Browsing by Author "Amewu, R.K."
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Item Differential constituents in roots, stems and leaves of Newbouldia laevis Thunb. screened by LC/ESI-Q-TOF-MS(Elsevier, 2020) Osei-Safo, D.; Amewu, R.K.; Dermane, A.; et al.Newbouldia laevis (P. Beauv.) Seem. or “Boundary Tree” is a medium sized angiosperm in the Bignoniaceae family. It is native to tropical Africa, especially used in West Africa to mark property boundaries in rural areas. Despite its intensive use in folk medicine, the plant chemical composition is under investigated. The study is aimed at identifying the chemical constituents of N. laevis crude plant extracts by high-performance liquid chromatography (HPLC) on line with an untargeted high-resolution mass spectrometry. The used HPLC method showed to be suitable for the determination of withasomnine, newbouldine, and lapachol derivatives together with other known bioactive compounds like phytosterols and triterpenoids. The importance of these chemical constituents is discussed with respect to the role of N. laevis in West African ethnomedicine. © 2020 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http:// creativecommons.org/licenses/by/4.0/).Item Evaluation of the fluorescent-thin layer chromatography (f-TLC) for the diagnosis of Buruli ulcer disease in Ghana(PLOS ONE, 2022) Amewu, R.K.; Akolgo, G.A.; Asare, M.E.; Abdula, Z.; Ablordey, A.S.; Asiedu, K.Buruli ulcer is a tissue necrosis infection caused by an environmental mycobacterium called Mycobacterium ulcerans (MU). The disease is most prevalent in rural areas with the highest rates in West and Central African countries. The bacterium produces a toxin called mycolactone which can lead to the destruction of the skin, resulting in incapacitating deformities with an enormous economic and social burden on patients and their caregivers. Even though there is an effective antibiotic treatment for BU, the control and management rely on early case detection and rapid diagnosis to avert morbidities. The diagnosis of Mycobacterium ulcerans relies on smear microscopy, culture histopathology, and PCR. Unfortunately, all the current laboratory diagnostics have various limitations and are not available in endemic communities. Consequently, there is a need for a rapid diagnostic tool for use at the community health centre level to enable diagnosis and confirmation of suspected cases for early treatment. The present study corroborated the diagnostic performance and utility of fluorescent-thin layer chromatography (f-TLC) for the diagnosis of Buruli ulcer.Item Optimisation of the synthesis of second generation 1,2,4,5 tetraoxane antimalarials(Elsevier Ltd, 2016) O' Neill, P.M.; Sabbani, S.; Nixon, G.L.; Schnaderbeck, M.; Roberts, N.L.; Shore, E.R.; Riley, C.; Murphy, B.; McGillan, P.; Ward, S.A.; Davies, J.; Amewu, R.K.An efficient route to the synthesis of potent antimalarial aryloxy 1,2,4,5-tetraoxanes is described that permits parallel synthesis for Structure–Activity Relationship (SAR) investigations. Brief details of the in vitro and in vivo antimalarial evaluation are included which enables identification of antimalarial leads for further development. Also described is an improved approach to the synthesis of a selected late-lead compound in just four or five synthetic steps from commercially available starting materials. © 2016Item The Search for Putative Hits in Combating Leishmaniasis: The Contributions of Natural Products Over the Last Decade(Natural Products and Bioprospecting, 2021) Sakyi, P.O.; Devine, R.N.O.A.; Amewu, R.K.; Miller, W.A.; Kwofie, S.K.; Ismaila, E.Despite advancements in the areas of omics and chemoinformatics, potent novel biotherapeutic molecules with new modes of actions are needed for leishmaniasis. The socioeconomic burden of leishmaniasis remains alarming in endemic regions. Currently, reports from existing endemic areas such as Nepal, Iran, Brazil, India, Sudan and Afghanistan, as well as newly affected countries such as Peru, Bolivia and Somalia indicate concerns of chemoresistance to the classical antimonial treatment. As a result, effective antileishmanial agents which are safe and affordable are urgently needed. Natural products from both flora and fauna have contributed immensely to chemotherapeutics and serve as vital sources of new chemical agents. This review focuses on a systematic cross-sectional view of all characterized anti-leishmanial compounds from natural sources over the last decade. Furthermore, IC50/ EC50, cytotoxicity and suggested mechanisms of action of some of these natural products are provided. The natural product classification