OpenUCT :: Browsing by Author "Chibale, Kelly"

Browsing by Author "Chibale, Kelly"

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Open Access
Anti-cancer and anti-malarial 4-aminoquinoline derivatives : synthesis and solid-state investigations
(2006) Melo, Candice Soares de; Chibale, Kelly; Caira, Mino R
The work presented in this thesis is two-fold: (i) development of single agents that provide inhibition of both the growth of malaria parasites and of tumour cells in vitro, and (ii) inclusion of these potential novel inhibitors in cyclodextrin host molecules in an attempt to render these dual drugs water-soluble. Of all the current clinically established antimalarials, the 4-aminoquinolines haveproven to be the most significant and efficacious for the treatment and prophylaxis of malaria. However, their efficacy has decreased by the spread of drug resistant strains of the causative agent Plasmodium Jalciparum. Future research into 4-aminoquinoline derivatives as antimalarial agents is still warranted and justified on the basis of several considerations. The quinoline moiety has also been shown to be a substructure in multi-drug resistance reversal agents against certain cancer cell lines and antitumour agents which have demonstrated the ability to act as differentiation-inducing agents. The strategy employed for this project was to hybridize chalcone moieties and their Mannich base derivatives with the 4-aminoquinoline moiety. This dual drug concept uses the basic structure of the chalcone scaffold, which has a wide range of known antimalarial and anticancer activities, and is hybridised with the 4-aminoquinoline moiety, in order to exert maximal biological activity and overcome or prevent drug resistance. Structural variation on the aromatic rings of the chalcone scaffold allowed preliminary structure-activity relationship studies to be undertaken.
Open Access
Anticancer properties of distinct antimalarial drug classes
(Public Library of Science, 2013) Hooft van Huijsduijnen, Rob; Guy, R Kiplin; Chibale, Kelly; Haynes, Richard K; Peitz, Ingmar; Kelter, Gerhard; Phillips, Margaret A; Vennerstrom, Jonathan L; Yuthavong, Yongyuth; Wells, Timothy N C
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.
Open Access
Antimalarial activity and pharmacokinetic properties of new chemical entities
(2013) Dambuza, Ntokozo Shirley; Smith, Peter John; Wiesner, Lubbe; Chibale, Kelly
Includes abstract. Includes bibliographical references.
Open Access
Antimalarial and cysteine protease inhibitor pharmacophores as scaffolds for new antimalarial agents
(2005) Musonda, Chitalu Christopher; Chibale, Kelly
The work in this thesis is threefold: (i) A new series of antiplasmodial agents were initially designed based on the β-amino alcohol bioactiphore, a subunit that is found in a number of antimalarial agents. (ii) Various thiosemicarbozones and semicarbozones were designed and synthesized as potential mechanism-based inhibiotrs of parasitic cysteine proteases. (iii) Multicomponenet reactions offer the advantage of introducing chemical diversity in fewer steps than conventional multi step organic synthesis. New chloroquine-type compounds were designed and synthesized using the Ugi 4 component condensation reaction and its variants. The synthesized compounds ranged from simple peptidic molecules to rigid heterocycles.
