HDAC3 inhibitors: a patent review of their broad-spectrum applications as therapeutic agents.

INTRODUCTION: Histone deacetylases (HDACs) are a class of zinc-dependent enzymes. They maintain acetylation homeostasis, with numerous biological functions and are associated with many diseases. HDAC3 strictly requires multi-subunit complex formation for activity. It is associated with the progression of numerous non-communicable diseases. Its widespread involvement in diseases makes it an epigenetic drug target. Preexisting HDAC3 inhibitors have many uses, highlighting the need for continued research in the discovery of HDAC3-selective inhibitors. AREA COVERED: This review provides an overview of 24 patents published from 2010-2023, focusing on compounds that inhibit the HDAC3 isoenzyme. EXPERT OPINION: HDAC3-selective inhibitors - pivotal for pharmacological application as single or combination therapies - are gaining traction as a strategy to move away from complications laden pan-HDAC inhibitors. Moreover, there is an unmet need for HDAC3 inhibitors with alternative zinc-binding groups (ZBG) because some preexisting ZBGs have limitations related to toxicity and side effects. Difficulties in achieving HDAC3 selectivity may be due to isoform selectivity. However, advancements in computer-aided drug design and experimental data of HDAC3 3D co-crystallized models could lead to discovery of novel HDAC3-selective inhibitors. Which bear alternative ZBGs with balanced selectivity for HDAC3 and potency.

NMDA Receptor Antagonists: Emerging Insights into Molecular Mechanisms and Clinical Applications in Neurological Disorders.

Neurodegenerative disorders (NDs) include a range of chronic conditions characterized by progressive neuronal loss, leading to cognitive, motor, and behavioral impairments. Common examples include Alzheimer's disease (AD) and Parkinson's disease (PD). The global prevalence of NDs is on the rise, imposing significant economic and social burdens. Despite extensive research, the mechanisms underlying NDs remain incompletely understood, hampering the development of effective treatments. Excitotoxicity, particularly glutamate-mediated excitotoxicity, is a key pathological process implicated in NDs. Targeting the N-methyl-D-aspartate (NMDA) receptor, which plays a central role in excitotoxicity, holds therapeutic promise. However, challenges, such as blood-brain barrier penetration and adverse effects, such as extrapyramidal effects, have hindered the success of many NMDA receptor antagonists in clinical trials. This review explores the molecular mechanisms of NMDA receptor antagonists, emphasizing their structure, function, types, challenges, and future prospects in treating NDs. Despite extensive research on competitive and noncompetitive NMDA receptor antagonists, the quest for effective treatments still faces significant hurdles. This is partly because the same NMDA receptor that necessitates blockage under pathological conditions is also responsible for the normal physiological function of NMDA receptors. Allosteric modulation of NMDA receptors presents a potential alternative, with the GluN2B subunit emerging as a particularly attractive target due to its enrichment in presynaptic and extrasynaptic NMDA receptors, which are major contributors to excitotoxic-induced neuronal cell death. Despite their low side-effect profiles, selective GluN2B antagonists like ifenprodil and radiprodil have encountered obstacles such as poor bioavailability in clinical trials. Moreover, the selectivity of these antagonists is often relative, as they have been shown to bind to other GluN2 subunits, albeit minimally. Recent advancements in developing phenanthroic and naphthoic acid derivatives offer promise for enhanced GluN2B, GluN2A or GluN2C/GluN2D selectivity and improved pharmacodynamic properties. Additional challenges in NMDA receptor antagonist development include conflicting preclinical and clinical results, as well as the complexity of neurodegenerative disorders and poorly defined NMDA receptor subtypes. Although multifunctional agents targeting multiple degenerative processes are also being explored, clinical data are limited. Designing and developing selective GluN2B antagonists/modulators with polycyclic moieties and multitarget properties would be significant in addressing neurodegenerative disorders. However, advancements in understanding NMDA receptor structure and function, coupled with collaborative efforts in drug design, are imperative for realizing the therapeutic potential of these NMDA receptor antagonists/modulators.

Calcium Modulating Effect of Polycyclic Cages: A Suitable Therapeutic Approach Against Excitotoxic-induced Neurodegeneration.