includes alkaloids, terpenes, terpenoids, and phenolics. The plethora of reported mechanisms involve calcium channel inhibition, immunomodulation and apoptosis. Making available enriched data pertaining to bioactivity and mechanisms of natural products complement current efforts geared towards unraveling potent leishmanicides of therapeutic relevance.Item Setting Our Sights on Infectious Diseases(ACS Infectious Diseases, 2019-12-06) Amewu, R.K.; De Rycker, M.; Horn, D.; Aldridge, B.; Barry, C.E.; Buckner, F.S.; Cook, S.; Ferguson, M.A.J.; Gobeau, N.; Herrmann, J.; Herrling, P.; Hope, W.; Keiser, J.; Lafuente-Monasterio, M.J.; Leeson, P.D.; Leroy, D.; Manjunatha, U.H.; Miles, T.J.; Mizrahi, V.; Moshynets, O.; Niles, J.; Overington, J.P.; Pottage, J.; Rao, S.P.S.; Read, K.D.; Ribeiro, I.; Silver, L.L.; Southern, J.; Spangenberg, T.; Sundar, S.; Taylor, C.; Van Voorhis, W.; White, N.J.; Wyllie, S.; Wyatt, P.G.; Gilbert, I.H.In May 2019, the Wellcome Centre for Anti-Infectives Research (WCAIR) at the University of Dundee, UK, held an international conference with the aim of discussing some key questions around discovering new medicines for infectious diseases and a particular focus on diseases affecting Low and Middle Income Countries. There is an urgent need for new drugs to treat most infectious diseases. We were keen to see if there were lessons that we could learn across different disease areas and between the preclinical and clinical phases with the aim of exploring how we can improve and speed up the drug discovery, translational, and clinical development processes. We started with an introductory session on the current situation and then worked backward from clinical development to combination therapy, pharmacokinetic/pharmacodynamic (PK/PD) studies, drug discovery pathways, and new starting points and targets. This Viewpoint aims to capture some of the learningsItem Synthesis and profiling of benzylmorpholine 1,2,4,5-tetraoxane analogue N205: Towards tetraoxane scaffolds with potential for single dose cure of malaria(Elsevier Ltd, 2018) O’ Neill, P.M.; Stocks, P.A.; Sabbani, S.; Roberts, N.L.; Amewu, R.K.; Shore, E.R.; Aljayyoussi, G.; Angulo-Barturén, I.; Belén, M.; Jiménez-Díaz; Bazaga, S.F.; Martínez, M.S.; Campo, B.; Sharma, R.; Charman, S.A.; Ryan, E.; Chen, G.; Shackleford, D.M.; Davies, J.; Nixon, G.L.; Biagini, G.A.; Ward, S.A.A series of aryl carboxamide and benzylamino dispiro 1,2,4,5-tetraoxane analogues have been designed and synthesized in a short synthetic sequence from readily available starting materials. From this series of endoperoxides, molecules with in vitro IC50s versus Plasmodium falciparum (3D7) as low as 0.84 nM were identified. Based on an assessment of blood stability and in vitro microsomal stability, N205 (10a) was selected for rodent pharmacokinetic and in vivo antimalarial efficacy studies in the mouse Plasmodium berghei and Plasmodium falciparum Pf3D70087/N9 severe combined immunodeficiency (SCID) mouse models. The results indicate that the 4-benzylamino derivatives have excellent profiles with a representative of this series, N205, an excellent starting point for further lead optimization studies. © 2018Item Synthetic and Naturally Occurring Heterocyclic Anticancer Compounds with Multiple Biological Targets(MDPI, 2021) Osei-Safo, D.; Amewu, R.K.; Sakyi, P.O.; et al.Abstract: Cancer is a complex group of diseases initiated by abnormal cell division with the potential of spreading to other parts of the body. The advancement in the discoveries of omics and bio- and cheminformatics has led to the identification of drugs inhibiting putative targets including vascular endothelial growth factor (VEGF) family receptors, fibroblast growth factors (FGF), platelet derived growth factors (PDGF), epidermal growth factor (EGF), thymidine phosphorylase (TP), and neuropeptide Y4 (NY4), amongst others. Drug resistance, systemic toxicity, and drug ineffectiveness for various cancer chemo-treatments are widespread. Due to this, efficient therapeutic agents targeting two or more of the putative targets in different cancer cells are proposed as cutting edge treatments. Heterocyclic compounds, both synthetic and natural products, have, however, contributed immensely to chemotherapeutics for treatments of various diseases, but little is known about such compounds and their multimodal anticancer properties. A compendium of heterocyclic synthetic and natural product multitarget anticancer compounds, their IC50, and biological targets of inhibition are therefore presented in this review.Item Targeting Leishmania donovani sterol methyltransferase for leads using pharmacophore modeling