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.