Neurodegenerative disorders pose a significant challenge to global healthcare systems due to their progressive nature and the resulting loss of neuronal cells and functions. Excitotoxicity, characterized by calcium overload, plays a critical role in the pathophysiology of these disorders. In this review article, we explore the involvement of calcium dysregulation in neurodegeneration and neurodegenerative disorders. A promising therapeutic strategy to counter calcium dysregulation involves the use of calcium modulators, particularly polycyclic cage compounds. These compounds, structurally related to amantadine and memantine, exhibit neuroprotective properties by attenuating calcium influx into neuronal cells. Notably, the pentacycloundecylamine NGP1-01, a cage-like structure, has shown efficacy in inhibiting both N-methyl-D-aspartate (NMDA) receptors and voltage-gated calcium channels (VGCCs), making it a potential candidate for neuroprotection against excitotoxic-induced neurodegenerative disorders. The structure-activity relationship of polycyclic cage compounds is discussed in detail, highlighting their calcium-inhibitory activities. Various closed, open, and rearranged cage compounds have demonstrated inhibitory effects on calcium influx through NMDA receptors and VGCCs. Additionally, these compounds have exhibited neuroprotective properties, including free radical scavenging, attenuation of neurotoxicities, and reduction of neuroinflammation. Although the calcium modulatory activities of polycyclic cage compounds have been extensively studied, apart from amantadine and memantine, none have undergone clinical trials. Further in vitro and in vivo studies and subsequent clinical trials are required to establish the efficacy and safety of these compounds. The development of polycyclic cages as potential multifunctional agents for treating complex neurodegenerative diseases holds great promise.

Discovery and biological evaluation of an adamantyl-amide derivative with likely MmpL3 inhibitory activity.

A series of molecules containing bulky lipophilic scaffolds was screened for activity against Mycobacterium tuberculosis and a number of compounds with antimycobacterial activity were identified. The most active compound, (2E)-N-(adamantan-1-yl)-3-phenylprop-2-enamide (C1), has a low micromolar minimum inhibitory concentration, low cytotoxicity (therapeutic index = 32.26), low mutation frequency and is active against intracellular Mycobacterium tuberculosis. Whole genome sequencing of mutants resistant to C1 showed a mutation in mmpL3 which may point to the involvement of MmpL3 in the antimycobacterial activity of the compound. In silico mutagenesis and molecular modelling studies were performed to better understand the binding of C1 within MmpL3 and the role that the specific mutation may play in the interaction at protein level. These analyses revealed that the mutation increases the energy required for binding of C1 within the protein translocation channel of MmpL3. The mutation also decreases the solvation energy of the protein, suggesting that the mutant protein might be more solvent-accessible, thereby restricting its interaction with other molecules. The results reported here describe a new molecule that may interact with the MmpL3 protein, providing insights into the effect of mutations on protein-ligand interactions and enhancing our understanding of this essential protein as a priority drug target.

Regulatory registration timelines of generic medicines in South Africa: Assessment of the performance of SAHPRA between 2011 and 2022.

BACKGROUND: Various regulatory authorities are experiencing backlogs of applications which result in delayed access to medicines for patients. The objective of this study is to critically assess the registration process utilised by SAHPRA between 2011 and 2022 and determine the fundamental root causes for the formation of a backlog. The study also aims to detail the remedial actions that were undertaken which resulted in the development of a new review pathway termed the risk-based assessment approach for regulatory authorities experiencing backlogs to implement. METHODS: A sample of 325 applications was used to evaluate the end-to-end registration process employed for the Medicine Control Council (MCC) process between 2011 and 2017; 129 applications were used for the backlog clearance project (BCP) between 2019 and 2022; 63 and 156 applications were used for the risk-based assessment (RBA) pilot studies in 2021 and 2022, respectively. The three processes are compared, and the timelines are discussed in detail. RESULTS: The longest median value of 2092 calendar days was obtained for the approval times between 2011 and 2017 using the MCC process. Continuous process optimisation and refinement are crucial to prevent recurring backlogs and hence implementation of the RBA process. Implementation of the RBA process resulted in a shorter median approval time of 511 calendar days. The finalisation timeline by the Pharmaceutical and Analytical (P&A) pre-registration Unit, which conducts the majority of the evaluations, is used as a tool for the direct comparison of the processes. The finalisation timeline for the MCC process was a median value of 1470 calendar days, the BCP was 501 calendar days and the RBA process phases 1 and 2 were 68 and 73 calendar days, respectively. The median values of the various stages of the end-to-end registration processes are also analysed in order to build efficiency within the process. CONCLUSIONS: The observations from the study have identified the RBA process which can be implemented to reduce regulatory assessment times while assuring the timeous approval of safe and effective, quality medicines. The continuous monitoring of a process remains one of the critical tools required to ensure the effectiveness of a registration process. The RBA process also becomes a better alternative for generic applications that do not qualify to undergo the reliance approach due to its drawbacks. This robust procedure can therefore be utilised by other regulatory agencies that may have a backlog or want to optimise their registration process.