Open Access
Antimalarial benzimidazoles and related structures incorporating an intramolecular hydrogen bonding motif: medicinal chemistry and mechanistic studies
(2021) Attram, Henrietta Dede; Chibale, Kelly
Malaria, an infectious disease caused by Plasmodium parasites, continues to take an enormous toll on human health, particularly in tropical regions. According to the World Health Organization (WHO), progress against malaria eradication has stalled, specifically in the African region. Global efforts to curb the disease are being undermined by the gaps in access to vital tools. In 2019, about 229 million cases were recorded compared to the 228 million cases recorded in 2018. This is an annual estimate that has not changed significantly over the last four (4) years. Also, children under the age of five (5) years account for most malaria deaths worldwide. Chemotherapy represents one of the most effective control measures to mitigate the malaria burden, with the WHO presently recommending the use of artemisinin combination therapies (ACTs) to treat uncomplicated malaria. However, there is compelling evidence from Southeast Asia and recently in Rwanda (Africa) describing the emergence and spread of ACT resistance, characterized by reduced clearance rates of P. falciparum parasites. In some countries, resistance to partner drugs such as amodiaquine has been observed. These developments highlight the need to expand the antimalarial drug arsenal by exploring and developing new compound classes, preferably with a combination of novel modes of action, multistage activity, good safety profile, efficacy at low doses and reduced tendency to the development of resistance. In this study, two classes of compounds, benzimidazoles and imidazopyridines, incorporating an intramolecular hydrogen bonding (IMHB) motif, were explored for their antimalarial potential. These two chemotypes were selected on account of their privileged nature due to their capacity to interact with various biological systems, leading to a wide variety of biological activities, including antimalarial activity. Structural modifications around the benzimidazole scaffold resulted in the classification of these analogues into 1H-benzimidazoles and N-benzyl benzimidazoles (astemizole-based). In this regard, 33 benzimidazole analogues were synthesized, fully characterized and evaluated in vitro for their antiplasmodium activity against both the drug-sensitive NF54 and the multidrug-resistant K1 strains of the Plasmodium parasite. As a result, the 1H-benzimidazole analogues manifested sub-micromolar potencies against the chloroquine-sensitive NF54 strain of P. falciparum, with IC50 values between 0.079 µM and 0.968 µM. The most potent analogue within this series was compound 1.3 (Figure 1) with an IC50 of 0.079 µM against the chloroquine-sensitive strain and 0.335 µM against the multidrug-resistant (K1) strain. The resistance index of compound 1.3 (RI = 4) suggests the possibility of cross-resistance with drugs like chloroquine. The N-benzyl benzimidazole (astemizole-based) also displayed sub-micromolar activity against the chloroquine-sensitive strain of the parasite, with compound 2.3 (Figure 1) displaying the highest potency (IC50 PfNF54 = 0.029 µM and IC50 PfK1 = 0.117 µM) within the series. Generally, the benzimidazole analogues exhibited poor activity against the sexual gametocyte stage of the Plasmodium parasite in comparison to the asexual blood stage. However, compound 1.3 displayed sub-micromolar potency (IC50 = 0.382 µM) against earlystage gametocytes. Furthermore, selected potent analogues showed low cytotoxicity (SI = 39- 1500) when tested in vitro against the Chinese Hamster Ovary cells. The N-benzyl benzimidazole analogues, designed based on the known antihistamine drug astemizole, were tested against the hERG (human ether-a-go-go-related)-encoded potassium ion channel. These analogues expressed >40% inhibition against the hERG ion channel at the highest test concentration with potencies between 0.96 and 13.24 µM. Regardless, these compounds showed an improved cardiotoxicity risk relative to verapamil, a potent hERG channel inhibitor (IC50 = 0.58 µM), and the control drug used in the experiment. In addition, the five (5) selected potent analogues displayed low microsomal metabolic stability in mouse, rat and human liver microsomes. This impeded the advancement of these potent analogues to in vivo efficacy studies. Meanwhile, metabolite identification studies provided insight into the metabolic hotspots, which can be addressed in future optimization campaigns to address this liability. On the other hand, the imidazopyridine analogues were designed using the 1H-benzimidazole frontrunner analogue 1.3 as a guide. A structure-activity relationship (SAR) plan was pursued to produce diverse analogues due to modifications around the core scaffold. The SAR was explored with aromatic and aliphatic groups. As a result, 19 structural variants were synthesized and evaluated in vitro for their antiplasmodium activity against both the drug sensitive NF54 and the multidrug-resistant K1 strains of the Plasmodium parasite. 