Synthesis of 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives as lead scaffolds for neuroprotective agents

Neurodegenerative disorders are characterised by progressive loss of neuronal functions. Of the proposed mechanisms, excitotoxicity, mediated by prolonged glutamate activation and calcium overload, is prominent. NGP1-01, a polycyclic cage amine, and tricyclo[6.2.1.02,7]undec-9-ene-3,6-dione have been shown to display calcium-modulating properties. In this study, we synthesised structurally-related 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione as the base scaffold, and incorporated various functional moieties through aminolysis, to afford a series of imide derivatives. All final compounds were obtained in yields between 47-97% and their structures were confirmed by NMR, IR and MS. These structurally-related derivatives could potentially act as neuroprotective agents. Additionally, their synthetic versatilities could make them precursors, as lead compounds, to potential pharmacologically-active agents

Prioritization of anti-malarial hits from nature: Chemo-informatic profiling of natural products with in vitro antiplasmodial activities and currently registered anti-malarial drugs

A large number of natural products have shown in vitro antiplasmodial activities. Early identification and prioritization of these natural products with potential for novel mechanism of action, desirable pharmacokinetics and likelihood for development into drugs is advantageous. Chemo-informatic profiling of these natural products were conducted and compared to currently registered anti-malarial drugs (CRAD). Natural products with in vitro antiplasmodial activities (NAA) were compiled from various sources. These natural products were sub-divided into four groups based on inhibitory concentration (IC50). Key molecular descriptors and physicochemical properties were computed for these compounds and analysis of variance used to assess statistical significance amongst the sets of compounds. Molecular similarity analysis, estimation of drug-likeness, in silico pharmacokinetic profiling, and exploration of structure–activity landscape were also carried out on these sets of compounds

Design, synthesis and biological evaluation of edaravone derivatives bearing theN-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

A series of multi-target directed edaravone derivatives bearingN-benzyl pyridinium moieties weredesigned and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects andN-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheralanionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edar-avone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indi-cated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dual-site inhibitory activity. Significantin vitroAChE inhibitory activities were observed for selected compounds(IC50:1.2–4.6mM) with limited butyrylcholinesterase inhibitory activity (IC50’s>160mM), indicating excellentselectivity towards AChE (SI: 46–>278). The compounds also showed considerable antioxidant ability,similar to edaravone.In silicostudies indicated that these compounds should cross the blood–brain bar-rier, making them promising lead molecules in the development of anti-Alzheimer’s agents

Predictive classifier models built from natural products with antimalarial bioactivity using machine learning approach

In view of the vast number of natural products with potential antiplasmodial bioactivity and cost of conducting antiplasmodial bioactivity assays, it may be judicious to learn from previous antiplasmodial bioassays and predict bioactivity of these natural products before experimental bioassays. This study set out to harness antimalarial bioactivity data of natural products to build accurate predictive models, utilizing classical machine learning approaches, which can find potential antimalarial hits from new sets of natural products. Classical machine learning approaches were used to build four classifier models (Naïve Bayesian, Voted Perceptron, Random Forest and Sequence Minimization Optimization of Support Vector Machines) from bioactivity data of natural products with in-vitro antiplasmodial activity (NAA) using a combination of the molecular descriptors and two-dimensional molecular fingerprints of the compounds. Models were evaluated with an independent test dataset. Possible chemical features associated with reported antimalarial activities of the compounds were also extracted. From the results, Random Forest (accuracy 82.81%, Kappa statistics 0.65 and Area under Receiver Operating Characteristics curve 0.91) and Sequential Minimization Optimization (accuracy 85.93%, Kappa statistics 0.72 and Area under Receiver Operating Characteristics curve 0.86) showed good predictive performance for the NAA dataset. The amine chemical group (specifically alkyl amines and basic nitrogen) was confirmed to be essential for antimalarial activity in active NAA dataset. This study built and evaluated classifier models that were used to predict the antiplasmodial bioactivity class (active or inactive) of a set of natural products from interBioScreen chemical library