The Implementation of a Risk-Based Assessment Approach by the South African Health Products Regulatory Authority (SAHPRA).

BACKGROUND: An extensive backlog of pending regulatory decisions is one of the major historical challenges that the South African Health Products Regulatory Authority (SAHPRA) inherited from the Medicine Control Council (MCC). Revising and implementing new regulatory pathways is one of the strategic mechanisms that SAHPRA employs to circumvent this problem. OBJECTIVES: To alleviate the backlog, the use of a new review pathway termed the risk-based review on the scientific quality and bioequivalence assessments was explored. The objective of the study was to articulate the risk-based assessment (RBA) pathway, to determine robust criteria for the classification of the levels of risk for medicines, and to define the improved process to be followed in the assessment and approval of medicines. METHODS: In 2015, an extensive exercise was conducted by SAHPRA to identify the unknown status of in-process applications. The RBA pilot project commenced in 2016 and further piloted in 2021 using the knowledge gained from the 2016 study for optimisation of efficiency. RESULTS: By 2015 the backlog was quantified as 7902 applications in the pre-registration phase. The 2015 project entailed two phases. The initial phase was conducted to identify the status of 3505 in-process applications, which resulted in the registration of 198 applications. The second phase commenced in 2016 on 4397 applications not yet reviewed whereby the RBA approach was explored. With the developed criteria for risk classification and refined end-to-end registration process, the pilot resulted in a finalisation time with a median value of 90 calendar days and a median approval time of 109 calendar days. The throughput of the RBA pilot study conducted in 2021 was 68 calendar days finalisation time for the 63 applications used. These finalisation times are lower in comparison to the 501 calendar days for the current process employed by SAHPRA for the backlog clearance programme initiated in 2019. Both the 2016 and 2021 studies had similar approval times calculated from the date of allocation of scientific assessments. The reported evaluation timelines for both studies were within 6-7 h for a low-risk quality assessment, 9-10 h for a high-risk quality assessment, 7-8 h for a bioequivalence assessment, and 2-3 h for a biowaiver and initial response assessment. CONCLUSIONS: The refined processes used in the risk-based pilot studies to alleviate the SAHPRA backlog are described in detail. The process managed a reduction of the finalisation time to 68 calendar days in comparison to 501 calendar days for the current process that was employed by SAHPRA for the backlog clearance programme initiated in 2019. The RBA approach, therefore, reduces the finalisation and approval times for quality and bioequivalence assessments for regulatory authorities without compromising on the quality, safety and efficacy of the medicinal products. In addition, the approach provides a prototype solution to counteract the influx of medicinal product applications received by the regulatory authorities.

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11ß-HSD1 Molecular Docking and ADMET Prediction.

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1-3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P21/c, P21 and P21/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1-3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1-3 were determined using in silico techniques. Molecular docking of the compounds into the 11ß-HSD1 active site showed comparable binding affinity scores (-7.50 to -8.92 kcal/mol) to the 11ß-HSD1 co-crystallized ligand 4YQ (-8.48 kcal/mol, 11ß-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.

Bioequivalence Common Deficiencies in Generic Products Submitted for Registration to the South African Health Products Regulatory Authority (SAHPRA).

