The Design and Development of a Potent and Selective Novel Diprolyl Derivative That Binds to the N-Domain of Angiotensin-I Converting Enzyme

Angiotensin-I converting enzyme (ACE) is a zinc metallo­protease consisting of two catalytic domains (N- and C-). Most clinical ACE inhibitor(s) (ACEi) have been shown to inhibit both domains nonselectively, resulting in adverse effects such as cough and angioedema. Selectively inhibiting the individual domains is likely to reduce these effects and potentially treat fibrosis in addition to hypertension. ACEi from the GVK Biosciences database were inspected for possible N-domain selective binding patterns. From this set, a diprolyl chemical series was modeled using docking simulations. The series was expanded based on key target interactions involving residues known to impart N-domain selectivity. In total, seven diprolyl compounds were synthesized and tested for N-domain selective ACE inhibition. One compound with an aspartic acid in the P₂ position (compound <b>16</b>) displayed potent inhibition (<i>K</i>_i = 11.45 nM) and was 84-fold more selective toward the N-domain. A high-resolution crystal structure of compound <b>16</b> in complex with the N-domain revealed the molecular basis for the observed selectivity

Mathematical analysis of a model for the transmission dynamics of Trichomonas vaginalis (TV) and HIV coinfection

A deterministic model for the transmission dynamics of HIV and Trichomonas vaginalis (TV) in a human population is designed and rigorously analysed. The model is shown to exhibit the phenomenon of backward bifurcation, where a stable disease‐free equilibrium coexists with a stable endemic equilibrium whenever the associated reproduction number is less than unity. This phenomenon can be removed by assuming that the coinfection of individuals with HIV and TV is negligible. Furthermore, in the absence of coinfection, the disease‐free equilibrium of the model is shown to be globally asymptotically stable whenever the associated reproduction number is less than unity. Numerical simulation of the model, using initial and demographic data, shows that increased incidence of TV in a population increases HIV incidence in the population. It is further shown that control strategies, such as the treatment, condom use, and counselling of individuals with TV symptoms, can lead to the effective control or elimination of the HIV in the population if their effectiveness level is high enough. The time to disease elimination is reduced if more than one strategy (hybrid strategy) is considered.South African DST/NRF SARChI chair on Mathematical Models and Methods in Bioengineering and Biosciences (M3B2) and DST-NRF Centre of Excellence in Mathematical and Statistical Sciences (CoE-MaSS).http://wileyonlinelibrary.com/journal/mma2019-12-01hj2019Mathematics and Applied Mathematic

Synthesis and Evaluation of the Performance of a Small Molecule Library Based on Diverse Tropane-Related Scaffolds

A unified synthetic approach was developed that enabled the synthesis of diverse tropane-related scaffolds. The key intermediates that were exploited were cycloadducts formed by reaction between 3-hydroxy-pyridinium salts and vinyl sulfones or sulfonamides. The diverse tropane-related scaffolds were formed by addition of substituents to, cyclisation reactions of, and fusion of additional ring(s) to the key bicyclic intermediates. A set of 53 screening compounds was designed, synthesised and evaluated in order to determine the biological relevance of the scaffolds accessible using the synthetic approach. Two inhibitors of Hedgehog signalling, and four compounds with weak activity against the parasite P. falciparum, were discovered. Three of the active compounds may be considered to be indotropane or pyrrotropane pseudo natural products in which a tropane is fused with a fragment from another natural product class. It was concluded that the unified synthetic approach had yielded diverse scaffolds suitable for the design of performance-diverse screening libraries

