phosphate levels, oxygen content to name a few of the tests. The results of such water testing at community level is then uploaded to the web-based platforms, as mentioned above. The outcome is we have public participation in scientific research, the school-learners use citizen science tools and there is generally an understanding of the importance of clean water or holding municipal bodies accountable.

My passion for participatory fieldwork goes back for as long as I have been teaching Geography. Currently I am a PhD student at the University of Pretoria, in the Faculty of Education, in the final stages of writing my doctoral thesis, in the Department of Humanities Education. My research has investigated the value of conducting local, place-based geographical fieldwork in secondary schools and the contribution that inquiry-based learning makes to the overall development of the metacognitive skills in this cohort of learners. Many of the case studies observed with the groups of learners have involved one or other aspect of Citizen Science. Their results have been uploaded onto MiniSASS and WaterCAN, allowing these school groups to contribute to solving the issue of river pollution.

In KwaZulu-Natal, there are many Action Groups and organisations reporting and motivating local communities to become more involved in maintaining the cleanliness of the city, and more specifically, monitoring the water quality of our rivers. Groups such as these operate in most of the towns, cities and metropolitan areas of the country. To name a few of the local groups in the Pietermaritzburg area: Duzi-uMngeni Conservation Trust (DUCT),  GroundTruth and UMngeni-uThukela Water. DUCT is a non-governmental organisation dedicated to promoting sustainable freshwater conservation through a community-centred approach. One of the areas Groundtruth has been involved in is the co-development of various tools, initiatives, and engagement events regarding citizen science water resource monitoring.

uMngeni-uThukela Water is involved in community and schools outreach programmes, for example: through their Adopt-A-School Programme. In addition to those organisations, The Wildlife and Environment Society of South Africa (WESSA) has championed active citizenship through their Eco-Schools’ environmental education programme, which includes using a miniSASS.

Many schools in the municipality are close to or within walking distance of the tributaries of the Msunduzi River, and with support from the above-mentioned organisations, could get involved with Citizen Science projects.

An important experiential or hands-on field activity for groups of learners is to get involved with monitoring the water quality of the many streams (tributaries) of their cities’ river systems. The local action groups mentioned above are always willing to assist in starting the monitoring process. A lead teacher from a school is also able to register a school group on MiniSASS. Various water quality results and photographs may be uploaded, as well as the GPS position. The results will be displayed on a web-based map showing the water quality by using a colour-coded crab symbol once the information is verified.

The secondary school group, which formed one of my case studies, used the water testing kits from WaterCAN. The biomonitoring score was obtained from using the MiniSASS sheets. Image 2 below shows the group’s second sample site in the Mkondeni industrial area, Local businesses in such areas are challenged to support a school by partnering with them to become involved as Citizen Scientists.

Image 2. A view along a tributary of the Blackborough Spruit, which joins the Msunduzi River.

The cohort of learners conducting the water quality testing at this site had to report that the water quality of the stream was in very poor condition after conducting their visual analysis, water quality testing and biomonitoring using the miniSASS scoring system. The MiniSASS score was less than 4.8 indicating a river in poor condition (Image 1).

Just pause and think: if every school in a city adopted a river spot and partnered with local businesses and the various Action Groups, as well as the online Citizen Science reporting platforms, we could soon make our rivers more sustainable, and the surrounding communities would be able to access clean water from the rivers. Are you ready to join hands and make an effort to promote healthy, sustainable rivers for all by promoting Citizen Science?

Acknowledgements

Photographs taken by the Author