Lesetja Legoabe - Academia.edu (original) (raw)
Papers by Lesetja Legoabe
Chemical Biology & Drug Design
Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties... more Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties, one of which is antitubercular activity. It demonstrates antitubercular activity by directly inhibiting Mycobacterium tuberculosis (M.tb) and also enhances immune responses that ultimately lead to the elimination of M.tb by macrophages. This natural product is, however, unstable, and several analogues, noticeably monocarbonyl analogues, have been synthesized to overcome this challenge. Curcumin and its monocarbonyl analogues reported so far exhibit moderate antitubercular activity in the range of 7 to 16 μM. Herein, we report a straightforward synthesis of novel monocarbonyl curcumin analogues, their antitubercular activity, and the structure–activity relationship. The hit compound from this study, 3a, exhibits potent MIC90 values in the range of 0.2 to 0.9 μM in both ADC and CAS media.
South African Journal of Botany
Molecular Diversity, 2021
Adenosine receptors (ARs) are ubiquitously distributed throughout the mammalian body where they a... more Adenosine receptors (ARs) are ubiquitously distributed throughout the mammalian body where they are involved in an extensive list of physiological and pathological processes that scientists have only begun to decipher. Resultantly, AR agonists and antagonists have been the focus of multiple drug design and development programmes within the past few decades. Considered to be a privileged scaffold in medicinal chemistry, the chalcone framework has attracted a substantial amount of interest in this regard. Due to the potential liabilities associated with its structure, however, it has become necessary to explore other potentially promising compounds, such as heterocycles, which have successfully been obtained from chalcone precursors in the past. This review aims to summarise the emerging therapeutic importance of adenosine receptors and their ligands, especially in the central nervous system (CNS), while highlighting chalcone and heterocyclic derivatives as promising AR ligand lead compounds.
Advanced Synthesis & Catalysis, 2020
Direct C−H bond functionalization through radical pathway has emerged as a powerful and ideal str... more Direct C−H bond functionalization through radical pathway has emerged as a powerful and ideal strategy for the synthesis of organic compounds. This review provides an overview of recent developments in radical C−H functionalization of imidazoheterocycles such as imidazo[1,2‐a]pyridine, benzo[d]imidazo[2,1‐b]thiazole, imidazo[2,1‐b]thiazole, imidazo[1,2‐a]pyrimidine, imidazo[2,1‐a]isoquinoline, imidazo[1,2‐a]pyrazine and imidazo[1,2‐a]quinoline using organic peroxides, photo/electric‐induced protocols, iodine‐based reagents, first‐row transition metal catalysts (Fe, Mn, Ni and Cu) and inorganic oxidants/or salts.magnified image
Advances in Traditional Medicine
Bioorganic Chemistry
The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug t... more The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug targets, and inhibitors of these enzymes are established therapy for symptomatic Parkinson's disease (PD). COMT inhibitors enhance the bioavailability of levodopa to the brain, and therefore are combined with levodopa for the treatment of motor fluctuations in PD. Inhibitors of the MAO-B isoform, in turn, are used as monotherapy or in conjunction with levodopa in PD, and function by reducing the central degradation of dopamine. It has been reported that 1-tetralone and 1-indanone derivatives are potent and specific inhibitors of MAO-B, while compounds containing the nitrocatechol moiety (e.g. tolcapone and entacapone) are often potent COMT inhibitors. The present study attempted to discover compounds that exhibit dual COMT and MAO-B inhibition by synthesizing series of 1-tetralone, 1-indanone and related derivatives substituted with the nitrocatechol moiety. These compounds are structurally related to series of nitrocatechol derivatives of chalcone that have recently been investigated as potential dual COMT/MAO inhibitors. The results show that 4-chromanone derivative (7) is the most promising dual inhibitor with IC50 values of 0.57 and 7.26 μM for COMT and MAO-B, respectively, followed by 1-tetralone derivative (4d) with IC50 values of 0.42 and 7.83 μM for COMT and MAO-B, respectively. Based on their potent inhibition of COMT, it may be concluded that nitrocatechol compounds investigated in this study are appropriate for peripheral COMT inhibition, which represents an important strategy in the treatment of PD.