Multi-targeted directed ligands for Alzheimer’s disease: design of novel lead coumarin conjugates

Alzheimer’s Disease (AD) is a neurodegenerative disease characterized by central nervous system insults with progressive cognitive (memory, attention) and non-cognitive (anxiety, depression) impairments. Pathophysiological events affect predominantly cholinergic neuronal loss and dysfunctions of the dopaminergic system. The aim of the current study was to design multi-targeted directed lead structures based on the coumarin scaffold with inhibitory properties at two key enzymes in disease relevant systems, i.e. acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B). Conventional and microwave synthetic methods were utilized to synthesize coumarin scaffoldbased novel morpholino, piperidino, thiophene and erucic acid conjugates. Biological assays indicated that the coumarin–morpholine ether conjugate BPR 10 was the most potent hMAO-B inhibitor. The coumarin–piperidine conjugates BPR 13 and BPR 12 were the most potent inhibitors of eeAChE at 100 μM and 1 μM, respectively. Molecular modelling studies were conducted with Accelrys® Discovery Studio® V3.1.1 utilising the published hMAO-B (2V61) and hAChE (4EY7) crystal structures. Compound BPR 10 occupies both the entrance and substrate cavities of the active site of MAO-B. BPR 13 resides in both the peripheral anionic site (PAS) and the catalytic anionic site (CAS) of hAChE. This study demonstrated that the coumarin scaffold serves as a promising pharmacophore for MTDLs design

Small molecule efflux pump inhibitors in Mycobacterium tuberculosis: a rational drug design perspective

Drug resistance in Mycobacterium tuberculosis (M. tuberculosis) complicates management of tuberculosis. Efflux pumps contribute to low level resistance and acquisition of additional high level resistance mutations through sub-therapeutic concentrations of intracellular antimycobacterials. Various efflux pump inhibitors (EPIs) have been described for M. tuberculosis but little is known regarding the mechanism of efflux inhibition. As knowledge relating to the mechanism of action and drug target is central to the rational drug design of safe and sufficiently selective EPIs, this review aims to examine recent developments in the study of EPIs in M. tuberculosis from a rational drug development perspective and to provide an overview to facilitate systematic development of therapeutically effective EPIs. Review of literature points to a reduction in cellular energy or direct binding to the efflux pump as likely mechanisms for most EPIs described for M. tuberculosis. This review demonstrates that, where a direct interaction with efflux pumps is expected, both molecular structure and general physicochemical properties should be considered to accurately predict efflux pump substrates and inhibitors. Non-competitive EPIs do not necessarily demonstrate the same requirements as competitive inhibitors and it is therefore essential to differentiate between competitive and non-competitive inhibition to accurately determine structure activity relationships for efflux pump inhibition. It is also evident that there are various similarities between inhibitors of prokaryotic and eukaryotic efflux pumps but, depending on the specific chemical scaffolds under investigation, it may be possible to design EPIs that are less prone to inhibition of human P-glycoprotein, thereby reducing side effects and drug-drug interactions

Design, synthesis and biological evaluation of edaravone derivatives bearing the N-benzyl pyridinium moiety as multifunctional anti-Alzheimer’s agents

A series of multi-target directed edaravone derivatives bearing N-benzyl pyridinium moieties were designed and synthesised. Edaravone is a potent antioxidant with significant neuroprotective effects and N-benzyl pyridinium has previously exhibited positive results as part of a dual-site binding, peripheral anionic site (PAS) and catalytic anionic site (CAS), acetylcholinesterase (AChE) inhibitor. The designed edaravone-N-benzyl pyridinium hybrid compounds were docked within the AChE active site. The results indicated interactions with conserved amino acids (Trp279 in PAS and Trp84 in CAS), suggesting good dual-site inhibitory activity. Significant in vitro AChE inhibitory activities were observed for selected compounds (IC50: 1.2–4.6 µM) with limited butyrylcholinesterase inhibitory activity (IC50’s >160 µM), indicating excellent selectivity towards AChE (SI: 46–>278). The compounds also showed considerable antioxidant ability, similar to edaravone

