Repositioning of astemizole for malaria

Malaria remains one of the most important parasitic infectious diseases as far as human suffering is concerned. With almost half of the world's population at risk, its burden is felt worldwide as seen by the high number of deaths recorded each year (405,000 in 2018: WHO World Malaria Report 2019). Unfortunately, over 90% of this mortality rate is recorded in Africa alone, with the highest risk being in children under the age of five (5) and pregnant women. Partly, this is due to the unfortunate spread of resistance to most drugs that were once effective and safe, including Artemisinins which form the basis of the current first-line regimen in the treatment of malaria. For this reason, it is crucial to invest research efforts using various approaches in the drug discovery arsenal to develop novel, and structurally diverse antimalarials with different modes of action. These new antimalarials should not only be able to circumvent resistance but need to be efficacious at different life cycle stages of the parasite (multi-stage activity). This Ph.D. project pursued a drug repositioning approach on Astemizole (AST, Figure 1), a second-generation antihistamine drug which was previously identified as an antimalarial agent by Chong et al., at the Johns Hopkins University School of Medicine through via a high-throughput screening (HTS) of diverse marketed drugs. AST was active against chloroquine-sensitive (CQ-S) and multi-drug resistant (MDR) laboratory strains of the human malaria parasite Plasmodium falciparum (P. falciparum) and demonstrated in vivo efficacy in two mouse infection models of malaria namely, P. Vinckei and P. Yoelii. However, in addition to its low solubility, AST possesses a serious and fatal cardiotoxicity risk, evidenced by its ability to potently inhibit the human ether-á-go-go-related gene (hERG) encoded potassium (K+) channels. This liability led to the withdrawal of AST in most countries during the late 1970's and it is still being discontinued for use in some countries to date

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 &lt; 11 μL·min-1·mg-1, EH &lt; 0.33), and solubility (150 μM). It shows a ∼6-fold and &gt;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.</p

hERG, Plasmodium life cycle, and cross resistance profiling of new azabenzimidazole analogues of astemizole

SUPPLEMENTARY INFORMATION : Experimental procedures and characterization data of synthetic intermediates (5a–5f, 6a–6f, 13, and 15) and target compounds (7–12 and 15); biochemical assay protocols, including solubility and cross-resistance studies; H NMR spectra of representative target compounds.Please read abstract in the article.The University of Cape Town (UCT), South African Medical Research Council, the South African Research Chairs Initiative (SARChI) of the Department of Science and Innovation (DSI) administered through the South African National Research Foundation (NRF), the Brazilian National Council for Scientific and Technological Development, Proep-Fiocruz Program (Brazil), the Neville Isdell Chair in African-centric Drug Discovery and Development, and Neville Isdell for generously funding the Chair.http://pubs.acs.org/journal/amclcthj2024BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC)SDG-03:Good heatlh and well-bein

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 must value diversity not only in words, but also in actions

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 must value diversity not only in words, but also in actions

No abstract available.publishe

Structure−activity relationship studies reveal new astemizole analogues active against Plasmodium falciparum in vitro

Please read abstract in the article.https://pubs.acs.org/journal/aidcbc2022-08-02hj2021BiochemistryGeneticsMicrobiology and Plant Patholog

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 (IC; 50; s) of &lt;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-IC; 50; &lt; 0.1 μM) were tested for cytotoxicity on Chinese hamster ovarian (CHO) cells and found to be highly selective (selectivity index &gt; 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

The future of scientific leadership is interdisciplinary: The 2019 CAS Future Leaders share their vision

For the last decade, the CAS Future Leaders program has gathered early-career scientists from across the globe based on their outstanding accomplishments in the field of chemistry to provide support to participants in cultivating their own voices and futures in scientific leadership. The goal of the program has been to empower early-career scientists like us to begin to shape our own future leadership roles, from learning to convey effective speech by developing our own research stories to growing to be better mentors for the next generation of future leaders. In 2019, to honor the 10th anniversary of the program, the CAS Future Leaders program encompassed essential leadership skills divided into five topics, namely, storytelling, insights, strategies, perspectives, and impact, some of which were new to the program this year. However, what was not new to the program was an emphasis on the potential global impact that this program could make. To do this, the program brought together in this cohort 29 post-docs and graduate students, from 16 countries. A staple of this program is not only the breadth of countries that are represented but also the many facets of chemistry that are represented as demonstrated later in the article. One reason for this is that a leader in the sciences will need to be open to innovations across discipline and geographical boundaries, something that we explored a lot during our time together

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. From the structure of DNA,1 to computer science,2 and space-station batteries,3 several key scientific discoveries that enhance our lives today, were made by marginalized scientists. These three scientists, Rosalind E. Franklin, Alan M. Turing and Olga D. González-Sanabria, did not conform to the cultural expectations of how scientists should look and behave. Unfortunately, marginalized scientists are often viewed as just a resource rather than the lifeblood that constitutes science itself. We need to embrace scientists from all walks of life and corners of the globe; this 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. Science policy deals with creating the framework and codes of conduct that determine how science can best serve society.4-6 Discussions around science policy are often accompanied by anecdotes of “good” and “bad” practices regarding the merits of diversity and inclusion. Excellence and truth, which flow inexorably from diversity and inclusion, are the bedrocks upon which science should influence political and economic outcomes. A vital area of science policy is to support the professional development of marginalized scientists, an objective that must be acted upon by scientific leaders and communicators..