and computational molecular mechanics studies(Informatics in Medicine Unlocked, 2023) Sakyi, P.O.; Broni, E.; Amewu, R.K.; Miller III, W.A.; Wilson, M.D.; Kwofie, S.K.The mortalities and morbidities of leishmaniasis are high and the disease is under reported globally. The absence of vaccines coupled with chemotherapeutic challenges including chemoresistance, scarcity and toxicity have made the fight against leishmaniasis an arduous one. Furthermore, the treatment options currently available for leishmaniasis are long and sometimes require hospitalization. There is therefore the need to explore novel pathways to identify new compounds with alternative mechanisms of action. A pharmacophore-based screening was employed in identifying new potential inhibitors with unique scaffolds targeting Leishmania donovani sterol methyltransferase (LdSMT), a key enzyme for ergosterol biosynthesis. To accomplish this, 22,26-azasterol, a known inhibitor of this target and five other derivatives with IC50 less than 10 μM were used to generate a robust 3D pharmacophore model via LigandScout with a score of 0.9144. The validated model was used as a query to screen a library of 69034 natural products obtained from the InterBioScreen Limited. Compounds with pharmacophore fit scores above 50 were docked against the modelled structure of LdSMT. Altogether, ten molecules with binding energies between − 7 and − 11 kcal/mol were identified as potential bioactive molecules. The molecular dynamics simulation and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations reinforced the results from the docking studies suggesting the selected hits bind effectively at the active sites of the target protein. The compounds were observed to bind in the S-adenosine-L-homocysteine binding pocket of the modelled LdSMT with Trp208 and Val330 predicted as key residues critical for ligand binding. Prediction of biological activity with probability of activity (Pa) greater than probability of inactivity (Pi) revealed that seven compounds (STOCKIN-54848, STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, STOCKIN-76694, STOCKIN-47277 and STOCKIN-95708) possessed antileishmanial properties. STOCKIN-89115, STOCKIN-68720, STOCKIN-44724, and STOCKIN-47277 were predicted to be membrane perme ability inhibitors, while all ten hit compounds possessed antineoplastic activity. The compounds have the propensity of disrupting ergosterol biosynthesis leading to the suppression of growth in Leishmania donovani. The compounds were predicted to have good absorption, distribution, metabolism, excretion and toxicity profiles, hence their potential antileishmanial activity can be exploited upon experimental corroboration.Item A tetraoxane-based antimalarial drug candidate that overcomes PfK13-C580Y dependent artemisinin resistance(Nature Communications, 2017) O'Neill, P.M.; Amewu, R.K.; Charman, S.A.; Sabbani, S.; Gnädig, N.F.; Straimer, J.; Fidock, D.A.; Shore, E.R.; Roberts, N.L.; Wong, M.H.-L.; Hong, W.D.; Pidathala, C.; Riley, C.; Murphy, B.; Aljayyoussi, G.; Gamo, F.J.; Sanz, L.; Rodrigues, J.; Cortes, C.G.; Herreros, E.; Angulo-Barturén, I.; Jiménez-Díaz, M.B.; Bazaga, S.F.; Martínez-Martíne, M.S.; Campo, B.; Sharma, R.; Ryan, E.; Shackleford, D.M.; Campbell, S.; Smith, D.A.; Wirjanata, G.; Noviyanti, R.; Price, R.N.; Marfurt, J.; Palmer, M.J.; Copple, I.M.; Mercer, A.E.; Ruecker, A.; Delves, M.J.; Sinden, R.E.; Siegl, P.; Davies, J.; Rochford, R.; Kocken, C.H.M.; Zeeman, A.-M.; Nixon, G.L.; Biagini, G.A.; Ward, S.A.K13 gene mutations are a primary marker of artemisinin resistance in Plasmodium falciparum malaria that threatens the long-term clinical utility of artemisinin-based combination therapies, the cornerstone of modern day malaria treatment. Here we describe a multinational drug discovery programme that has delivered a synthetic tetraoxane-based molecule, E209, which meets key requirements of the Medicines for Malaria Venture drug candidate profiles. E209 has potent nanomolar inhibitory activity against multiple strains of P. falciparum and P. vivax in vitro, is efficacious against P. falciparum in in vivo rodent models, produces parasite reduction ratios equivalent to dihydroartemisinin and has pharmacokinetic and pharmacodynamic characteristics compatible with a single-dose cure. In vitro studies with transgenic parasites expressing variant forms of K13 show no cross-resistance with the C580Y mutation, the primary variant observed in Southeast Asia. E209 is a superior next generation endoperoxide with combined pharmacokinetic and pharmacodynamic features that overcome the liabilities of artemisinin derivatives. © 2017 The Author(s).