BACKGROUND: The cost of healthcare has become expensive globally, of which the greater part of the money is spent on buying innovator medicines. In order to make medicine affordable, the development of generic medicines has become paramount. The science of bioequivalence studies of generic products to demonstrate therapeutic equivalence with innovator products has been developed over the last 50 years. These studies cost far less as compared to innovator products thereby reducing the cost of medicines. Accelerating access to medicines has become an increasing challenge due to insufficient resources from regulatory authorities, while pharmaceutical industry continues to expand. An investigation on the deficiencies identified during scientific assessments by SAHPRA in submitted bioequivalence studies is therefore paramount. Identification and publication of these deficiencies will assist in accelerating the access of medicines to patients. OBJECTIVE: The aim of the study is to investigate the types and frequency of the common deficiencies observed in the bioequivalence section of generic submissions to SAHPRA. The study was conducted retrospectively over a 7-year period (2011-2017) for generic products that were finalised by the Pharmaceutical and Analytical pre-registration Unit. A more recent analysis on common deficiencies witnessed for applications assessed between 2020 and 2021 was also done to illustrate the consistency in the evaluation practises adopted by SAHPRA. METHODS: There were 3148 applications finalised between 2011 and 2017, and to attain a representative sample for the study, statistical sampling was conducted. The multi-stage sampling called stratified systematic sampling was selected as the method of choice. The sample size was obtained using the statistical tables found in the literature and confirmed by a sample size calculation resulting in the selection of 325 applications (Fig. 2a). Additionally, 300 master applications were assessed between 2020 and 2021 for up-to-date data (Fig. 2b). All the deficiencies were collected and categorised according to the ICH E3 guideline and components relevant to biostudies. RESULTS: A total of 2458 deficiencies were collected from the selected sample size for applications finalised between 2011 and 2017 where a biostudy was submitted. The majority of the identified deficiencies were from the following categories; in vitro dissolution testing and specifications (18%), study design (17%), details on the test and reference products (16%), issues on sample analysis (16%), and statistical analysis (10%) (Fig. 3). From the applications assessed in 2020-2021, 492 deficiencies were identified with a similar trend compared to those finalised between 2011 and 2017. Comparison of the deficiencies with those reported by the USFDA and WHO PQTm is discussed with similarities outlined. CONCLUSIONS: The five most common deficiencies observed were extensively discussed. The outcomes of this study will guide pharmaceutical companies, sponsors, and Clinical Research Organisations (CROs) in submitting quality biostudies which will reduce turnaround times for registration and accelerate access to medicines for patients. In addition, the deficiencies identified will assist assessors from the different regulatory authorities to improve on their bioequivalence assessment.

Common deficiencies found in generic Finished Pharmaceutical Product (FPP) applications submitted for registration to the South African Health Products Regulatory Authority (SAHPRA).

BACKGROUND: The aim of the study was to investigate the common deficiencies observed in the Finished Pharmaceutical Product (FPP) section of generic product applications submitted to SAHPRA. The study was conducted retrospectively over a 7-year period (2011-2017) for products that were finalised by the Pharmaceutical and Analytical pre-registration Unit. METHODS: There were 3148 finalised products in 2011-2017, 667 of which were sterile while 2089 were non-sterile. In order to attain a representative sample for the study, statistical sampling was conducted. Sample size was obtained using the statistical tables found in literature and confirmed by a sample size calculation with a 95% confidence level. The selection of the products was according to the therapeutic category using the multi-stage sampling method called stratified-systematic sampling. This resulted in the selection of 325 applications for non-sterile products and 244 applications for sterile products. Subsequently, all the deficiencies were collected and categorised according to Common Technical Document (CTD) subsections of the FPP section (3.2.P). RESULTS: A total of 3253 deficiencies were collected from 325 non-sterile applications while 2742 deficiencies were collected from 244 sterile applications. The most common deficiencies in the FPP section for non-sterile products were on the following sections: Specifications (15%), Description and Composition (14%), Description of the Manufacturing Process (13%), Stability Data (7.6%) and the Container Closure System (7.3%). The deficiencies applicable to the sterile products were quantified and the subsection, Validation and/or Evaluation (18%) has the most deficiencies. Comparison of the deficiencies with those reported by other agencies such as the USFDA, EMA, TFDA and WHOPQTm are discussed with similarities outlined. CONCLUSIONS: The overall top five most common deficiencies observed by SAHPRA were extensively discussed for the generic products. The findings provide an overview on the submissions and regulatory considerations for generic applications in South Africa, which is useful for FPP manufacturers in the compilation of their dossiers and will assist in accelerating the registration process.

Common Deficiencies Found in the Active Pharmaceutical Ingredient (API) Section of Non-sterile Generic Products Submitted for Registration by SAHPRA.

