South Africa is home to a rich tapestry of cultural and linguistic diversity, with 11 official spoken languages and South African Sign Language recognised as the twelfth. While this plurality reflects the nation’s vibrant social fabric, it poses challenges for equitable healthcare delivery and pharmacy practice. The predominance of English as the primary language used on medication labels, patient information leaflets and in healthcare communication can create language barriers. This can limit patient understanding and potentially compromise safe and effective medicine use for non-English-speaking populations. This study examines the development and implementation of a generative Artificial Intelligence translation workflow. Developed with OpenAI’s ChatGPT Builder and configured by the research team, the translation application has the potential to translate medicine instructions at pharmacy dispensaries into four major South African languages. Two scoring rounds evaluated the accuracy of translated medicine information. In round one, Section two of a South African Health Products Regulatory Authority-approved Patient Information Leaflet was translated into Afrikaans, isiXhosa, isiZulu, and siSwati using a customised General-purpose Technology. Linguists assessed outputs with a structured scoring tool measuring accuracy, fluency, and cultural appropriateness. After model refinement, round two repeated evaluation on a comparable selection from a new Section two South African Health Products Regulatory Authority-approved Patient Information Leaflet to reduce bias from prior feedback. Across two evaluation rounds, translation accuracy improved for siSwati and isiZulu, with substantial reductions in critical error rates (siSwati: RR = 0.57; 95

The dual modulation of Glycogen Synthase Kinase 3 Beta (GSK3β) and Sirtuin 1 (SIRT1) offers a promising therapeutic strategy for neurodegenerative diseases and cancer. In this study, we investigated, for the first time, the dual activity of known SIRT1 activators and GSK3β inhibitors using advanced in silico methods followed by experimental validation. Specifically, we employed multiple virtual screening (VS) approaches, including ligand- and structure-based methods, blind docking, and molecular dynamics (MD) simulations with binding free energy calculations. Using enzyme activity assays, we confirmed the dual activity of two compounds. SIRT1 activator SC22 (SIRT1 EC150 = 7 μM) exhibited moderate GSK3β inhibition with an IC50 = 7.65 μM. GSK3β inhibitor GC43 (GSK3β IC50 = 0.005 μM) inhibited SIRT1 with SIRT1 IC50 = 0.39 μM, demonstrating potential for pancreatic cancer treatment. These results underscore the importance of integrating computational and experimental methods to identify multifunctional agents, providing insights into the modulation of GSK3β and SIRT1 and their therapeutic implications. Finally, our findings highlight the limits of in silico techniques, particularly in predicting SIRT1 activation due to potential allosteric effects.

INTRODUCTION:The growing burden of drug-resistant mycobacterial infections demands novel therapeutic agents. One strategy for discovering new tuberculosis (TB) drugs is to target essential proteins within validated biosynthetic pathways. FadD32 is a key enzyme in mycolic acid synthesis and is critical for the viability of Mycobacterium tuberculosis (Mtb). Accordingly, identifying potent FadD32 inhibitors represents a promising approach that may help circumvent resistance to existing TB drugs such as isoniazid. METHODS:This study employed structure-based drug design using molecular docking to evaluate the binding potential of 7-substituted coumarin derivatives and compounds from the Maybridge database against FadD32. Docking was performed using Hybrid 4.0 software. Top-scoring ligands were screened for antimycobacterial activity against Mycobacterium smegmatis mc²155 using the Alamar Blue assay. RESULTS:All 7-substituted coumarin derivatives exhibited better docking scores than the native ligand of FadD32. Additionally, 14 Maybridge compounds, including diverse scaffolds, also showed favorable docking results. Among them, HTS08202 (a benzimidazole derivative) demonstrated significant activity, inhibiting M. smegmatis mc2155 by 94.12% (±2.34%) and 94.82% (±1.73%) at 50 μM and 25 μM, respectively. CP15, a coumarin-based compound, achieved 82.38% (±3.18%) inhibition at 50 μM. Cytotoxicity assessment revealed that HTS08202 was not toxic at 25 μM, its active concentration. DISCUSSION:The findings highlight the potential of both benzimidazole and coumarin-based derivatives as promising leads for antimycobacterial drug development. The favorable docking scores and biological activity suggest that FadD32 inhibition may be a viable strategy to overcome resistance mechanisms in TB. HTS08202 stands out for its higher inhibition and lower cytotoxicity, and requires further optimization and in vivo evaluation. CONCLUSION:The identified compounds, especially HTS08202 merit further investigation as potential antimycobacterial agents.

