Browsing by Author "Harrison, J.J.E.K."
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Item Bis[(3-chlorobenzy]) 2-phenyl- propanediotate dehydrate(Acta Crystallographica section E 8(E66):02/68, 2010) Kingsford-Adaboh, R.; Harrison, J.J.E.K.; Gotoh, K.; Ishida, H.In the asymmetric unit of the title compound. 2C7H9CIN+… C2H2O22-2H2O, there are two crystallographically independent cations, one dianion and two water molecules. The dihedral angle between the two carboxylate groups of the dianion is 78.1 (2). In the crystal, the components are held together by N-H, O, O-H … O and C-H … O hydrogen bonds forming a layer parallel to the bc plane, with the bydrophilic and hydrophobic groups located I the inner and outer regions of the layers, respectively.Item Centrosymmetric structures of three substituted malonic acids(Journal of Chemical Crystallography 3(41): 306-311, 2010) Kingsford-Adaboh, R.; Harrison, J.J.E.K.; Ueda, S.; Gotoh, K.; Ishida, H.Crystal structures of 2-methylmalonic acid 2-ethlmalonic acid and 2-phenylmalonic acid, which are derivatives of malonic acid and have found usefulness in diagnostics and biochemical evaluations as markers and organic synthesis, are reported. 2-Methylmalonic acid and 2-ethylmalonic acid both crystallize in triclinic P-1 space group with cell parameters of a = 5.1033(7), b = 5.4231(7), c = 10.0887(14) , Ǎ = 88.074(4), = 89.999(5) and = 67.955()o for 2-methylmalonic acid, and a = 5.2073(4), b = 7.2258(6), c = 8.5655(6) Ǎ, a = 88.086(2), β = 75.307(2) and y = 85.904(3)o for 2-ethylmalonic acid, 2-phenylamlonic acid on the other hand crystallizes in monoclinic P21/c with cell parameters a = 8.6494(4), b = 5.48733(1(), c = 17.1706(6) Ǎ and β = 90.1068(17)o. The observed topology of the hydrogen bonding network is to a large extent dictated by the symmetrical substitution pattern with an open arrangement of hydrogen bonds. Each of the C=O double bonds in both 2-methylmalonic acid and 2-ethylmalonic acid in translationally offset, forming planarcentrosymmetric carboxy-dimmers. Molecules related by centre of inversion in spite of the constraints imposed by substituents are linked by O-H .. O hydrogen bonds. This results in the formation of paralled zig-zag chains running along the [101] direction. In 2-phenylmalonic acid, the zig-zag molecular residue is parallely stacked with successive catemers. These laterally displaced catemers are also coiled in a twofold twist on the screw axis (x, ½ + y, ½ - z) along the b-glide (x, ½ = y, ½ z) when viewed along the (101) plane.Item Crystal structure and in vitro antimicrobial activity studies of Robustic acid and other Alpinumisoflavones isolated from Millettia thonningii(Zeitschrift fur Kristallographie - Crystalline Materials, 2019-04) Harrison, J.J.E.K.; Ayine-Tora, M.D.; Appiagyei, B.; Mills-Robertson, F.C.; Asomaning, W.A.; Achel, D.G.; Ishida, H.; Kingsford-Adaboh, R.We report a systematic study of the antibacterial inhibitory potential of isoflavone natural products isolated from the seeds extracts of Millettia thonningii. In an effort to gain bond topological information which may have consequences for the observed bioactivities, the crystal structure of robustic acid was solved and refined using the independent atom as well as the invariom model, and the structures were compared. Robustic acid contains a fused tricyclic unit with a benzopyran moiety, with a phenylene ring substitution on the coumarin ring similar to the alpinumisoflavones isolated from this plant. At a minimum inhibitory concentration of ~1 mg/mL, alpinumisoflavone and robustic acid were found to be cytotoxic to Staphylococcus aureus (ATCC 25923) showing a zone of inhibition (ZOI) of ~9 mm. On the other hand, at ~2 mg/mL, these compounds were found to be bacteriostatic to a hospital isolate of Salmonella typhi with about 7 mm ZOI. Taken together, these compounds offer potential new avenues for targeting both Gram positive and negative bacteria and could be useful as chemical probes for understanding these pathogens in an effort to overcome drug resistance.Item Crystal Structure of a Retroviral Polyprotein: Prototype Foamy Virus Protease-Reverse Transcriptase (PR-RT)(Viruses, 2021) Harrison, J.J.E.K.; Tuske, S.; Das, K.; Ruiz, F.X.; Bauman, J.D.; Boyer, P.L.; DeStefano, J.J.; Hughes, S.H.; Arnold, E.In