Chemical Papers, 2020
To identify novel adenosine receptor (AR) ligands based on the chalcone scaffold, herein the synt... more To identify novel adenosine receptor (AR) ligands based on the chalcone scaffold, herein the synthesis, characterization and in vitro and in silico evaluation of 33 chalcones (15-36 and 37-41) and structurally related compounds (42-47) are reported. These compounds were characterized by radioligand binding and GTP shift assays to determine the degree and type of binding affinity, respectively, against rat (r) A 1 and A 2A ARs. The chalcone derivatives 24, 29, 37 and 38 possessed selective A 1 affinity below 10 µM, and thus, are the most active compounds of the present series; compound 38 was the most potent selective A 1 AR antagonist (K i (r) = 1.6 µM). The structure-affinity relationships (SAR) revealed that the NH 2-group at position C3 of ring A of the chalcone scaffold played a key role in affinity, and also, the Br-atom at position C3′ on benzylidene ring B. Upon in vitro and in silico evaluation, the novel C3 amino-substituted chalcone derivative 38-that contains an α,ßunsaturated carbonyl system and easily allows structural modification-may possibly be a synthon in future drug discovery. Graphic abstract C3 amino-substituted chalcone derivative (38) with C3′ Br substitution on benzylidene ring B possesses selective adenosine rA 1 receptor affinity in micromolar range.
Cancer is reported to be one of the top ten leading causes of death worldwide and its treatment p... more Cancer is reported to be one of the top ten leading causes of death worldwide and its treatment poses a number of challenges. Cytarabine is a deoxycytidine analogue commonly used in the treatment of haematological malignant diseases. Its clinical utility, however, is severely limited by its short plasma half-life due to the catabolic action of nucleoside deaminases. Due to the cell cycle (S-phase) specificity of cytarabine, a prolonged exposure of cells to cytarabine's cytotoxic concentrations is essential to achieve maximum activity and is often achieved by more invasive and inconvenient modes of administration such as continuous intravenous infusion. Transdermal drug delivery systems (TO OS), on the other hand, have the potential to achieve this sustained release which is useful for drugs with short biological half-lives without the inconvenience associated with intravenous infusion. However, not .all the drugs are suited for TDDS. Owing to good barrier function of skin mainly...
The purpose of this work is to investigate the protein kinase inhibitory activity of constituents... more The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from ethyl acetate soluble fraction of Acacia auriculiformis stem bark. Column chromatography, gel filtration and NMR spectroscopy were used to purified and characterized betulin from the extract. Betulin which is a known inducer of apoptosis was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1epsilon (CK1epsilon), glycogen synthase kinase 3alpha/β (GSK-3alpha/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6) and vascular endothelial growth factor receptor 2 kinase (VEGFR2) and with activity in µM range. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to underline its putative use as anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pat...
Pharmaceuticals, 2021
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease curr... more Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern...
Chemico-Biological Interactions, 2021
Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in can... more Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in cancer therapy. Findings from a previous study suggested 7-azaindole as a privileged scaffold for producing inhibitors of CDK9/CyclinT and Haspin. Inspired by these findings, the current study synthesised and evaluated thirteen (13) C6-substituted 7-azaindole and twenty (20) C4-substituted structurally related 7H-pyrrolo[2,3-d]pyrimidine derivatives against a panel of protein kinases, including CDK9/CyclinT and Haspin. Eleven of the 7H-pyrrolo[2,3-d]pyrimidine derivatives exhibited activity toward CDK9/CyclinT, while 4 of compounds had activity against Haspin. The best CDK9/CyclinT (IC50 of 0.38 μM) and Haspin (IC50 of 0.11 μM) activities were achieved by compounds 7d and 7f, respectively. Hence, these compounds may be valuable starting points for development of new anti-cancer drugs.