PURPOSE: This research study aims to determine the qualitative and quantitative common deficiencies included in the API section of dossiers submitted to SAHPRA. The study was conducted retrospectively over a 7-year period (2011-2017) for non-sterile generic products that were finalised by the Pharmaceutical and Analytical pre-registration Unit. In this period, the restricted part of the CTD was evaluated when needed therefore this was not conducted on all applications. The requirement to evaluate the restricted part for all applications was initiated in January 2020, thus, a separate study has been conducted to identify the common deficiencies in the restricted part. METHODS: There were 2089 applications finalised between 2011 and 2017 and in order to attain a representative sample for the study, the multi-stage statistical sampling called the 'stratified systematic sampling' was selected as the method of choice. Sample size was obtained using the statistical tables found in the literature and confirmed by a sample size calculation with a 95% confidence level, resulting in the selection of 325 applications. Subsequently, all the deficiencies were collected and categorised according to CTD subsections. For the restricted part study, all new applications evaluated between January to May 2020 were used. RESULTS: A total of 1130 deficiencies were collected from 325 applications sampled. The majority of the identified deficiencies were from Module 3.2.S.3.1 (19.38%) on characterisation, Module 3.2.S.1.3 (19.11%) on general properties, Module 3.2.S.4.1 (10.44%) on specifications and Module 3.2.S.4.3 (8.32%) on validation of analytical methods. The study on the restricted parts included the five most common deficiencies that SAHPRA has identified, which are similar to those observed from the 2011-2017 applications. This confirms that the quality of the evaluations has been maintained over the years. Comparison of the deficiencies with those reported by other agencies such as the USFDA, EMA, WHOPQTm and TFDA are discussed with similarities clearly outlined. CONCLUSIONS: The most common deficiencies observed by SAHPRA were extensively discussed. These findings could serve as a guidance for API manufacturers to submit better quality APIMFs which will improve turnaround times for registration and accelerate access to medicines for patients.

Radical Releasing Anti-tuberculosis Agents and the Treatment of Mycobacterial Tuberculosis Infections - An Overview.

The treatment and management of tuberculosis (TB) is a major global concern. Approved drugs for the treatment of TB, to date, have displayed various modes of action which can be grouped into radical releasing and non-radical releasing anti-TB agents. Radical releasing agents are of special interest because they diffuse directly into the mycobacterium cell wall, interact with the host cell DNA, causing DNA strand breakages and fatal destabilization of the DNA helix inhibiting nucleic acid synthase. As a therapeutic agent with the aforementioned activity, nitroimidazoles and most especially bicyclic nitroimidazoles are currently in clinical use for the treatment of tuberculosis. However, the approved drugs, pretomanid (PR) and delamanid (DE) are limited in their nitric oxide radical (NO•) releasing abilities to cause effective bactericidity. It is believed that their bactericidal activity can be improved by harnessing alternative strategies to increase NO• release. The last decade has witnessed the strategic inclusion of NO-donors into native drugs to improve their activities and/or reverse resistance. The rationale behind this strategy is the targeting of NO• release at specific therapeutic sites. This review, therefore, aims to highlight various radical releasing agents that may be effective in the treatment of TB. The review also investigates various structural modifications to PR and DE and suggests alternative strategies to improve NO•release as well as some applications where NO-donor hybrid drugs have been used with good therapeutic effect.

Structural Insights and Docking Analysis of Adamantane-Linked 1,2,4-Triazole Derivatives as Potential 11ß-HSD1 Inhibitors.

The solid-state structural analysis and docking studies of three adamantane-linked 1,2,4-triazole derivatives are presented. Crystal structure analyses revealed that compound 2 crystallizes in the triclinic P-1 space group, while compounds 1 and 3 crystallize in the same monoclinic P21/c space group. Since the only difference between them is the para substitution on the aryl group, the electronic nature of these NO2 and halogen groups seems to have no influence over the formation of the solid. However, a probable correlation with the size of the groups is not discarded due to the similar intermolecular disposition between the NO2/Cl substituted molecules. Despite the similarities, CE-B3LYP energy model calculations show that pairwise interaction energies vary between them, and therefore the total packing energy is affected. HOMO-LUMO calculated energies show that the NO2 group influences the reactivity properties characterizing the molecule as soft and with the best disposition to accept electrons. Further, in silico studies predicted that the compounds might be able to inhibit the 11ß-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11ß-HSD1 inhibitors were able to accurately dock within the 11ß-HSD1 X-ray structure 4C7J. The molecular docking of the adamantane-linked 1,2,4-triazoles have similar predicted binding affinity scores compared to the 4C7J native ligand 4YQ. However, they were unable to form interactions with key active site residues. Based on these docking results, a series of potentially improved compounds were designed using computer aided drug design tools. The docking results of the new compounds showed similar predicted 11ß-HSD1 binding affinity scores as well as interactions to a known potent 11ß-HSD1 inhibitor.