13 of these analogues showed potencies of <1 µM with compound 3.14 (IC50 = 0.08 µM) displaying the highest potency within the series. Subsequently, most of the active analogues showed a favourable cytotoxicity profile against CHO cells, with compound 3.14 being the least cytotoxic (SI = 466). Like the benzimidazoles, selected potent imidazopyridine analogues exhibited low microsomal metabolic stability in mouse, rat and human liver microsomes, posing a hurdle to the progression of these compounds to in vivo proof of concept studies. Aqueous solubility studies and physicochemical profiling of all the target compounds were carried out. The solubility results obtained were correlated with physicochemical parameters such as cLogP, melting points, TLC retardation factors and HPLC retention times to establish a solubility-property relationship across both classes of compounds. The correlation assessment revealed that different factors simultaneously affect the solubility of compounds across a series; hence, it may be crucial to assess these factors based on individual cases rather than an entire class of compounds. Also, the physicochemical assessment showed that both the benzimidazoles and the imidazopyridines complied with Lipinski's RO5 and Veber's rule. Single crystal X-ray structure analysis, IR spectroscopy, and DFT calculations were used to ascertain the presence of IMHB in the target compounds. Representative analogues 1.2 and 2.2 were used for these studies. In an effort to elucidate the mechanism of action, novel fluorescent analogues [1.3-NBD (IC50 PfNF54 = 0.044 µM) and 3.14-NBD (IC50 PfNF54 = 0.049 µM)] of the frontrunner compounds 1.3 and 3.14 were synthesized and pharmacologically validated as suitable probes for fluorescence live-cell imaging. The extrinsic fluorophore 7-nitrobenz-2-oxa-1,3-diazole (NBD) was employed due to the absence of intrinsic fluorescence properties in both compounds. Live-cell microscopy showed localization of both fluorescent analogues in all the studied organelles except the nucleus. While this suggests that the nucleus may not be a site of action for antiplasmodium activity, incorrect localization due to the NBD tag cannot be excluded. Based on the results from the live-cell imaging where both fluorescent probes accumulated in acidic organelles like the digestive vacuole and the neutral lipid bodies that have been implicated in hemozoin formation, it was hypothesized that the parent compounds 1.3 and 3.14 could be inhibiting the formation of hemozoin. Docking studies employed to investigate this hypothesis predicted intermolecular interactions between the parent compounds and the heme/hemozoin surfaces to inhibit hemozoin formation. The heme fractionation studies of compound 1.3 showed a dose-dependent increase in heme levels with a subsequent decrease in hemozoin levels at increasing compound concentrations. In essence, these observations support hemozoin inhibition as a mechanism of action of compound 1.3 while pointing to other targets within the parasite based on widespread association with other organelles. However, compound 3.14 showed no significant change in heme levels, but a decrease in hemozoin levels with increasing compound concentration was observed. This indicates that compound 3.14 is not a hemozoin inhibitor but could be targeting different digestive vacuole processes.
Open Access
Antimalarial drug rescue through safety improvement: design, synthesis and evaluation of amaodiaquine analogues
(2014) Ongarora, Dennis Sure Bagwasi; Chibale, Kelly; Masimirembwa, Collen
Malaria is a major cause of morbidity and mortality globally, resulting in over 200 million cases and 650, 000 deaths in 2010 according to the 2012 WHO Malaria Report. Furthermore, malaria endemicity is associated with poor economic growth. One of the greatest challenges facing malaria chemotherapy is the emergence of Plasmodium strains resistant to all known clinically used antimalarials. This underscores the need for the development of new drugs that retain efficacy against the resistant parasites. In this study, analogue-based drug design was employed as a form of drug ‘rescue’ in the development of novel potential antimalarials. The main aim was to design and synthesize analogues of the 4-aminoquinoline drug amodiaquine with potentially improved safety and efficacy profiles using prior knowledge of the drug metabolism and pharmacokinetics (DMPK), toxicity and efficacy profile of the drug. A representative set of compounds in four different series was synthesized in which the 4-aminoquinoline ring was coupled with benzothiazole, benzimidazole, benzoxazole and pyridyl rings bearing different aliphatic amines and diamines. The chemistry involved aromatic nucleophilic substitution reactions and hydrogenation of nitro aromatic compounds. Benzothiazole and benzoxazole analogues with a tertiary protonatable nitrogen were found to possess potent antiplasmodial activity against the drug resistant W2 and K1 Plasmodium falciparum strains.
