Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually, including 875 million children in developing economies. These diseases are also responsible for over 500,000 deaths per year and are characterized by long-term disability and severe pain. The impact of the combined NTDs closely rivals that of malaria and tuberculosis. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Natural products have been a valuable source of drug regimens that form the cornerstone of modern pharmaceutical care. In this review, we highlight the potential that remains untapped in natural products as drug leads for NTDs. We cover natural products from plant, marine, and microbial sources including natural-product-inspired semi-synthetic derivatives which have been evaluated against the various causative agents of NTDs. Our coverage is limited to four major NTDs which include human African trypanosomiasis (sleeping sickness), leishmaniasis, schistosomiasis and lymphatic filariasis.

3,6-Diarylated imidazopyridazines have recently been shown to possess good in vitro antiplasmodial and in vivo antimalarial activity. However, frontrunner compounds have been associated with poor solubility and a hERG (human ether-a-go-go-related gene) inhibition liability raising concerns for potential cardiotoxicity risks. Herein, we report the synthesis and structure–activity relationship studies of new imidazopyridazines aimed at improving aqueous solubility and countering hERG inhibition while maintaining antiplasmodial potency. While we identified new analogues with potent antiplasmodial activity (IC₅₀ = 0.031 μM against the NF54 drug-sensitive strain, and IC₅₀ = 0.0246 μM against the K1 multidrug resistant strain), hERG inhibition remained an issue. Excitingly, on the other hand, new analogues with a substantially improved hERG inhibition profile (IC₅₀ = 7.83–32.3 μM) with sub-micromolar antiplasmodial activity (NF54, IC₅₀ = 0.151–0.922 μM) were identified. Similarly, the introduced molecular features also resulted in analogues with moderate to high solubility (60–200 μM) while also displaying sub-micromolar antiplasmodial potency (NF54, IC₅₀ = 0.136–0.99 μM).

Natural products are vital to drug discovery, yet Africa's vast biodiversity remains underutilized. This perspective examines barriers limiting Africa's impact─such as weak infrastructure, limited translational capacity, and minimal integration of medicinal chemistry. We advocate for advancing beyond basic extraction to include systematic isolation, pharmacokinetics studies, and semisynthetic derivatization. Emphasis is placed on integrating AI, cheminformatics, and biotransformation, alongside embedding drug discovery training into academic curricula. Strengthening regional networks, fostering interdisciplinary collaborations, and securing Africa-sensitive funding are essential. Strategic implementation of these actions will enable Africa to harness its natural resources for global drug discovery and address local health challenges.