Design, synthesis, and evaluation of 3,7-substituted coumarin derivatives as multifunctional Alzheimer’s disease agents

Multitarget directed ligands (MTDLs) are emerging as promising treatment options for Alzheimer’s disease (AD). Coumarin derivatives serve as a good starting point for designing MTDLs due to their inherent inhibition of monoamine oxidase (MAO) and cholinesterase enzymes, which are complicit in AD’s complex pathophysiology. A preliminary series of 3,7-substituted coumarin derivatives were synthesised and evaluated for enzyme inhibitory activity, cytotoxicity as well as neuroprotective ability. The results indicated that the compounds are weak cholinesterase inhibitors with five compounds demonstrating relatively potent inhibition and selectivity towards MAO-B with IC50 values between 0.014 and 0.498 hx00B5;mM. Significant neuroprotective effects towards MPPþ-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 mM for all compounds. The overall results demonstrated that substitution of the phenylethyloxy moiety at the 7-position imparted superior general activity to the derivatives, with the propargylamine substitution at the 3-position, in particular, displaying the best MAO-B selectivity and neuroprotection

Microwave-assisted methods for the synthesis of pentacyclo[5.4.0.02,6.03,10.05,9]undecylamines

Efficient methodologies for the preparation of pentacyclo[5..4.0.02,6.03,10.05,9]undecane (PCU) amine derivatives are described via microwave-assisted synthesis. The obtained results revealed that microwave-assisted synthetic procedures under controlled conditions (power, temperature and time) are very convenient, high yielding, efficient and low-cost methods for the preparation of PCU amine derivatives. The new methods show several advantages including operational simplicity, good performance, significant reduction in reaction time, less by-product formation and easier purification.Web of Scienc

Antimycobacterial Activity, Synergism, and Mechanism of Action Evaluation of Novel Polycyclic Amines against Mycobacterium tuberculosis

Mycobacterium tuberculosis has developed extensive resistance to numerous antimycobacterial agents used in the treatment of tuberculosis. Insufficient intracellular accumulation of active moieties allows for selective survival of mycobacteria with drug resistance mutations and accordingly promotes the development of microbial drug resistance. Discovery of compounds with new mechanisms of action and physicochemical properties that promote intracellular accumulation, or compounds that act synergistically with other antimycobacterial drugs, has the potential to reduce and prevent further drug resistance. To this end, antimycobacterial activity, mechanism of action, and synergism in combination therapy were investigated for a series of polycyclic amine derivatives. Compound selection was based on the presence of moieties with possible antimycobacterial activity, the inclusion of bulky lipophilic carriers to promote intracellular accumulation, and previously demonstrated bioactivity that potentially support inhibition of efflux pump activity. The most potent antimycobacterial demonstrated a minimum inhibitory concentration (MIC99) of 9.6 μM against Mycobacterium tuberculosis H37Rv. Genotoxicity and inhibition of the cytochrome bc1 respiratory complex were excluded as mechanisms of action for all compounds. Inhibition of cell wall synthesis was identified as a likely mechanism of action for the two most active compounds (14 and 15). Compounds 5 and 6 demonstrated synergistic activity with the known Rv1258c efflux pump substrate, spectinomycin, pointing to possible efflux pump inhibition. For this series, the nature of the side chain, rather than the type of polycyclic carrier, seems to play a determining role in the antimycobacterial activity and cytotoxicity of the compounds. Contrariwise, the nature of the polycyclic carrier, particularly the azapentacycloundecane cage, appears to promote synergistic activity. Results point to the possibility of combining an azapentacycloundecane carrier with a side chain that promotes antimycobacterial activity to develop dual acting molecules for the treatment of Mycobacterium tuberculosis