Open Access
Antimalarial imidazopyridazines and aminopyrazines: synthesis, physicochemical optimization and structure-activity relationships
(2018) Cheuka, Peter Mubanga; Chibale, Kelly
According to the World Health Organization (WHO) world malaria report released in 2017, about 445,000 malaria deaths were recorded in 2016, a similar mortality as that recorded in the preceding year (446,000 deaths in 2015). Once effective and cheap drugs such as chloroquine and sulfadoxine-pyrimethamine have suffered widespread drug resistance. Additionally, despite the remarkable effectiveness of the currently recommended first line treatment, the artemisinin combination therapies (ACTs), resistance to artemisinin and the partner drugs is beginning to emerge in South East Asia. Furthermore, the current portfolio of medicines, both in clinical use and development has several other shortfalls which need redress. In addition, prevention of transmission and relapse with better safety profiles than current medicines are some of the important features that should be a prioritized characteristic of new medicines. Most importantly, these new regimens should be able to offer chemoprotection and prevent reinfection. Thus, there is need for constant research efforts aimed at identifying and developing novel chemotherapeutic agents for malaria, which are structurally diverse with novel mechanisms of action. In this PhD thesis, the medicinal chemistry optimization of two antimalarial chemotypes, the imidazopyridazines and aminopyrazines, is reported. In earlier studies, Le Manach and coworkers reported the impressive in vitro antiplasmodial activity and in vivo antimalarial efficacy of the imidazopyridazine lead compound 19 (Figure 1). However, this compound was plagued by poor solubility and a cardiotoxicity risk as shown from its inhibition of the hERG (human ether-a-go-go-related gene)-encoded potassium channel. Further medicinal chemistry optimization led to identification of other derivatives which, albeit exhibiting complete cure of P. berghei-infected mice, still displayed poor solubility and hERG inhibition issues. In this project, chemical modification approaches such as the introduction of water solubilizing groups, disruption of molecular planarity and making subtle changes (SAR 1 – 6, Figure 1) were adopted towards improving the solubility and countering hERG inhibition of this class of molecules. Through the thesis work undertaken, analogues with a combination of reduced hERG inhibition (IC50 = 7.8 – 32 μM) and submicromolar antiplasmodial activity (NF54, IC50 = 0.15 – 0.92 μM) were identified. Likewise, the modifications made delivered analogues with moderate to high solubility (60 – 200 μM) while exhibiting submicromolar antiplasmodial potency (NF54, IC50 = 0.14 – 0.99 μM). Furthermore, cytotoxicity assessment of selected analogues against the Chinese Hamster Ovarian (CHO) cell line revealed that most analogues were relatively noncytotoxic (selectivity indices in the range 72 - > 874). Selected compounds were also screened against gametocyte and liver stage parasites in order to assess transmission blocking and chemoprotection potential, respectively. In this regard, analogues with good gametocytocidal activity (IC50 = 0.098 – 0.75 μM) against late stage gametocytes and potent liver stage activity (IC50 = 0.045 μM) were identified. On the other hand, aminopyrazines have also recently shown potential as new antimalarial agents exhibiting promising in vivo efficacy in animal models of malaria infection with one analogue having progressed to an optimised late lead stage. However, this aminopyrazine lead compound 24 (Figure 2) as well as the first generation aminopyridine human Phase 2a clinical candidate MMV390048 showed sub-optimal solubility. In this aspect of the project, chemical modifications mainly focusing on replacing the two aromatic rings with fully and partially saturated heterocyclic systems, hypothesized to potentially disrupt intermolecular π – π stacking thereby improving aqueous solubility, were introduced. The first set of analogues corresponded to the replacement of the trifluoromethylpyridyl ring with partially and fully saturated heterocyclic rings as well as the 4-carboxyphenyl ring while keeping the 4- methylsulfonylphenyl group on the right-hand side portion of the aminopyrazine core scaffold fixed (SAR 1). In SAR 2, the trifluoromethylpyridyl group was fixed on the left-hand side of the aminopyrazine core scaffold while introducing partial and full saturation on the right-hand side of the core. SAR 3 analogues with both aromatic groups simultaneously replaced with partially and fully saturated heterocyclic rings were further generated. Compared to the lead compound 24 (NF54, IC50 = 0.008 μM), the introduced modifications drastically reduced antiplasmodial potency with only one analogue retaining submicromolar activity (NF54, IC50 = 0.51 μM). However, the introduced molecular features positively influenced solubility with the new analogues showing 4 - > 20-fold increase in aqueous solubility compared to the lead compound 24. For both imidazopyridazines and aminopyrazines, docking studies on a homology model of PfPI4K (P. falciparum phosphatidylinositol 4 kinase) were retrospectively undertaken. In both cases, the docking experiments showed that the introduction of the new molecular features was accompanied by loss of key binding interactions to the ATP binding pocket. This was in conformity with the generated parasite-based SAR.
