Analysis of non-peptidic compounds as potential malarial inhibitors against plasmodial cysteine proteases via integrated virtual screening workflow
- Musyoka, Thommas M, Kanzi, Aquillah M, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123074 , vital:35403 , https://doi.10.1080/07391102.2015.1108231
- Description: Malaria is an infectious disease caused by a diverse group of erythrocytic protozoan parasites of the genus Plasmodium. It remains an exigent public health problem in the tropical areas of Africa, South America and parts of Asia and continues to take its toll in morbidity and mortality with half of the world’s population under a permanent risk of infection leading to more than half a million deaths annually (WHO, 2013). Five Plasmodium species, namely P. falciparum (Pf ), P. vivax (Pv), P. ovale (Po), P. malariae (Pm) and P. knowlesi (Pk), are known to infect humans with Pf responsible for more than 90% of the malarial fatalities reported in sub-Saharan Africa. The predominance of Pf is attributed to its adaptability (Ashley, McGready, Proux, & Nosten, 2006; Prugnolle et al., 2011). Although the high occurrence of the Duffy negative trait among African populations lowers the threat posed by Pv, it is the most frequent and widely causative agent of benign tertian malaria in other parts of the world (Mendis, Sina, Marchesini, & Carter, 2001). In addition to the listed human malarial parasite forms, several other Plasmodium species, which infect non-human laboratory models, have been identified and are of significant importance in understanding the parasite biology, the host–parasite interactions and in the drug development process (Langhorne et al., 2011).
- Full Text:
- Date Issued: 2016
- Authors: Musyoka, Thommas M , Kanzi, Aquillah M , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2016
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/123074 , vital:35403 , https://doi.10.1080/07391102.2015.1108231
- Description: Malaria is an infectious disease caused by a diverse group of erythrocytic protozoan parasites of the genus Plasmodium. It remains an exigent public health problem in the tropical areas of Africa, South America and parts of Asia and continues to take its toll in morbidity and mortality with half of the world’s population under a permanent risk of infection leading to more than half a million deaths annually (WHO, 2013). Five Plasmodium species, namely P. falciparum (Pf ), P. vivax (Pv), P. ovale (Po), P. malariae (Pm) and P. knowlesi (Pk), are known to infect humans with Pf responsible for more than 90% of the malarial fatalities reported in sub-Saharan Africa. The predominance of Pf is attributed to its adaptability (Ashley, McGready, Proux, & Nosten, 2006; Prugnolle et al., 2011). Although the high occurrence of the Duffy negative trait among African populations lowers the threat posed by Pv, it is the most frequent and widely causative agent of benign tertian malaria in other parts of the world (Mendis, Sina, Marchesini, & Carter, 2001). In addition to the listed human malarial parasite forms, several other Plasmodium species, which infect non-human laboratory models, have been identified and are of significant importance in understanding the parasite biology, the host–parasite interactions and in the drug development process (Langhorne et al., 2011).
- Full Text:
- Date Issued: 2016
Benzimidazole or Diamide From a Reaction of Diamines and Carboxylic Acids or Acid Chlorides: Crystal Structures and Theoretical Studies
- Odame, Felix, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447938 , vital:74685 , xlink:href="https://pdfs.semanticscholar.org/bf5a/ce94c9436f40059793eb988e08da8ef09886.pdf"
- Description: A reaction of an acid chloride with a diamine yielded a diamide. m-Toluic acid was chlorinated to m-toluoyl chloride and subsequently reacted with 4-methyl-o-phenylenediamine in pyridine to obtain 3-methyl-N-[2-(3-methylbenzamido)phenylbenzamide (I). 2-(3-Methylphenyl)-1H-benzimidazole (II) has been obtained upon reacting o-phenylenediamine with m-toluic acid in polyphosphoric acid and toluene. The compounds have been characterized by IR, NMR, microanalyses and GC-MS. The crystal structures of the compounds have been discussed. DFT calculations of the frontier orbitals of the precursor compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity in the formation of the diamides and benzimidazoles. The synthesis of the amide from a diamine was seen to be favoured in the presence of a good leaving group attached to the carbonyl as in the case of acid chloride. However, the synthesis of benzimidazoles was found to be favoured in the presence of an excess of a protonating agent and high temperature.