Journal of Neuroscience Research, 2021
Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obs... more Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive‐compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine‐receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive‐like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T‐maze continuous alternation task (T‐CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20 mg kg−1 day−1) on the expression of stereotypy and T‐CAT performance in high (H) and non‐(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T‐CAT performance was found. However, H but not N animals presented with istradefylline‐sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti‐adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.
Drug Research, 2021
Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein ... more Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein current treatments suffer from several drawbacks such as toxicity, low activity, and poor pharmacokinetic properties, and hence the need for alternative treatment is apparent. To this effect, we screened in vitro a library of 2-quinazolinone derivatives for antitrypanosomal activity against T.b. brucei and cytotoxicity against HeLa cells. Seven compounds having no overt cytotoxicity against HeLa cells exhibited antitrypanosomal activity in the range of 0.093–45 µM were identified. The activity data suggests that the antitrypanosomal activity of this compound class is amenable to substituents at N1 and C6 positions. Compound 14 having a molecular weight of 238Da, ClogP value of 1 and a total polar surface area of 49 was identified as the most active, exhibiting an IC50 value of 0.093 µM Graphical .
European Journal of Medicinal Chemistry, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Molecules, 2020
Malaria control relies heavily on the small number of existing antimalarial drugs. However, recur... more Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.
Chemical Biology & Drug Design, 2020
Chalcones are a group of naturally occurring or synthetic compounds which possess a wide range of... more Chalcones are a group of naturally occurring or synthetic compounds which possess a wide range of biological activities. In this paper, a series of twenty-three 7-azaindole-chalcone hybrids (5a-w) were synthesised and evaluated as potential protein kinase inhibitors. Analyses of structure activity relationships (SAR) revealed that some of these compounds exhibit significant activity against Haspin kinase; with compound 5f, and 5q exhibiting IC 50 values of 0.47 µM and 0.41 µM respectively. Furthermore, 5f also inhibits cyclin-dependent kinase 9 (CDK9/ CyclinT) in a micromolar potency (IC 50 = 2.26 µM). This novel dual-target inhibitor is a promising lead for the development of chemopreventive/chemotherapeutic agents.
Chemical Biology & Drug Design, 2020
In this study, we synthesized novel nitro quinolone‐based compounds and tested them in vitro agai... more In this study, we synthesized novel nitro quinolone‐based compounds and tested them in vitro against a panel of Gram‐positive and Gram‐negative pathogens including Mycobacterium tuberculosis (MTB), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumonia, Staphylococcus aureus, and Escherichia coli for antibacterial activities and also against HeLa cells for overt cytotoxicity. Compound 8e was identified as a non‐toxic, potent hit with selective activity (MIC90 ˂ 0.24 µm) against MTB. 8e, however, showed no activity against DprE1 mutant, suggesting DprE1 as the likely target for this compound class.
Bioorganic & Medicinal Chemistry, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Chemical Biology & Drug Design
Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties... more Curcumin is a natural product that has been reported to exhibit myriad pharmacological properties, one of which is antitubercular activity. It demonstrates antitubercular activity by directly inhibiting Mycobacterium tuberculosis (M.tb) and also enhances immune responses that ultimately lead to the elimination of M.tb by macrophages. This natural product is, however, unstable, and several analogues, noticeably monocarbonyl analogues, have been synthesized to overcome this challenge. Curcumin and its monocarbonyl analogues reported so far exhibit moderate antitubercular activity in the range of 7 to 16 μM. Herein, we report a straightforward synthesis of novel monocarbonyl curcumin analogues, their antitubercular activity, and the structure–activity relationship. The hit compound from this study, 3a, exhibits potent MIC90 values in the range of 0.2 to 0.9 μM in both ADC and CAS media.
