A drug repositioning approach was leveraged to derivatize astemizole (AST), an antihistamine drug whose antimalarial activity was previously identified in a high-throughput screen. The multistage activity potential against the Plasmodium parasite's life cycle of the subsequent analogues was examined by evaluating against the parasite asexual blood, liver, and sexual gametocytic stages. In addition, the previously reported contribution of heme detoxification to the compound's mode of action was interrogated. Ten of the 17 derivatives showed half-maximal inhibitory concentrations (IC 50 s) of <0.1 μM against the chloroquine (CQ)-sensitive Plasmodium falciparum NF54 (Pf NF54) strain while maintaining submicromolar potency against the multidrugresistant strain, Pf K1, with most showing low likelihood of cross-resistance with CQ. Selected analogues (Pf NF54-IC 50 < 0.1 μM) were tested for cytotoxicity on Chinese hamster ovarian (CHO) cells and found to be highly selective (selectivity index > 100). Screening of AST and its analogues against gametocytes revealed their moderate activity (IC 50 : 1−5 μM) against late stage P. falciparum gametocytes, while the evaluation of activity against P. berghei liver stages identified one compound (3) with 3-fold greater activity than the parent AST compound. Mechanistic studies showed a strong correlation between in vitro inhibition of β-hematin formation by the AST derivatives and their antiplasmodium IC 50 s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.

Iterative medicinal chemistry optimization of an ester-containing astemizole (AST) analogue 1 with an associated metabolic instability liability led to the identification of a highly potent 3-trifluoromethyl-1,2,4-oxadiazole analogue 23 (Pf NF54 IC 50 = 0.012 μM; Pf K1 IC 50 = 0.040 μM) displaying high microsomal metabolic stability (HLM CL int < 11.6 μL•min −1 • mg −1 ) and > 1000-fold higher selectivity over hERG compared to AST. In addition to asexual blood stage activity, the compound also shows activity against liver and gametocyte life cycle stages and demonstrates in vivo efficacy in Plasmodium berghei-infected mice at 4 × 50 mg•kg −1 oral dose. Preliminary interrogation of the mode of action using live-cell microscopy and cellular heme speciation revealed that 23 could be affecting multiple processes in the parasitic digestive vacuole, with the possibility of a novel target at play in the organelles associated with it.

In the context of drug repositioning and expanding the existing structure−activity relationship around astemizole (AST), a new series of analogues were designed, synthesized, and evaluated for their antiplasmodium activity. Among 46 analogues tested, compounds 21, 30, and 33 displayed high activities against asexual blood stage parasites (Pf NF54 IC 50 = 0.025−0.043 μM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; Pf LG IC 50 = 0.6 ± 0.1 μM) and 860-fold higher selectivity over hERG (46, SI = 43) compared to AST. Several analogues displaying high solubility (Sol > 100 μM) and low cytoxicity in the Chinese hamster ovary (SI > 148) cell line have also been identified.

From the structure of DNA, [1] to computer science, [2] and space-station batteries, [3] several key scientific discoveries that enhance our lives today,w ere made by marginalized scientists.T hese three scientists,R osalind E. Franklin, Alan M. Turing and Olga D. Gonzµlez-Sanabria, did not conform to the cultural expectations of how scientists should look and behave.U nfortunately,m arginalized scientists are often viewed as just aresource rather than the lifeblood that constitutes science itself.W eneed to embrace scientists from all walks of life and corners of the globe;t his will also mean that nobody is excluded from tackling the life-threatening societal challenges that lie ahead. An awareness of science policy is essential to safeguarding our future.

No abstract

Valuing diversity leads to scientific excellence, the progress of science and, most importantly, it is simply the right thing to do. We must value diversity not only in words, but also in actions.

As the so-called “next frontier” in global economic terms, Africa’s disease burden continues to choke and cripple economic growth across the continent. The highest burden is attributable to malaria and tuberculosis (TB), which also remain among the deadliest infectious diseases affecting mankind the world over (Malaria, 627,000 deaths; TB, 1.5 million deaths, in 2020). In achieving self-determination with respect to the health needs of all who live on the continent, Africa must align with global north efforts and be a source of health innovation. This will in part require the creation of an ecosystem of innovative pharmaceutical R&D and expanding it across the continent by scaling up through sustained performance and excellence. To this end, the Holistic Drug Discovery and Development (H3D) Centre at University of Cape Town in South Africa has risen to this challenge. Here, we highlight the innovation experiences gained at H3D, covering the advances made in our quest to contribute to a global pipeline of therapeutic interventions against malaria and TB. We discuss selected chemical series starting from their identification, structure–activity relationships, mode of action, safety, proof-of-concept studies, and lessons learned.

From the structure of DNA, [1] to computer science, [2] and space-station batteries, [3] several key scientific discoveries that enhance our lives today,w ere made by marginalized scientists.T hese three scientists,R osalind E. Franklin, Alan M. Turing and Olga D. Gonzµlez-Sanabria, did not conform to the cultural expectations of how scientists should look and behave.U nfortunately,m arginalized scientists are often viewed as just aresource rather than the lifeblood that constitutes science itself.W eneed to embrace scientists from all walks of life and corners of the globe;t his will also mean that nobody is excluded from tackling the life-threatening societal challenges that lie ahead. An awareness of science policy is essential to safeguarding our future.