Open Access
Antimalarials based on the arylpiperazine privileged substructure
(2005) Molyneaux, Carrie-Anne; Chibale, Kelly
Based on a previous study, arylpiperazines (2-chlorophenylpiperazine, 2-ethoxyphenylpiperazine and phenylpiperazine) were found to be significantly more potent against the chloroquine-resistant (K1) strain than against the chloroquine-sensitive(DIO) strain. In other studies, 8-hydroxy-2-(di-n-propylamino)tetralin (8-0H-DPAT) has been identified as a potential antimalarial agent for the inhibition of the 5-hydroxytryptamine type 1A receptor in Plasmodium falciparum. A number of arylpiperazines are also known to target this receptor in other systems. Coupled with the potential role of arylpiperazines as replacements for the antimalarial 8-OH-OPA T, these results prompted a further investigation into the antiplasmodial properties of a broader range of simple un substituted and substituted arylpiperazines against a broader range of chloroquine-sensitive and chloroquine-resistant strains of PlasmodiumJalciparum.
Open Access
Antimycobacterial 2-aminoquinazolinones and benzoxazole-based oximes: synthesis, biological evaluation, physicochemical profiling and supramolecular derivatization
(2017) Njaria, Paul Magutu; Chibale, Kelly; Caira, Mino R
Tuberculosis (TB) is a life-threatening infectious disease caused by Mycobacterium tuberculosis (Mtb). Globally, TB is a major public health burden with an estimated 10.4 million new cases and 1.8 million deaths reported in 2015. Although TB is curable, the treatment options currently available are beset by numerous shortcomings such as lengthy and complex treatment regimens, drug-drug interactions, drug toxicities, as well as emergence of widespread multi-drug resistance. Therefore, there is an urgent and compelling need to develop new, more effective, safer drugs with novel mechanisms of action, and which are capable of shortening treatment duration. This study focused on hit-to-lead optimization of two new classes of compounds with potential anti-TB properties: 2-aminoquinazolinones (AQZs) and benzoxazole-based oximes (BZOs). A hit compound for each of these classes with low micromolar antimycobacterial activity had previously been identified through phenotypic whole-cell in vitro screening.
Open Access
Antiplasmodial neolignans from Trema orientalis : identification, synthesis and analogue generation.
(2011) Pillay, Pamisha; Chibale, Kelly; Maharaj, Vinesh
Trema orientalis, a widely distributed evergreen tree with various medicinal properties including the treatment of malaria, was investigated as a potential source of new antimalarial lead compounds. Organic extracts of the young growing twigs of T. orientalis were reproducibly shown to be active against the chloroquine-sensitive (D10) and chloroquine resistant (K1) strains of Plasmodium falciparum. The 8-O-4' oxyneolignans, dadahols A and B, were identified as the major active compounds using two bioassay-guided fractionation approaches. The new accelerated “HPLC biogram” methodology allowed for early recognition of the active compounds in the complex plant extract, requiring considerably less time and material compared to the classical reiterative approach.
Open Access
The antiplasmodial, toxicity and pharmacokinetic properties of synthetic derivatives of the natural product Curcumin
(2008) Okalebo, Faith Apolot; Smith, Peter J; Chibale, Kelly; Guantai, Anastasia N
Includes bibliographical references.
Open Access
Antiprotozoal quinolines containing electrophilic moieties
(2004) Ganto, Mlungiseleli Macdonald; Chibale, Kelly
Compounds containing the quinoline moiety have been the mainstay of antimalarial chemotherapy. However, the emergence of resistant strains of Plasmodium falciparum, the causative agent of malaria, has compromised the efficacy of these antimalarial quinolines. Therefore the development of new efficient drugs is of critical importance. Extensive research has identified the cysteine proteases in malaria and other parasitic diseases as potential targets for new chemotherapy due to their critical roles in the life cycles of the causative agents. Due to their role in the antimalarial activity of clinically available drugs, quinolines were used as scaffolds to which electrophilic groups, such as thiosemicarbazone, a,β-unsaturated ketone and pyrazoline moieties were appended.