South African Journal of Botany
Molecular Diversity, 2021
Adenosine receptors (ARs) are ubiquitously distributed throughout the mammalian body where they a... more Adenosine receptors (ARs) are ubiquitously distributed throughout the mammalian body where they are involved in an extensive list of physiological and pathological processes that scientists have only begun to decipher. Resultantly, AR agonists and antagonists have been the focus of multiple drug design and development programmes within the past few decades. Considered to be a privileged scaffold in medicinal chemistry, the chalcone framework has attracted a substantial amount of interest in this regard. Due to the potential liabilities associated with its structure, however, it has become necessary to explore other potentially promising compounds, such as heterocycles, which have successfully been obtained from chalcone precursors in the past. This review aims to summarise the emerging therapeutic importance of adenosine receptors and their ligands, especially in the central nervous system (CNS), while highlighting chalcone and heterocyclic derivatives as promising AR ligand lead compounds.
Advanced Synthesis & Catalysis, 2020
Direct C−H bond functionalization through radical pathway has emerged as a powerful and ideal str... more Direct C−H bond functionalization through radical pathway has emerged as a powerful and ideal strategy for the synthesis of organic compounds. This review provides an overview of recent developments in radical C−H functionalization of imidazoheterocycles such as imidazo[1,2‐a]pyridine, benzo[d]imidazo[2,1‐b]thiazole, imidazo[2,1‐b]thiazole, imidazo[1,2‐a]pyrimidine, imidazo[2,1‐a]isoquinoline, imidazo[1,2‐a]pyrazine and imidazo[1,2‐a]quinoline using organic peroxides, photo/electric‐induced protocols, iodine‐based reagents, first‐row transition metal catalysts (Fe, Mn, Ni and Cu) and inorganic oxidants/or salts.magnified image
Advances in Traditional Medicine
Bioorganic Chemistry
The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug t... more The enzymes, catechol O-methyltransferase (COMT) and monoamine oxidase (MAO) are important drug targets, and inhibitors of these enzymes are established therapy for symptomatic Parkinson's disease (PD). COMT inhibitors enhance the bioavailability of levodopa to the brain, and therefore are combined with levodopa for the treatment of motor fluctuations in PD. Inhibitors of the MAO-B isoform, in turn, are used as monotherapy or in conjunction with levodopa in PD, and function by reducing the central degradation of dopamine. It has been reported that 1-tetralone and 1-indanone derivatives are potent and specific inhibitors of MAO-B, while compounds containing the nitrocatechol moiety (e.g. tolcapone and entacapone) are often potent COMT inhibitors. The present study attempted to discover compounds that exhibit dual COMT and MAO-B inhibition by synthesizing series of 1-tetralone, 1-indanone and related derivatives substituted with the nitrocatechol moiety. These compounds are structurally related to series of nitrocatechol derivatives of chalcone that have recently been investigated as potential dual COMT/MAO inhibitors. The results show that 4-chromanone derivative (7) is the most promising dual inhibitor with IC50 values of 0.57 and 7.26 μM for COMT and MAO-B, respectively, followed by 1-tetralone derivative (4d) with IC50 values of 0.42 and 7.83 μM for COMT and MAO-B, respectively. Based on their potent inhibition of COMT, it may be concluded that nitrocatechol compounds investigated in this study are appropriate for peripheral COMT inhibition, which represents an important strategy in the treatment of PD.
Chemical Papers, 2020
To identify novel adenosine receptor (AR) ligands based on the chalcone scaffold, herein the synt... more To identify novel adenosine receptor (AR) ligands based on the chalcone scaffold, herein the synthesis, characterization and in vitro and in silico evaluation of 33 chalcones (15-36 and 37-41) and structurally related compounds (42-47) are reported. These compounds were characterized by radioligand binding and GTP shift assays to determine the degree and type of binding affinity, respectively, against rat (r) A 1 and A 2A ARs. The chalcone derivatives 24, 29, 37 and 38 possessed selective A 1 affinity below 10 µM, and thus, are the most active compounds of the present series; compound 38 was the most potent selective A 1 AR antagonist (K i (r) = 1.6 µM). The structure-affinity relationships (SAR) revealed that the NH 2-group at position C3 of ring A of the chalcone scaffold played a key role in affinity, and also, the Br-atom at position C3′ on benzylidene ring B. Upon in vitro and in silico evaluation, the novel C3 amino-substituted chalcone derivative 38-that contains an α,ßunsaturated carbonyl system and easily allows structural modification-may possibly be a synthon in future drug discovery. Graphic abstract C3 amino-substituted chalcone derivative (38) with C3′ Br substitution on benzylidene ring B possesses selective adenosine rA 1 receptor affinity in micromolar range.