most cases, proteolytic processing of the retroviral Pol portion of the Gag-Pol polyprotein precursor produces protease (PR), reverse transcriptase (RT), and integrase (IN). However, foamy viruses (FVs) express Pol separately from Gag and, when Pol is processed, only the IN domain is released. Here, we report a 2.9 Å resolution crystal structure of the mature PR-RT from prototype FV (PFV) that can carry out both proteolytic processing and reverse transcription but is in a configuration not competent for proteolytic or polymerase activity. PFV PR-RT is monomeric and the architecture of PFV PR is similar to one of the subunits of HIV-1 PR, which is a dimer. There is a C-terminal extension of PFV PR (101-145) that consists of two helices which are adjacent to the base of the RT palm subdomain, and anchors PR to RT. The polymerase domain of PFV RT consists of fingers, palm, thumb, and connection subdomains whose spatial arrangements are similar to the p51 subunit of HIV-1 RT. The RNase H and polymerase domains of PFV RT are connected by flexible linkers. Significant spatial and conformational (sub)domain rearrangements are therefore required for nucleic acid binding. The structure of PFV PR-RT provides insights into the conformational maturation of retroviral Pol polyproteins.Item Crystal structure of three solvated Alpinumisoflavones(Structural Chemistry, 2009-04) Harrison, J.J.E.K.; Tabuchi, Y.; Ishida, H.; Kingsford-Adaboh, R.Single crystals of alpinumisoflavone, C20H16O 5, {systematic name: 5-hydroxy-7-(4 hydroxyphenyl)-2, 2-dimethyl-2H, 6H-benzo [1, 2-b: 5, 4-b′]-dipyran-6-one}, solvated with water, methanol, and ethanol, have been obtained. The incorporation of the solvent molecules into the crystal structure creates a new short inter-molecular O- H•••O and C-H•••O contacts between the alpinumisoflavone moiety and its solvate molecule. The temperatures at which the solvated molecules lose their solvent molecules are 53, 54, and 65 °C for water, methanol, and ethanol, respectively. The observed temperatures at which the solvates efflorescence are reflective of the progressive increase in mass of the solvates from water to ethanol in the series. The benzopyrone moiety shows the usual planar conformation with the pyran ring deformed into a half-chair conformer as seen previously in the other analogous compounds with puckering parameters [Å], 0.2656(8), 0.3703(8), and 0.3957(9), respectively, for the water, ethanol, and methanol solvates. These are higher than the non-solvated alpinumisoflavone compound previously studied. The size of a substituent group proximal to the keto group has a more pronounced effect on the degree of puckering than substitution on the terminal phenyl ring. The attached phenyl ring shows consistent out-of-plane twist from the mean plane of the benzopyrone system as observed previously for this class of compounds. The observed dihedral angles are 30.26(3), 37.75(3), and 34.00(3)°, respectively, for the water, methanol, and ethanol solvates. © 2009 Springer Science+Business Media, LLC.Item Evaluation of the quality of artemisinin-based antimalarial medicines distributed in Ghana and Togo.(Malaria Research and Treatment, Article ID 806416, 2014) Osei-Safo, D.; Agbonon, A.; Konadu, D.Y.; Harrison, J.J.E.K.; Edoh, M.; Gordon, A.; Gbeassor, M.; Addae-Mensah, I.This study, conducted as part of our overall goal of regular pharmacovigilance of antimalarial medicines, reports on the quality of 132 artemisinin-based antimalarial medicines distributed in Ghana and Togo. Three methods were employed in the quality evaluation – Basic (colorimetric) Tests for establishing the identity of the requisite Active Pharmaceutical Ingredients (APIs), semi-quantitative TLC assay for the identification and estimation of API content and HPLC assay for a more accurate quantification of API content. From the basic tests, only one sample totally lacked API. The HPLC assay, however, showed that 83.7% of the ACTs and 57.9% of the artemisinin-based monotherapies failed to comply with International Pharmacopoeia requirements due to insufficient API content. In most of the ACTs, the artemisinin component was usually the insufficient API. Generally, there was a good correlation between the HPLC and SQ-TLC assays. The overall failure rates for both locally-manufactured (77.3%) and imported medicines (77.5%) were comparable. Similarly the unregistered medicines recorded a slightly higher overall failure rate (84.7%) than registered medicines (70.8%). Only two instances of possible cross-border exchange of medicines were observed and there was little difference between the medicine quality of collections from border towns and those from inland parts of both countries.Item Further Validation of a Rapid Screening Semiquantitative Thin-Layer Chromatographic Method for Marketed Antimalarial Medicines for Adoption in Malawi(Journal of Analytical Methods in Chemistry, 2018-05) Osei-Safo, D.; Chikowe, I.; Harrison, J.J.E.K.; Yeboah, D.K.; Addae-Mensah, I.A recently developed semiquantitative thin-layer chromatographic (SQ-TLC) assay has been employed in postmarketing surveillance of antimalarial medicines used in Malawi prior to HPLC assay. Both methods gave analogous results in a significant majority of the samples, with a good correlation ( r = 0.9012) for the active pharmaceutical ingredients of the dosage forms assayed. Artemether-containing medicines had the highest percentage (92.67%) of samples with comparable results for both assays. The lowest percentage (66.67%) was observed in artesunate-containing medicines. The SQ-TLC method was validated for specificity, accuracy, precision, linearity, and stability according to the International Conference on Harmonisation guidelines, with the results falling within acceptable limits. For specificity, retention factor values of the test samples and reference standards were comparable, while accuracy and precision of 91.1 ± 5.7% were obtained for all samples. The method was linear in the range 1.0–2.0 µ g/spot with a correlation coefficient of r = 0.9783. Stability tests also fell within acceptable limits. In this study, we present the validation of the SQ-TLC method and propose its adoption as a rapid screening tool for field estimation of the quality of antimalarial and other essential medicines in Malawi and other parts of the developing world prior to a more accurate HPLC assay.Item In search of new leads: A closer look at the therapeutic potential of the constituents of millettia thonningii, Millettia pachycarpa and their structural analogues(International Journal of Pharmacy and Pharmaceutical Sciences, 2011-01) Harrison, J.J.E.K.; Dankyi, E.; Kingsford-Adaboh, R.; Ishida, H.This review discusses the potential applications of isoflavonoids from Millettia thonningii and M. pachycarpa in developing new pharmaceutical agents based on folkloric anecdotes and evidences from pharmacological and biochemical assays and to encourage further research into their pharmacological applications. Millettia thonningii is a deciduous plant indigenous to tropical West Africa, M. pachycarpa, is a climbing shrub indigenous to South-East Asia and other species have been used in folk-medicine for the treatment of inflammatory diseases, chronic diseases and several pathogenic diseases. Scientific research has implicated several prenylated isoflavonoids as being useful antioxidants and used in the management of radical-mediated diseases such as cancer, diabetes, ischemic heart diseases, Alzheimer's and Parkinson's diseases etc. Chemical investigations into these plants have revealed that they contain several isoflavonoids which bear structural resemblance to some of the isoflavonoids already in allopathic medical usage. Plants continue to maintain their historical stead as a store house of important drug candidates and source of new "leads" for synthetic modifications to improve activity through optimization of pharmacodynamic and pharmacokinetic properties. Natural products have also been found useful in specific pharmacological probes, a potential which is grossly underestimated. The alpinumisoflavones which have been isolated from the Millettia thonningii have shown high toxicities to the brine shrimp while isolates from M. pachycarpa have also shown anti-estrogenic and anticancer properties. Information obtained from crystal structural studies of these alpinumisoflavonoids coupled with their molecular and electronic distribution properties can further our understanding of their therapeutic potential and their observed bioactivities. The alpinumisoflavones are characterized by a fused