BACKGROUND:Histone deacetylases (HDACs) are epigenetic enzymes linked to several biological functions and diseases. Among HDACs, the class I enzymes show high similarity in protein sequence and active site. Non-selective inhibition of HDACs has side effects. However, HDAC3-selective inhibitors in preclinical studies showed promise in non-communicable diseases with fewer complications. Most HDAC3-selective inhibitors contain a benzamide zinc-binding group (ZBG). Hydroxamates are highly potent HDAC inhibitors, but they exhibit toxicity, poor pharmacokinetic and selectivity profiles. Benzamide-based inhibitors offer improved selectivity but lack potency and often optimisation compromises potency. There is a need for HDAC3 inhibitors with novel ZBGs, balanced potency and selectivity, while maintaining good safety and pharmacokinetic profiles. This study aims to identify HDAC3-selective inhibitors with novel ZBGs using in silico techniques. METHOD:The in silico tools PROCHECK, VERIFY3D, Molecular Operating Environment, and ProteinsPlus, were utilised to validate HDAC3 protein structure, active site prediction and consensus confirmation, and predict zinc ion coordination geometry. Schrodinger Maestro was used for protein and ligand preparation, and molecular docking. Benchmarking was performed through re-docking and docking of actives and decoys to evaluate and validate the docking program, docking parameters and algorithm. Structure-based virtual screening with predefined criteria identified 22 structurally diverse compounds from focused libraries for purchase and subsequent in vitro evaluation. RESULT:Out of the 22 compounds tested against HDAC3, 11 compounds showed inhibitory activity. Compound a showed the highest inhibitory activity (89.93%), compound k showed the lowest inhibitory activity (0.61%) at a 20 µM screening concentration. Compound a showed IC50 of 0.99 µM against HDAC3 but it showed poor selectivity against HDAC1 and HDAC2. Compound b showed an IC50 of 15.5 µM and it showed 7.4- and 5.7-fold selectivity against HDAC1 and 2 respectively. Neither compound inhibited HDAC8, and they were predicted to be blood brain barrier (BBB) impermeant. Toxicity predictions showed that compound a may cause neurotoxicity and respiratory toxicity and compound b may cause neurotoxicity and hepatotoxicity. CONCLUSION:The study identified novel compounds with HDAC3 inhibition. However, it also highlighted the need for further structural optimisation to improve inhibitory activity, maintain selectivity, ensure BBB permeability and reduce toxicity.

Histone deacetylases (HDACs) are epigenetic enzymes linked to several biological functions and diseases. Among HDACs, the class I enzymes show high similarity in protein sequence and active site. Non-selective inhibition of HDACs has side effects. However, HDAC3-selective inhibitors in preclinical studies showed promise in non-communicable diseases with fewer complications. Most HDAC3-selective inhibitors contain a benzamide zinc-binding group (ZBG). Hydroxamates are highly potent HDAC inhibitors, but they exhibit toxicity, poor pharmacokinetic and selectivity profiles. Benzamide-based inhibitors offer improved selectivity but lack potency and often optimisation compromises potency. There is a need for HDAC3 inhibitors with novel ZBGs, balanced potency and selectivity, while maintaining good safety and pharmacokinetic profiles. This study aims to identify HDAC3-selective inhibitors with novel ZBGs using in silico techniques. The in silico tools PROCHECK, VERIFY3D, Molecular Operating Environment, and ProteinsPlus, were utilised to validate HDAC3 protein structure, active site prediction and consensus confirmation, and predict zinc ion coordination geometry. Schrodinger Maestro was used for protein and ligand preparation, and molecular docking. Benchmarking was performed through re-docking and docking of actives and decoys to evaluate and validate the docking program, docking parameters and algorithm. Structure-based virtual screening with predefined criteria identified 22 structurally diverse compounds from focused libraries for purchase and subsequent in vitro evaluation. Out of the 22 compounds tested against HDAC3, 11 compounds showed inhibitory activity. Compound a showed the highest inhibitory activity (89.93%), compound k showed the lowest inhibitory activity (0.61%) at a 20 µM screening concentration. Compound a showed IC50 of 0.99 µM against HDAC3 but it showed poor selectivity against HDAC1 and HDAC2. Compound b showed an IC50 of 15.5 µM and it showed 7.4- and 5.7-fold selectivity against HDAC1 and 2 respectively. Neither compound inhibited HDAC8, and they were predicted to be blood brain barrier (BBB) impermeant. Toxicity predictions showed that compound a may cause neurotoxicity and respiratory toxicity and compound b may cause neurotoxicity and hepatotoxicity. The study identified novel compounds with HDAC3 inhibition. However, it also highlighted the need for further structural optimisation to improve inhibitory activity, maintain selectivity, ensure BBB permeability and reduce toxicity.