Cancer is reported to be one of the top ten leading causes of death worldwide and its treatment p... more Cancer is reported to be one of the top ten leading causes of death worldwide and its treatment poses a number of challenges. Cytarabine is a deoxycytidine analogue commonly used in the treatment of haematological malignant diseases. Its clinical utility, however, is severely limited by its short plasma half-life due to the catabolic action of nucleoside deaminases. Due to the cell cycle (S-phase) specificity of cytarabine, a prolonged exposure of cells to cytarabine's cytotoxic concentrations is essential to achieve maximum activity and is often achieved by more invasive and inconvenient modes of administration such as continuous intravenous infusion. Transdermal drug delivery systems (TO OS), on the other hand, have the potential to achieve this sustained release which is useful for drugs with short biological half-lives without the inconvenience associated with intravenous infusion. However, not .all the drugs are suited for TDDS. Owing to good barrier function of skin mainly...
The purpose of this work is to investigate the protein kinase inhibitory activity of constituents... more The purpose of this work is to investigate the protein kinase inhibitory activity of constituents from ethyl acetate soluble fraction of Acacia auriculiformis stem bark. Column chromatography, gel filtration and NMR spectroscopy were used to purified and characterized betulin from the extract. Betulin which is a known inducer of apoptosis was screened against a panel of 16 disease-related protein kinases. Betulin was shown to inhibit Abelson murine leukemia viral oncogene homolog 1 (ABL1) kinase, casein kinase 1epsilon (CK1epsilon), glycogen synthase kinase 3alpha/β (GSK-3alpha/β), Janus kinase 3 (JAK3), NIMA Related Kinase 6 (NEK6) and vascular endothelial growth factor receptor 2 kinase (VEGFR2) and with activity in µM range. The effect of betulin on the cell viability of doxorubicin-resistant K562R chronic myelogenous leukemia cells was then verified to underline its putative use as anti-cancer compound. Betulin was shown to modulate the mitogen-activated protein (MAP) kinase pat...
Pharmaceuticals, 2021
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease curr... more Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), is a curable airborne disease currently treated using a drug regimen consisting of four drugs. Global TB control has been a persistent challenge for many decades due to the emergence of drug-resistant Mtb strains. The duration and complexity of TB treatment are the main issues leading to treatment failures. Other challenges faced by currently deployed TB regimens include drug-drug interactions, miss-matched pharmacokinetics parameters of drugs in a regimen, and lack of activity against slow replicating sub-population. These challenges underpin the continuous search for novel TB drugs and treatment regimens. This review summarizes new TB drugs/drug candidates under development with emphasis on their chemical classes, biological targets, mode of resistance generation, and pharmacokinetic properties. As effective TB treatment requires a combination of drugs, the issue of drug-drug interaction is, therefore, of great concern...
Chemico-Biological Interactions, 2021
Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in can... more Protein kinases, including CDK9/CyclinT and Haspin, are regarded as potential drug targets in cancer therapy. Findings from a previous study suggested 7-azaindole as a privileged scaffold for producing inhibitors of CDK9/CyclinT and Haspin. Inspired by these findings, the current study synthesised and evaluated thirteen (13) C6-substituted 7-azaindole and twenty (20) C4-substituted structurally related 7H-pyrrolo[2,3-d]pyrimidine derivatives against a panel of protein kinases, including CDK9/CyclinT and Haspin. Eleven of the 7H-pyrrolo[2,3-d]pyrimidine derivatives exhibited activity toward CDK9/CyclinT, while 4 of compounds had activity against Haspin. The best CDK9/CyclinT (IC50 of 0.38 μM) and Haspin (IC50 of 0.11 μM) activities were achieved by compounds 7d and 7f, respectively. Hence, these compounds may be valuable starting points for development of new anti-cancer drugs.