tricyclic ring system which contains nearly coplanar benzopyrone ring fragments and a puckered six membered pyran ring that adopts a half-chair conformation with inter and intra molecular O-H....O and C-H...O contacts. A phenyl ring attached to the benzopyrone moiety shows out of plane twist with various degrees of torsion depending on the substitution on the phenyl ring.Item Post-marketing surveillance of anti-malarial medicines used in Malawi(Malaria Journal, 2015-03) Chikowe, I.; Osei-Safo, D.; Harrison, J.J.E.K.; Konadu, D.Y.; Addae-Mensah, I.The growing concern over the extent of anti-malarial medicine resistance in sub-Saharan Africa, driven largely by administration of sub-therapeutic doses derived from falsified and substandard medicines necessitates regular monitoring of the quality of these medicines to avert any potential public health disaster. This study aimed at determining the active pharmaceutical ingredient (API) content of anti-malarial medicines available in Malawi with respect to the manufacturers’ label claim and pharmacopoeia specifications. Samples of anti-malarial medicines (112) collected from both licensed and unlicensed markets throughout Malawi were subjected to visual inspection of dosage form and packaging, and registration verification with the regulatory body. Basic (colourimetric) tests were employed to establish the presence and identity of the requisite APIs. Semi-quantitative thin layer chromatography (SQ-TLC) was employed as a quick assay for the verification of identity and estimation of the API content while HPLC assays were used to quantify the APIs. The results were compared with pharmacopoeia specifications and manufacturers’ label claims. For combination therapies, a sample was considered to have failed if one or more of its component APIs did not meet pharmacopoeia specifications. There was 86.6% registration status and 100% compliance with visual inspection and basic tests confirming the presence of requisite APIs. The identification test was confirmed by the SQ-TLC assay. API quantification by HPLC assay however, showed that 88.4% (99/112) of the samples failed the quality tests due to the presence of either insufficient or excessive API. The results suggest the existence of substandard anti-malarial medicines in Malawi. The presence of both excessive and insufficient artemisinin-based and non-artemisinin-based API, clearly points to poor adherence to GMP and improper handling during storage or distribution. The country relies heavily on imported anti-malarial medicines so there is an urgent need to carry out regular and thorough post-market surveillance of medicines to ensure better quality health care delivery. (PDF) Post-marketing surveillance of anti-malarial medicines used in Malawi. Available from: https://www.researchgate.net/publication/275027336_Post-marketing_surveillance_of_anti-malarial_medicines_used_in_Malawi [accessed Oct 22 2018].Item Revealing the Structural Plasticity of SARS-CoV‑2 nsp7 and nsp8 Using Structural Proteomics(2021) Courouble, V.V.; Dey, S.K.; Yadav, R.; Timm, J.; Harrison, J.J.E.K.; Ruiz, F.X.; Arnold, E.; Griffin, P.R.Coronavirus (CoV) nonstructural proteins (nsps) assemble to form the replication−transcription complex (RTC) responsible for viral RNA synthesis. nsp7 and nsp8 are important cofactors of the RTC, as they interact and regulate the activity of RNA-dependent RNA polymerase and other nsps. To date, no structure of the full-length SARS-CoV-2 nsp7:nsp8 complex has been published. The current understanding of this complex is based on structures from truncated constructs, with missing electron densities, or from related CoV species where SARS-CoV-2 nsp7 and nsp8 share upward of 90% sequence identity. Despite available structures solved using crystallography and cryo-EM representing detailed static snapshots of the nsp7:nsp8 complex, it is evident that the complex has a high degree of structural plasticity. However, relatively little is known about the conformational dynamics of the individual proteins and how they complex to interact with other nsps. Here, the solution-based structural proteomic techniques, hydrogen−deuterium exchange mass spectrometry (HDX-MS) and cross-linking mass spectrometry (XL-MS), illuminate the dynamics of SARS-CoV-2 full-length nsp7 and nsp8 