Synthesis and Biological Evaluation of Thiazole-Based Derivatives as Potential Acetylcholinesterase Inhibitors.

Nineteen new thiazole-based derivatives were synthesized and their structures characterized with analytical and spectral data. The in vitro assessment of their acetylcholinesterase (AChE) inhibitory activity revealed that compounds 10 and 16 produced potent AChE inhibitory activities with IC50 values of 103.24 and 108.94 nM, respectively. Compounds 13, 17, 18, 21, 23, 31, and 33 displayed moderate activity with 25-50% relative potency compared to the known potent AChE inhibitor donepezil. Molecular docking studies of the active compounds docked within the active site cavity of AChE showed a binding orientation similar to that of donepezil, with good predicted binding affinities. These compounds could therefore be considered as potential lead compounds for the development of new and potentially improved AChE inhibitors.

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 bc 1 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.

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;µM. Significant neuroprotective effects towards MPP+-compromised SH-SY5Y neuroblastoma cells were also observed, with no inherent cytotoxicity at 10 µM 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.

Towards the Development of an Intervention to Address Social Determinants of Non-Communicable Disease in Kerala, India: A Mixed Methods Study.

In India, cardiovascular disease (CVD), with hypertension as its foremost risk factor, has the highest prevalence rate of non-communicable diseases (NCDs) and a rising mortality. Previous research has found a clustering of behavioural and social risks pertaining to NCDs, though the latter are infrequently addressed in public health interventions in India. This paper reaches toward the development of a social intervention to address social determinants of NCD relating to hypertension and diabetes. We used Theory of Change (ToC) as a theoretical approach to programme design. Mixed methods were used, including qualitative interviews with community members (n = 20), Accredited Social Health Activists (n = 6) and health professionals (n = 8), and a stakeholder workshop (n = 5 participants). The recruitment of participants from one local area in Kerala enabled us to map service provision and gain a holistic understanding of how to utilise the existing workforce to target social risk factors. The findings suggest that social interventions need to focus on ensuring health behaviour information reaches all parts of the community, and that those with more social risk factors are identified and supported to engage with treatment. Further research is required to test the resulting intervention model.

4-Oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione Derivatives as NMDA Receptor- and VGCC Blockers with Neuroprotective Potential.

The impact of excitotoxicity mediated by N-methyl-D-aspartate (NMDA) receptor overactivation and voltage gated calcium channel (VGCC) depolarization is prominent among the postulated processes involved in the development of neurodegenerative disorders. NGP1-01, a polycyclic amine, has been shown to be neuroprotective through modulation of the NMDA receptor and VGCC, and attenuation of MPP+-induced neurotoxicity. Recently, we reported on the calcium modulating effects of tricycloundecene derivatives, structurally similar to NGP1-01, on the NMDA receptor and VGCC of synaptoneurosomes. In the present study, we investigated novel 4-oxatricyclo[5.2.1.02,6]dec-8-ene-3,5-dione derivatives for their cytotoxicity, neuroprotective effects via attenuation of MPP+-induced neurotoxicity and calcium influx inhibition abilities through the NMDA receptor and VGCC using neuroblastoma SH-SY5Y cells. All compounds, in general, showed low or no toxicity against neuroblastoma cells at 10-50 µM concentrations. At 10 µM, all compounds significantly attenuated MPP+-induced neurotoxicity as evident by the enhancement in cell viability between 23.05 ± 3.45% to 53.56 ± 9.29%. In comparison to known active compounds, the derivatives demonstrated mono or dual calcium modulating effect on the NMDA receptor and/or VGCC. Molecular docking studies using the NMDA receptor protein structure indicated that the compounds are able to bind in a comparable manner to the crystallographic pose of MK-801 inside the NMDA ion channel. The biological characteristics, together with results from in silico studies, suggest that these compounds could act as neuroprotective agents for the purpose of halting or slowing down the degenerative processes in neuronal cells.

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. In silico studies indicated that these compounds should cross the blood-brain barrier, making them promising lead molecules in the development of anti-Alzheimer's agents.