Journal of Neuroscience Research, 2021
Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obs... more Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive‐compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine‐receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive‐like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T‐maze continuous alternation task (T‐CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20 mg kg−1 day−1) on the expression of stereotypy and T‐CAT performance in high (H) and non‐(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n = 8 or 9 per group). No correlation between H behavior and T‐CAT performance was found. However, H but not N animals presented with istradefylline‐sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti‐adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.
Drug Research, 2021
Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein ... more Sleeping sickness, caused by trypanosomes, is a debilitating, neglected tropical disease wherein current treatments suffer from several drawbacks such as toxicity, low activity, and poor pharmacokinetic properties, and hence the need for alternative treatment is apparent. To this effect, we screened in vitro a library of 2-quinazolinone derivatives for antitrypanosomal activity against T.b. brucei and cytotoxicity against HeLa cells. Seven compounds having no overt cytotoxicity against HeLa cells exhibited antitrypanosomal activity in the range of 0.093–45 µM were identified. The activity data suggests that the antitrypanosomal activity of this compound class is amenable to substituents at N1 and C6 positions. Compound 14 having a molecular weight of 238Da, ClogP value of 1 and a total polar surface area of 49 was identified as the most active, exhibiting an IC50 value of 0.093 µM Graphical .
European Journal of Medicinal Chemistry, 2021
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Molecules, 2020
Malaria control relies heavily on the small number of existing antimalarial drugs. However, recur... more Malaria control relies heavily on the small number of existing antimalarial drugs. However, recurring antimalarial drug resistance necessitates the continual generation of new antimalarial drugs with novel modes of action. In order to shift the focus from only controlling this disease towards elimination and eradication, next-generation antimalarial agents need to address the gaps in the malaria drug arsenal. This includes developing drugs for chemoprotection, treating severe malaria and blocking transmission. Plasmodial kinases are promising targets for next-generation antimalarial drug development as they mediate critical cellular processes and some are active across multiple stages of the parasite’s life cycle. This review gives an update on the progress made thus far with regards to plasmodial kinase small-molecule inhibitor development.
Chemical Biology & Drug Design, 2020
Chalcones are a group of naturally occurring or synthetic compounds which possess a wide range of... more Chalcones are a group of naturally occurring or synthetic compounds which possess a wide range of biological activities. In this paper, a series of twenty-three 7-azaindole-chalcone hybrids (5a-w) were synthesised and evaluated as potential protein kinase inhibitors. Analyses of structure activity relationships (SAR) revealed that some of these compounds exhibit significant activity against Haspin kinase; with compound 5f, and 5q exhibiting IC 50 values of 0.47 µM and 0.41 µM respectively. Furthermore, 5f also inhibits cyclin-dependent kinase 9 (CDK9/ CyclinT) in a micromolar potency (IC 50 = 2.26 µM). This novel dual-target inhibitor is a promising lead for the development of chemopreventive/chemotherapeutic agents.
Chemical Biology & Drug Design, 2020
In this study, we synthesized novel nitro quinolone‐based compounds and tested them in vitro agai... more In this study, we synthesized novel nitro quinolone‐based compounds and tested them in vitro against a panel of Gram‐positive and Gram‐negative pathogens including Mycobacterium tuberculosis (MTB), Pseudomonas aeruginosa, Acinetobacter baumannii, Klebsiella pneumonia, Staphylococcus aureus, and Escherichia coli for antibacterial activities and also against HeLa cells for overt cytotoxicity. Compound 8e was identified as a non‐toxic, potent hit with selective activity (MIC90 ˂ 0.24 µm) against MTB. 8e, however, showed no activity against DprE1 mutant, suggesting DprE1 as the likely target for this compound class.
Bioorganic & Medicinal Chemistry, 2020
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.