- Full Text:
- Date Issued: 2015
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447938 , vital:74685 , xlink:href="https://pdfs.semanticscholar.org/bf5a/ce94c9436f40059793eb988e08da8ef09886.pdf"
- Description: A reaction of an acid chloride with a diamine yielded a diamide. m-Toluic acid was chlorinated to m-toluoyl chloride and subsequently reacted with 4-methyl-o-phenylenediamine in pyridine to obtain 3-methyl-N-[2-(3-methylbenzamido)phenylbenzamide (I). 2-(3-Methylphenyl)-1H-benzimidazole (II) has been obtained upon reacting o-phenylenediamine with m-toluic acid in polyphosphoric acid and toluene. The compounds have been characterized by IR, NMR, microanalyses and GC-MS. The crystal structures of the compounds have been discussed. DFT calculations of the frontier orbitals of the precursor compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity in the formation of the diamides and benzimidazoles. The synthesis of the amide from a diamine was seen to be favoured in the presence of a good leaving group attached to the carbonyl as in the case of acid chloride. However, the synthesis of benzimidazoles was found to be favoured in the presence of an excess of a protonating agent and high temperature.
- Full Text:
- Date Issued: 2015
Characterization of some amino acid derivatives of benzoyl isothiocyanate: Crystal structures and theoretical prediction of their reactivity
- Odame, Felix, Hosten, Eric C, Betz, Richard, Lobb, Kevin A, Tshentu, Zenixole R
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447952 , vital:74686 , xlink:href="https://doi.org/10.1016/j.molstruc.2015.05.053"
- Description: The reaction of benzoyl isothiocyanate with L-serine, L-proline, D-methionine and L-alanine gave 2-[(benzoylcarbamothioyl)amino]-3-hydroxypropanoic acid (I), 1-(benzoylcarbamothioyl)pyrrolidine-2-carboxylic acid (II), 2-[(benzoylcarbamothioyl)amino]-4-(methylsulfanyl)butanoic acid (III) and 2-[(benzoylcarbamothioyl)amino]propanoic acid (IV), respectively. The compounds have been characterized by IR, NMR, microanalyses and mass spectrometry. The crystal structures of all the compounds have also been discussed. Compound II showed rotamers in solution. DFT calculations of the frontier orbitals of the compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity of these compounds. The calculations indicated that the carboxylic acid group in these compounds is unreactive hence making the conversion to benzimidazoles via cyclization on the carboxylic acids impractical. This has been further confirmed by the reaction of compounds I–IV, respectively, with o-phenylene diamine which was unsuccessful but gave compound V.
- Full Text:
- Date Issued: 2015
- Authors: Odame, Felix , Hosten, Eric C , Betz, Richard , Lobb, Kevin A , Tshentu, Zenixole R
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447952 , vital:74686 , xlink:href="https://doi.org/10.1016/j.molstruc.2015.05.053"
- Description: The reaction of benzoyl isothiocyanate with L-serine, L-proline, D-methionine and L-alanine gave 2-[(benzoylcarbamothioyl)amino]-3-hydroxypropanoic acid (I), 1-(benzoylcarbamothioyl)pyrrolidine-2-carboxylic acid (II), 2-[(benzoylcarbamothioyl)amino]-4-(methylsulfanyl)butanoic acid (III) and 2-[(benzoylcarbamothioyl)amino]propanoic acid (IV), respectively. The compounds have been characterized by IR, NMR, microanalyses and mass spectrometry. The crystal structures of all the compounds have also been discussed. Compound II showed rotamers in solution. DFT calculations of the frontier orbitals of the compounds have been carried out to ascertain the groups that contribute to the HOMO and LUMO, and to study their contribution to the reactivity of these compounds. The calculations indicated that the carboxylic acid group in these compounds is unreactive hence making the conversion to benzimidazoles via cyclization on the carboxylic acids impractical. This has been further confirmed by the reaction of compounds I–IV, respectively, with o-phenylene diamine which was unsuccessful but gave compound V.
- Full Text:
- Date Issued: 2015
Isomerization of the 2-Norbornyl Carbocation
- Authors: Lobb, Kevin A
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447992 , vital:74689 , xlink:href="https://doi.org/10.1002/ejoc.201500518"
- Description: In order to elucidate the mechanism for the isomerization of the 2-norbornyl carbocation into its most stable isomer, the 1,3-dimethylcyclopentenyl carbocation, an extensive set of the possible isomers of C7H11+ has been generated. Each one of these may undergo a number of transformations, and location of these transition states provides a searchable graph, from which pathways may be identified. This reveals that the preferred route for isomerization of the 2-norbornyl carbocation is not by ring opening of the non-classical center as has been reported in the literature (with an activation energy of 33.2 kcal/mol), but is initiated by cleavage of the C3–C4 bond (23.5 kcal/mol). Further, no single mechanism is sufficient to describe the full sequence of isomerizations of the 2-norbornyl carbocation to its most stable isomer, the 1,3-dimethylcylcopentenyl carbocation, but rather a collection (> 109) of pathways.