proteins and the nsp7:nsp8 protein complex. Results presented from the two techniques are complementary and validate the interaction surfaces identified from the published three-dimensional heterotetrameric crystal structure of the SARS-CoV-2 truncated nsp7:nsp8 complex. Furthermore, mapping of XL-MS data onto higher-order complexes suggests that SARS-CoV-2 nsp7 and nsp8 do not assemble into a hexadecameric structure as implied by the SARS-CoV full-length nsp7:nsp8 crystal structure. Instead, our results suggest that the nsp7:nsp8 heterotetramer can dissociate into a stable dimeric unit that might bind to nsp12 in the RTC without significantly altering nsp7−nsp8 interactions.Item Synthesis and crystal structure studies of three n-phenylphthalimide derivatives(Journal of Chemical Crystallography, 2013-03) Rauf, M.K.; Badshah, A.; Kingsford-Adaboh, R.; Harrison, J.J.E.K.; Ishida, H.The three N-phenylphthalimide derivatives, 2-(3,4-dichlorophenyl) isoindoline-1,3-dione (I), 2-(2,4-dichlorophenyl)isoindoline-1,3-dione (II) and 2-(2,4,5-trichlorophenyl)isoindoline-1,3-dione (III), were synthesized by the condensation of equimolar amounts of phthalic anhydride and 3,4-dichloroaniline, 2,4-dichloroaniline, 2,4,5-trichloroaniline, respectively, under acetic acid reflux and their structures determined by a combination of elemental analysis, FT-IR, 1H & 13C-NMR spectroscopy and single crystal X-ray diffraction studies. Compounds I and II crystallize in a monoclinic crystal system (space group P21/c) with cell parameters of a = 5.7414(2), b = 8.0917(6), c = 26.077(1) Å and β = 99.4709(12) o for compound I, and a = 12.7133(9), b = 13.4328(9), c = 7.2603(5) Å and β = 93.210 (2)o for compound II. On the other hand, compound III crystallizes in a tetragonal crystal system (space group I4 1/a) with a = 13.4607(9) and c = 30.100(2) Å. The phthalimide moieties of these compounds are essentially planar, while the chloro-substituted phenyl ring of each compound shows consistent twist from the phthalimide plane with dihedral angles of 61.02(3), 69.09(3) and 85.78(5)o, respectively, for I, II and III. In the crystal structures of these compounds, a few weak C-H···O interactions form double-tape structures of centrosymmetric dimers of graph-set notation R 2 2 (10) for I and III, and an inversion dimer of graph-set motif R 2 2 (14) for II. In addition, some short contacts of C···C, C···O and Cl·· ·Cl are observed for I, II and III, respectively. © 2013 Springer Science+Business Media New York.Item Validation and application of quality assurance methods developed for artemisinin-based antimalarial drugs to assess the quality of a selection of such drugs distributed in Accra, Ghana(Pyramid Pharmaceutical Group Inc., USA Publication, 2010) Osei-Safo, D.; Harrison, J.J.E.K.; Addae-Mensah, I.A recently developed rapid semi-quantitative Thin Layer Chromatographic (TLC) assay method was applied in the determination of the existence of substandard or counterfeit artemisinin-based antimalarial drugs in the Ghanaian market and also tested for its suitability for rapid assessment of drug quality prior to more rigorous analysis of any suspected counterfeit or substandard drugs. Three methods were employed – Basic Tests, Semi-quantitative TLC assay and High Performance Liquid Chromatographic (HPLC) assay. The basic tests showed that each drug contained the requisite active pharmaceutical ingredient (API). Of the 49 samples (24 single-dose and 25 fixed dose combination formulations) assayed by TLC, only 14 (28.6%) were found to comply with pharmacopoeial specifications. Of the 24 single-dose formulations, 9 of which had been found by the TLC assay to be likely within pharmacopoeial limits, only 4 were eventually found to be fully compliant by HPLC analyses. Two others were marginal. On the basis of the TLC assay, only 5 out of the 25 fixed dose combination formulations that are yet to be accurately assayed by HPLC, appear likely to meet pharmacopoeial specifications. The results of the semi-quantitative TLC technique compare favourably with those of the HPLC and hence can be used for rapid assessment of the quality of antimalarial drugs. The results also indicate that the problem of distribution of substandard and possibly counterfeit artemisinin-based antimalarial drugs exists in Ghana.