Alzheimer’s disease (AD) remains without effective disease-modifying therapies, in part due to the limited efficacy of single-target approaches. Dual modulation of glycogen synthase kinase-3β (GSK3β), a key driver of tau hyperphosphorylation and amyloid-β (Aβ) production, and sirtuin-1 (SIRT1), a neuroprotective NAD+-dependent deacetylase, has emerged as a promising therapeutic strategy. This review explores the mechanistic rationale for concurrently inhibiting GSK3β and activating SIRT1 to disrupt AD’s pathological cascade while enhancing endogenous neuroprotective pathways. Natural compounds such as resveratrol, berberine, pterostilbene, and quercetin exhibit this dual activity and provide scaffolds for rational drug design. However, challenges related to target selectivity, blood-brain barrier penetration, and clinical translation persist. Advances in multi-target drug discovery, including pharmacophore hybridization, structure-based modelling, cheminformatics, nanoformulation and delivery strategies offer new avenues to overcome these hurdles. A dual GSK3β/SIRT1-targeting strategy exemplifies a systems-level approach to restoring neurophysiological balance and holds potential to achieve more effective, disease-modifying outcomes in AD.

Alzheimer's disease (AD) is a debilitating disorder marked by progressive memory and cognitive function loss. Current treatments, including acetylcholinesterase and N-methyl-d-aspartate receptor inhibitors, offer symptomatic relief but lack disease-modifying effects. The recent approval of aducanumab, an antibody clearing amyloid beta plaques, brings hope, though its therapeutic benefits are controversial. AD's etiology is multifactorial, involving over 40 genetic variants, and remains poorly defined. Nanotechnology offers a promising avenue for optimized drug candidates, addressing challenges such as solubility, stability, and blood-brain barrier permeation. This review explores nanoformulations targeting key AD aspects, including amyloid beta, Tau protein, oxidative stress, and neuroinflammation. Notably, multifunctional nanocarriers present a comprehensive approach, demonstrating the potential for effective AD therapy. Despite extensive research, only a small fraction of these studies progress to clinical trials. Continuous nanomedicine research is poised to play a vital role in future AD management, providing innovative solutions to this devastating disease.

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 to 2023, focusing on compounds that inhibit the HDAC3 isoenzyme. EXPERT OPINION:HDAC3-selective inhibitors - pivotal for pharmacological applications, 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 (ZBGs) 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 the discovery of novel HDAC3-selective inhibitors, which bear alternative ZBGs with balanced selectivity for HDAC3 and potency.

BACE-1 plays a pivotal role in the production of β-amyloid (Aβ) peptides, implicated in Alzheimer's Disease (AD) pathology. We previously described edaravone N-benzyl pyridinium derivatives (EBPDs) that exhibited multifunctional activity against multiple AD targets. In this study we explored the EBPDs BACE-1 inhibitory activity to potentially enhance the compounds therapeutic profile. The EBPDs exhibited moderate BACE-1 inhibitory activity (IC50 = 44.10 µM - 123.70 µM) and obtained IC50 values between 2.0 and 5.8-fold greater than resveratrol, a known BACE-1 inhibitor (IC50 = 253.20 µM), in this assay. Compound 3 was the most potent inhibitor with an IC50 of 44.10 µM and a Ki of 19.96 µM and a mixed-type mode of inhibition that favored binding in a competitive manner. Molecular docking identified crucial interactions with BACE-1 active site residues, supported by 100 ns MD simulations. The study highlighted the EBPDs therapeutic potential as BACE-1 inhibitors and multifunctional anti-AD therapeutic agents.

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.

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.

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.

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. 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. 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. 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. 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.

Background: Well-functioning health systems need effective medicine regulation. The regulatory authorities are governed by basic principles such as transparency, accountability and science to facilitate access to medicines. The South African authority has had a backlog for 10 years, delaying patient access to medicines. To increase transparency, a series of articles on common deficiencies were published. The sharing of deficiencies would assist applicants in improving their submissions in the regional, active pharmaceutical ingredient (API), finished pharmaceutical product (FPP) and bioequivalence sections. The current study focuses on the authority's common deficiencies in the regional section.Methods: Module 1 deficiencies from sections evaluated by the pharmaceutical evaluation and management (PEM) pre-registration unit were collected from 2011-2017 applications. From 3 148 finalised applications, 325 non-sterile and 244 sterile were selected. A further analysis of 62 applications was evaluated between January and May 2021 to confirm the consistency of assessments and requirements. Results: For the 2011-2017 study, 3 042 deficiencies were collected. Labelling sections accounted for 52% of the deficiencies, followed by amendment schedule (12%), general deficiencies (11%), foreign registration status section (10%), application details (8%) and good manufacturing practice (GMP) standards (7%). Labelling had the highest deficiencies (57%) in the 2021 study, followed by foreign regulatory status (15%) as well as GMP documentation and application details (10%). These deficiencies were found in 52 query letters, as 10 contained no queries from Module 1.Conclusion: The qualitative and quantitative data provided herein intends to assist applicants in building quality submissions in order to convey acceptable regional requirements during submission, and reduce the authority(sic)s overall registration turnaround time.