Open Access
The application of the Multi-Component Reaction (MCR) strategy in the design and synthesis of new antiplasmodial and antimycobacterial agents
(2012) Tukulula, Matshawandile; Chibale, Kelly
Malaria and tuberculosis are ancient diseases that continue to have a profound impact on mankind, 5 millennia after their first documentation. Malaria is endemic in more than 100 countries and about 50% of the world's population is at risk of infection. Sub-Saharan Africa accounts for nearly 91% of malaria-related deaths annually. Tuberculosis on the other hand infects about one third of the word's population and is the second major cause of death in adults worldwide, with about 1.8 million deaths reported annually. The major challenge to the control of these diseases has been the rapid emergence of multi-drug resistant strains to the currently administered drugs, as such, these exert an enormous pressure on health care systems, especially in resource-limited areas. Alleviation of this pressure requires the development of highly efficacious new chemical entities (NCEs) to curb or manage these pathogens. The main aim of this study was to design NCEs based on quinoline-, PA-824-, and tetrazole-scaffolds, which exhibit in vitro antiplasmodial and antimycobacterial activity.
Open Access
Approaches toward the enantioselective total synthesis of amarogentic
(2001) Stevens, Anne Therese; Bull, James R; Chibale, Kelly
Three different, but complementary strategies for the enantioselective synthesis of the secoiridoid core of amarogentin were evaluated. The first is based on the enantioselective desymmetrisation of meso-anhydrides using titanium TADDOLates. 1,2,4,6-Tetrahydrophthalic anhydride was desymmetrised and chemoselectively reduced to give (3aR, 7aS)-3a,4,7,7a-Tetrahydro-3H-isobenzofuran-1-one. Further development of this route was performed on a racemic model.
Open Access
Bioactive chloroquine-based ligands and their gold complexes as potential novel antimalarial agents
(2008) Watermeyer, Nicholas D; Chibale, Kelly
Chloroquine(CO)-derived 4-aminoquinolines have proven to be the most efficacious antimalarial drugs for both the treatment and prophylaxis of malaria. However, with the advent of drug resistance, their ability to treat the disease has been significantly hindered. Future research into the synthesis of new 4-aminoquinoline derivatives is warranted, since it has been found that the resistance is based on the identity of the side chain and not on the aminoquinoline ring, the functionality by which these compounds derive their activity. Consequently, the synthesis of CO derivatives with a modified side chain attached to a substituted quinoline ring is a reasonable approach in the search of novel antimalarial compounds that are active against drug-resistant parasite strains.
Open Access
Chemical modification and pharmacological evaluation of the antimalarial natural product totarol
(2004) Tacon, Claire; Smith, Peter J; Chibale, Kelly; Campbell, William E
Includes bibliographical references.
Open Access
Chemogenomic approaches to drug design : docking-based virtual screening of nematode GPCRs for potential anthelmintic agents
(2016) Masuka, Raban Wilfred; Jackson, Graham Ellis; Chibale, Kelly
Among common problems affecting human health and veterinary medicines, helmintic infections are major. The pathogens affect 550-750 Million people worldwide, and affect childhood growth, pregnancies, and development of the intellect. Helminths affects the well-being of animals as well including livestock and reduce the animal populations. However, the current anthelmintics are no longer as effective and some strains have developed resistance thus increasing the need for new anthelmintics. Unfortunately, not too much information is available detailing the physiology of helminths. The published genomic sequence of nematode Caenorrhabdtis elegans as well the primary sequence of the FLP18R1 G-Protein Coupled Receptor are available. GPCRs play a significant role as targets for therapeutics and are responsible for signal transduction in cells. Thus, nematode GPCRs offer an alternative target to design new anthelmintics. Unfortunately, very little information exists about these targets and there are no known x-ray or NMR structures. In this work, the 3D structure of nematode GPCR receptor (FLP18R1) was determined using homology modeling using the beta-2-adrenergic receptor as a template. The homology model developed had 24.87 % sequence identity with the template. Explicit membrane molecular dynamic simulations were used to optimize and refine the helices of the model over 100 ns. The homology model was of acceptable quality.
