Activity of N-phenylbenzamide analogs against the neglected disease pathogen, Schistosoma mansoni.

For the Schistosoma mansoni flatworm pathogen, we report a structure-activity relationship of 25 derivatives of the N-phenylbenzamide compound, 1 (MMV687807), a Medicines for Malaria Venture compound for which bioactivity was originally identified in 2018. Synthesized compounds were cross-screened against the HEK 293 mammalian cells. Compounds 9 and 11 were identified as fast-acting schistosomicidal compounds whereby adult worm integrity was severely compromised within 1 h. Against HEK 293 mammalian cells, both compounds exhibited high CC50 values (9.8 ± 1.6 and 11.1 ± 0.2 µM respectively) which could translate to comfortable selectivity. When evaluated in a concentration-response format, compound 9 was active in the nanomolar range (EC50 = 80 nM), translating to a selectivity index of 123 over HEK 293 cells. The data encourage the further investigation of N-phenylbenzamides as antischistosomals.

A Diverse View of Science to Catalyse Change.

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

hERG, Plasmodium Life Cycle, and Cross Resistance Profiling of New Azabenzimidazole Analogues of Astemizole.

Toward addressing the cardiotoxicity liability associated with the antimalarial drug astemizole (AST, hERG IC50 = 0.0042 µM) and its derivatives, we designed and synthesized analogues based on compound 1 (Pf NF54 IC50 = 0.012 µM; hERG IC50 = 0.63 µM), our previously identified 3-trifluoromethyl-1,2,4-oxadiazole AST analogue. Compound 11 retained in vitro multistage antiplasmodium activity (ABS PfNF54 IC50 = 0.017 µM; gametocytes PfiGc/PfLGc IC50 = 1.24/1.39 µM, and liver-stage PbHepG2 IC50 = 2.30 µM), good microsomal metabolic stability (MLM CLint < 11 µL·min-1·mg-1, EH < 0.33), and solubility (150 µM). It shows a ∼6-fold and >6000-fold higher selectivity against human ether-á-go-go-related gene higher selectively potential over hERG relative to 1 and AST, respectively. Despite the excellent in vitro antiplasmodium activity profile, in vivo efficacy in the Plasmodium berghei mouse infection model was diminished, attributable to suboptimal oral bioavailability (F = 14.9%) at 10 mg·kg-1 resulting from poor permeability (log D7.4 = -0.82). No cross-resistance was observed against 44 common Pf mutant lines, suggesting activity via a novel mechanism of action.

Medicinal Chemistry and Target Identification of Synthetic Clinical and Advanced Preclinical Antimalarial Candidates (2000 - 2022).

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 subregion, which was initially associated with this kind of resistance. Therefore, the development of novel 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 rodent species and at least one higher species such as dog or monkey) and beyond. METHODS: We searched Google Scholar and selected studies meeting these defined criteria. We highlight the medicinal chemistry optimization of these compounds; the preclinical/clinical evaluation and the mechanisms of action. RESULTS AND CONCLUSION: Although the pipeline seems promising, the prospect of having an antimalarial 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, resistance- proof; ability to achieve a single dose cure and safety across a wide range of patient populations. Clinical trials are ongoing for some promising molecules, inspiring optimism toward identifying better drugs that meet these defined TPPs. Until then, concerted research efforts should continue to be mounted to populate the antimalarial drug discovery and development pipeline.

Innovation Experiences from Africa-Led Drug Discovery at the Holistic Drug Discovery and Development (H3D) Centre.

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.

Novel 3-Trifluoromethyl-1,2,4-oxadiazole Analogues of Astemizole with Multi-stage Antiplasmodium Activity and In Vivo Efficacy in a Plasmodium berghei Mouse Malaria Infection Model.

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 (PfNF54 IC50 = 0.012 µM; PfK1 IC50 = 0.040 µM) displaying high microsomal metabolic stability (HLM CLint < 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.

Structure-Activity Relationship Studies Reveal New Astemizole Analogues Active against Plasmodium falciparum In Vitro.

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 (PfNF54 IC50 = 0.025-0.043 µM), whereas amide compound 46 additionally showed activity against late-stage gametocytes (stage IV/V; PfLG IC50 = 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.

Multistage Antiplasmodium Activity of Astemizole Analogues and Inhibition of Hemozoin Formation as a Contributor to Their Mode of Action.

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 (IC50s) of <0.1 µM against the chloroquine (CQ)-sensitive Plasmodium falciparum NF54 ( PfNF54) strain while maintaining submicromolar potency against the multidrug-resistant strain, PfK1, with most showing low likelihood of cross-resistance with CQ. Selected analogues ( PfNF54-IC50 < 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 (IC50: 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 ß-hematin formation by the AST derivatives and their antiplasmodium IC50s. Analyses of intracellular inhibition of hemozoin formation within the parasite further yielded signatures attributable to a possible perturbation of the heme detoxification machinery.