- Full Text:
- Date Issued: 2015
- Authors: Lobb, Kevin A
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/447992 , vital:74689 , xlink:href="https://doi.org/10.1002/ejoc.201500518"
- Description: In order to elucidate the mechanism for the isomerization of the 2-norbornyl carbocation into its most stable isomer, the 1,3-dimethylcyclopentenyl carbocation, an extensive set of the possible isomers of C7H11+ has been generated. Each one of these may undergo a number of transformations, and location of these transition states provides a searchable graph, from which pathways may be identified. This reveals that the preferred route for isomerization of the 2-norbornyl carbocation is not by ring opening of the non-classical center as has been reported in the literature (with an activation energy of 33.2 kcal/mol), but is initiated by cleavage of the C3–C4 bond (23.5 kcal/mol). Further, no single mechanism is sufficient to describe the full sequence of isomerizations of the 2-norbornyl carbocation to its most stable isomer, the 1,3-dimethylcylcopentenyl carbocation, but rather a collection (> 109) of pathways.
- Full Text:
- Date Issued: 2015
SANCDB: a South African natural compound database
- Hatherley, Rowan, Brown, David K, Musyoka, Thommas M, Penkler, David L, Faya, Ngonidzashe, Lobb, Kevin A, Tastan Bishop, Özlem
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148337 , vital:38730 , DOI: 10.1186/s13321-015-0080-8
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
- Authors: Hatherley, Rowan , Brown, David K , Musyoka, Thommas M , Penkler, David L , Faya, Ngonidzashe , Lobb, Kevin A , Tastan Bishop, Özlem
- Date: 2015
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/148337 , vital:38730 , DOI: 10.1186/s13321-015-0080-8
- Description: Natural products (NPs) are important to the drug discovery process. NP research efforts are expanding world-wide and South Africa is no exception to this. While freely-accessible small molecule databases, containing compounds isolated from indigenous sources, have been established in a number of other countries, there is currently no such online database in South Africa.
- Full Text:
- Date Issued: 2015
Synthetic analogues of the marine bisindole deoxytopsentin: potent selective inhibitors of MRSA pyruvate kinase
- Veale, Clinton G L, Zoraghi, Roya, Young, Ryan M, Morrison, James P, Pretheeban, Manoj, Lobb, Kevin A, Reiner, Neil E, Andersen, Raymond J, Davies-Coleman, Michael T
- Authors: Veale, Clinton G L , Zoraghi, Roya , Young, Ryan M , Morrison, James P , Pretheeban, Manoj , Lobb, Kevin A , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448045 , vital:74693 , xlink:href="https://doi.org/10.1021/np500755v"
- Description: As part of an ongoing study to elucidate the SAR of bisindole alkaloid inhibitors against the evolutionary conserved MRSA pyruvate kinase (PK), we present here the synthesis and biological activity of six dihalogenated analogues of the naturally occurring sponge metabolite deoxytopsentin, including the naturally occurring dibromodeoxytopsentin. The most active compounds displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity.
- Full Text:
- Date Issued: 2015
- Authors: Veale, Clinton G L , Zoraghi, Roya , Young, Ryan M , Morrison, James P , Pretheeban, Manoj , Lobb, Kevin A , Reiner, Neil E , Andersen, Raymond J , Davies-Coleman, Michael T
- Date: 2015
- Subjects: To be catalogued
- Language: English
- Type: text , article
- Identifier: http://hdl.handle.net/10962/448045 , vital:74693 , xlink:href="https://doi.org/10.1021/np500755v"
- Description: As part of an ongoing study to elucidate the SAR of bisindole alkaloid inhibitors against the evolutionary conserved MRSA pyruvate kinase (PK), we present here the synthesis and biological activity of six dihalogenated analogues of the naturally occurring sponge metabolite deoxytopsentin, including the naturally occurring dibromodeoxytopsentin. The most active compounds displayed potent low nanomolar inhibitory activity against MRSA PK with concomitant significant selectivity for MRSA PK over human PK orthologues. Computational studies suggest that these potent MRSA PK inhibitors occupy a region of the small interface of the enzyme tetramer where amino acid sequence divergence from common human PK orthologues may contribute to the observed selectivity.
- Full Text:
- Date Issued: 2015
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