Open Access
Cloning, expression, purification and drug targeting of Plasmodium falciparum hypoxanthine guanine xanthine phosphoribosyltransferase (HGXPRT)
(2005) Mbewe, Boniface; Mcintosh, David B; Chibale, Kelly
The research concerns sub-cloning the gene for HGXPRT from Plasmodium falciparum from a vector with a His-tag facility to one without, expression of the protein in E. coli, and purification. On an analytical scale (40 ml culture), a purification procedure was developed that involves extraction of contaminating proteins by anion exchange chromatography (HGXPRT does not bind under the conditions used), followed by Reactive Red 120 agarose affinity chromatography.
Open Access
Computer-aided drug design and the biological evaluation of anti-cancer drugs
(2016) Moorad, Razia; Zerbini, Luiz F; Chibale, Kelly
Computer-aided drug design has become a promising alternative to high-throughput screening by identifying potential hits in silico for in vitro evaluation. In this study a combination of ligand-based and structure-based virtual screening was performed to identify in silico hits. This was based on finding similar inhibitors to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline, a potent inhibitor of the Nuclear Factor kappa B (NF-κB), a transcription factor that has a pivotal role in cancer survival and Pentamidine, an anti-parasitic drug that has recently been demonstrated to possess tumour-killing activity. A hierarchical methodology consisting of a similarity search followed by structure-based virtual screening of the ZINC database was performed. In order to perform the docking studies, binding sites for 6-amino-4-(4-phenoxyphenylethylamino) quinazoline on the NF-κB/IκBα complex were identified through blind docking. In addition, the National Cancer Institute (NCI) database was screened, utilising existing structure-activity relationship data from literature. A pharmacophore search was designed to test the hypothesis of the structural features necessary for activity as seen with quinazoline inhibitors of NF-κB. No virtual hits from the ZINC database were confirmed with in vitro activity. On the other hand, three compounds identified from the pharmacophore search were confirmed to inhibit cancer cell proliferation in vitro, with compound NSC727152 demonstrating the most potent activity. In order to determine if NSC727152 acted similarly to 6-amino-4-(4-phenoxyphenylethylamino) quinazoline by inhibiting NF-κB, the effects of NSC727152 on the expression of NF-κB targeted genes, including the Growth Arrest and DNA Damage 45 (GADD45) α and γ and the Interleukin 6 (IL-6) genes were evaluated. GADD45 α and γ have been shown to be regulated by NF-κB during cancer progression and aberrant IL-6 gene expression has been implicated in cancer progression and mortality and its expression is at least partially mediated via constitutive activation of NF-κB. In this study, it has been demonstrated that GADD45 α and γ are upregulated after treatment with NSC727152. A down-regulation of the IL-6 promoter activity and mRNA expression in cancer cells treated with NSC727152 has also been demonstrated in this study. However, no hits similar to Pentamidine were confirmed with in vitro activity. In conclusion, the compound NSC727152 has been shown to inhibit NF-κB and further analysis is necessary to determine its full potential as an NF-κB inhibitor.
Open Access
CRIMALDDI: a co-ordinated, rational, and integrated effort to set logical priorities in anti-malarial drug discovery initiatives
(BioMed Central Ltd, 2010) Boulton, Ian C; Nwaka, Solomon; Bathurst, Ian; Lanzer, Michael; Taramelli, Donatella; Vial, Henri; Doerig, Christian; Chibale, Kelly; Ward, Steve A
Despite increasing efforts and support for anti-malarial drug R&D, globally anti-malarial drug discovery and development remains largely uncoordinated and fragmented. The current window of opportunity for large scale funding of R&D into malaria is likely to narrow in the coming decade due to a contraction in available resources caused by the current economic difficulties and new priorities (e.g. climate change). It is, therefore, essential that stakeholders are given well-articulated action plans and priorities to guide judgments on where resources can be best targeted.The CRIMALDDI Consortium (a European Union funded initiative) has been set up to develop, through a process of stakeholder and expert consultations, such priorities and recommendations to address them. It is hoped that the recommendations will help to guide the priorities of the European anti-malarial research as well as the wider global discovery agenda in the coming decade.