Anticancer properties of distinct antimalarial drug classes

We have tested five distinct classes of established and experimental antimalarial drugs for their anticancer potential, using a panel of 91 human cancer lines. Three classes of drugs: artemisinins, synthetic peroxides and DHFR (dihydrofolate reductase) inhibitors effected potent inhibition of proliferation with IC 50 s in the nM- low µM range, whereas a DHODH (dihydroorotate dehydrogenase) and a putative kinase inhibitor displayed no activity. Furthermore, significant synergies were identified with erlotinib, imatinib, cisplatin, dasatinib and vincristine. Cluster analysis of the antimalarials based on their differential inhibition of the various cancer lines clearly segregated the synthetic peroxides OZ277 and OZ439 from the artemisinin cluster that included artesunate, dihydroartemisinin and artemisone, and from the DHFR inhibitors pyrimethamine and P218 (a parasite DHFR inhibitor), emphasizing their shared mode of action. In order to further understand the basis of the selectivity of these compounds against different cancers, microarray-based gene expression data for 85 of the used cell lines were generated. For each compound, distinct sets of genes were identified whose expression significantly correlated with compound sensitivity. Several of the antimalarials tested in this study have well-established and excellent safety profiles with a plasma exposure, when conservatively used in malaria, that is well above the IC 50 s that we identified in this study. Given their unique mode of action and potential for unique synergies with established anticancer drugs, our results provide a strong basis to further explore the potential application of these compounds in cancer in pre-clinical or and clinical settings

Identification of 2,4-Disubstituted Imidazopyridines as Hemozoin Formation Inhibitors with Fast-Killing Kinetics and In Vivo Efficacy in the Plasmodium falciparum NSG Mouse Model

A series of 2,4-disubstituted imidazopyridines, originating from a SoftFocus Kinase library, was identified from a high throughput phenotypic screen against the human malaria parasite Plasmodium falciparum. Hit compounds showed moderate asexual blood stage activity. During lead optimization, several issues were flagged such as cross-resistance against the multidrug-resistant K1 strain, in vitro cytotoxicity, and cardiotoxicity and were addressed through structure–activity and structure–property relationship studies. Pharmacokinetic properties were assessed in mice for compounds showing desirable in vitro activity, a selectivity window over cytotoxicity, and microsomal metabolic stability. Frontrunner compound 37 showed good exposure in mice combined with good in vitro activity against the malaria parasite, which translated into in vivo efficacy in the P. falciparum NOD-scid IL-2Rγnull (NSG) mouse model. Preliminary mechanistic studies suggest inhibition of hemozoin formation as a contributing mode of action

Stuart Warren (24 Dec 1938–22 Mar 2020)

Celebrating the life of Stuart Warren

Antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains inhibit microtubule and hemozoin formation : structure–activity relationship and in vivo oral efficacy studies

A novel series of antimalarial benzimidazole derivatives incorporating phenolic Mannich base side chains at the C2 position, which possess dual asexual blood and sexual stage activities, is presented. Structure–activity relationship studies revealed that the 1-benzylbenzimidazole analogues possessed submicromolar asexual blood and sexual stage activities in contrast to the 1H-benzimidazole analogues, which were only active against asexual blood stage (ABS) parasites. Further, the former demonstrated microtubule inhibitory activity in ABS parasites but more significantly in stage II/III gametocytes. In addition to being bona fide inhibitors of hemozoin formation, the 1H-benzimidazole analogues also showed inhibitory effects on microtubules. In vivo efficacy studies in Plasmodium berghei-infected mice revealed that the frontrunner compound 41 exhibited high efficacy (98% reduction in parasitemia) when dosed orally at 4 × 50 mg/kg. Generally, the compounds were noncytotoxic to mammalian cells.The University of Cape Town, South African Medical Research Council and South African Research Chairs Initiative of the Department of Science and Innovation, administered through the South African National Research Foundation (NRF) and a NRF Community of Practice on ‘Evaluating Malaria Control Interventions’.http://pubs.acs.org/loi/jmcmar2022-04-12hj2021BiochemistryGeneticsMicrobiology and Plant PathologyUP Centre for Sustainable Malaria Control (UP CSMC

How can natural products serve as a viable source of lead compounds for the development of new/novel anti-malarials?

Malaria continues to be an enormous global health challenge, with millions of new infections and deaths reported annually. This is partly due to the development of resistance by the malaria parasite to the majority of established anti-malarial drugs, a situation that continues to hamper attempts at controlling the disease. This has spurred intensive drug discovery endeavours geared towards identifying novel, highly active anti-malarial drugs, and the identification of quality leads from natural sources would greatly augment these efforts. The current reality is that other than compounds that have their foundation in historic natural products, there are no other compounds in drug discovery as part of lead optimization projects and preclinical development or further that have originated from a natural product start-point in recent years. This paper briefly presents both classical as well as some more modern, but underutilized, approaches that have been applied outside the field of malaria, and which could be considered in enhancing the potential of natural products to provide or inspire the development of anti-malarial lead compounds