Peter Mubanga Cheuka

Progress in the fight against malaria appears to have stalled, as reflected by the nearly unchanged mortality figures reported in 2022 and 2023-600,000 and 597,000 deaths, respectively. In addition to reports of resistance to artemisinin-combination therapies (ACTs) in South-East Asia, resistance to ACTs has now been confirmed in Africa. Therefore, new drugs are urgently needed. In this perspective, we summarize different medicinal chemistry strategies employed to address various liabilities in hit antimalarial peptidomimetics. These include an increase in Log P; macrocyclization; chemically reducing amide bonds within peptide backbones; modifying natural amino acid residues; and rigidification. We also propose aggressive integration of drug metabolism and pharmacokinetics (DMPK) profiling; a careful choice of drug targets; and incorporation of more phenotypic-based approaches in hit identification. We believe this perspective is an important repository of medicinal chemistry strategies, and a useful resource for peptidomimetic antimalarial drug discovery.

Malaria causes major mortality, with the downward trend in the number of cases and deaths seemingly stalled. In 2023, 95% of global malaria deaths were reported in the World Health Organization (WHO) African region, with children under the age of 5 years being the most affected. Artemisinin-combination therapies (ACTs), the currently recommended first-line treatments, are threatened by resistance, which has so far been reported in Africa and Southeast Asia. Thus, new drugs are needed. In this review, we discuss the two main antimalarial drug discovery paradigms (phenotypic- and target-based drug discovery approaches) and highlight their impact in antimalarial drug development, as judged by the clinical candidates these two drug development philosophies have delivered in the last two decades. We also highlight the geographical imbalance in contributions to research and development (R&D) efforts that led to the development of these clinical candidates. While phenotypic-based drug discovery outperformed the target-based approach, we propose some strategies to improve chances of success in the latter strategy. Furthermore, although antimalarial drug discovery and development has seen an encouraging shift toward more collaborations among industry, academia, and product development partners, R&D in this space remains concentrated in the global north.

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.

Despite Africa's progress in basic and clinical sciences, gaps persist in its translational capacities, especially medicinal chemistry, a cornerstone of early stage drug discovery. Drawing on experiences as early career researchers and alumni of Africa's premier holistic drug discovery and development center (H3D), this perspective highlights key successes, challenges, and opportunities in Africa. Major barriers to drug discovery in Africa include limited hit-to-lead and lead optimization programs, insufficient Africa-tailored funding, and educational curricula misaligned with real-world drug discovery. We advocate scaling successful models, integrating drug discovery concepts into educational curricula, and forming strategic partnerships with leading African and international institutions. Africa's progress in drug discovery requires innovative funding mechanisms and resource-sharing frameworks adapted to its unique challenges. Targeted investments, collaborative networks, and reciprocal knowledge exchange are essential for Africa to transition from a consumer of global medical innovations to a leading contributor, addressing local healthcare needs and advancing global health equity.

Approximately 619,000 malaria deaths were reported in 2021, and resistance to recommended drugs, including artemisinin-combination therapies (ACTs), threatens malaria control. Treatment failure with ACTs has been found to be as high as 93% in northeastern Thailand, and parasite mutations responsible for artemisinin resistance have already been reported in some African countries. Therefore, there is an urgent need to identify alternative treatments with novel targets. In this Perspective, we discuss some promising antimalarial drug targets, including enzymes involved in proteolysis, DNA and RNA metabolism, protein synthesis, and isoprenoid metabolism. Other targets discussed are transporters, Plasmodium falciparum acetyl-coenzyme A synthetase, N-myristoyltransferase, and the cyclic guanosine monophosphate-dependent protein kinase G. We have outlined mechanistic details, where these are understood, underpinning the biological roles and hence druggability of such targets. We believe that having a clear understanding of the underlying chemical interactions is valuable to medicinal chemists in their quest to design appropriate inhibitors.

Background: The downward trend in malaria cases and deaths is steadily reversed - 627,000 deaths in 2020 compared to 405,000 deaths in 2018. Drug resistance has compromised the effectiveness of currently available treatment options, with some reports documenting molecular markers of resistance to artemisinins in African countries in addition to the Greater Mekong subre-gion, which was initially associated with this kind of resistance. Therefore, the development of nov-el drugs is crucial to replenishing the antimalarial drug arsenal toward malaria eradication. In this review, we summarize the progress made in antimalarial drug discovery in the period 2000 - 2022, focusing on drug candidates which have made it to advanced preclinical trials (drugs tested in ro-dent species and at least one higher species such as dog or monkey) and beyond. Method: We searched Google Scholar and selected studies meeting these defined criteria. We highlight the medicinal chemistry optimization of these compounds; the preclinical/clinical evalua-tion and the mechanisms of action. Results and Conclusion: Although the pipeline seems promising, the prospect of having an antima-larial medicine that meets the current target product profiles (TPPs) towards the malaria eradication agenda is far from reality. Some of the key TPP attributes required include multistage activity, re-sistance-proof; ability to achieve a single dose cure and safety across a wide range of patient popu-lations. Clinical trials are ongoing for some promising molecules, inspiring optimism toward identi-fying better drugs that meet these defined TPPs. Until then, concerted research efforts should con-tinue to be mounted to populate the antimalarial drug discovery and development pipeline.