BackgroundVarious 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.MethodsA 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.ResultsThe 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.ConclusionsThe 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.

Pharmaceutical Patent AnalystVol. 11, No. 5 EditorialEver-expanding landscape: Alzheimer's – new targets and new patentsAyodeji O Egunlusi & Jacques JoubertAyodeji O Egunlusi https://orcid.org/0000-0003-2251-6043Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, 7535, South Africa & Jacques Joubert *Author for correspondence: +272 1959 2195; E-mail Address: jjoubert@uwc.ac.zahttps://orcid.org/0000-0003-0378-7091Pharmaceutical Chemistry, School of Pharmacy, University of the Western Cape, Private Bag X17, Bellville, 7535, South AfricaPublished Online:2 Sep 2022https://doi.org/10.4155/ppa-2022-0031AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit View articleKeywords: aggregated amyloid-betaAlzheimer's diseasehyperphosphorylated tau-neurotherapeutic agentsnew therapeutic targetsReferences1. Matej R, Tesar A, Rusina R. Alzheimer's disease and other neurodegenerative dementias in comorbidity: a clinical and neuropathological overview. Clin. Biochem. 73, 26–31 (2019).Crossref, Medline, CAS, Google Scholar2. Mufson E, Ikonomovic M, Counts S et al. Molecular and cellular pathophysiology of preclinical Alzheimer's disease. Behav. Brain Res. 311, 54–69 (2016).Crossref, Medline, CAS, Google Scholar3. Kumar N, Kumar V, Anand P, Kumar V, Dwivedi A, Kumar V. Advancements in the development of multi-target directed ligands for the treatment of Alzheimer's disease. Bioorg. Med. Chem. 61, 116742 (2022).Crossref, Medline, CAS, Google Scholar4. Fish P, Steadman D, Bayle E, Whiting P. New approaches for the treatment of Alzheimer's disease. Bioorg. Med. Chem. Lett. 29, 125–133 (2019).Crossref, Medline, CAS, Google Scholar5. Arbo B, Riberiro M, Garcia-Segura L. Development of new treatment for Alzheimer's diseases based on the modulation of translocator protein (TSPO). Ageing Res. Rev. 54, 100943 (2019).Crossref, Medline, CAS, Google Scholar6. Vaz M, Silvestre S. Alzheimer's disease: recent treatment strategies. Eur. J. Pharmacol. 887, 173554 (2020).Crossref, Medline, CAS, Google Scholar7. Pradeepkiran J, Reddy P. Phosphorylated tau targeted small-molecule PROTACs for the treatment of Alzheimer's disease and tauopathies. Biochim. Biophys. Acta – Mol. Basis Dis. 1867, 166162 (2021).Crossref, Medline, Google Scholar8. Verma A, Waiker D, Bhardwaji B, Saraf P, Shrivastava S. The molecular mechanism, targets, and novel molecules in the treatment of Alzheimer's disease. Bioorg. Chem. 119, 105562 (2022).Crossref, Medline, CAS, Google Scholar9. Lim S. The recent pharmaceutical patent landscape for Alzheimer's disease: an interview with Sang Min Lim. Pharm. Pat. Anal. 8(6), 215–216 (2019).Link, CAS, Google Scholar10. Lee H, Lim D, Lee J, Lim S, Pae A. Development of tau-directed small molecule modulators for Alzheimer's disease: a recent patent review (2014–2018). Pharm. Pat. Anal. 8(1), 15–39 (2019).Link, CAS, Google Scholar11. BASF SE. WO2021/1234191 (2021).Google Scholar12. OHIO STATE INNOVATION FOUNDATION AND THE BRIGHAM AND WOMAN'S HOSPITAL INC. WO2019/2366251 (2019).Google Scholar13. ABAERATA LIMITED PARTNERSHIP. WO2020/1133381 (2020).Google Scholar14. MEDIMMUNE LIMITED AND ELI LILLY AND COMPANY. WO2021/2601931 (2021).Google Scholar15. VLAAMS INSTITUUT VOOR BIOTECHNOLOGIE AND KATHOLIEKE UNIVERSITEIT LEUVEN. WO2019/0161231 (2019).Google Scholar16. CENTREA DE INVESTIGACION Y DE ESTUDIOS AVANZADOS DEL INSTITUTO POLITECNICO NACIONAL AND BUSTAR ALIMENTOS S.A.P.I.DE C.V. WO2022/0765071 (2022).Google Scholar17. CEDARS-SINAI MEDICAL CENTER AND FORTEM NEUROSCIENCES. WO2022/0316062 (2022).Google Scholar18. AC IMMUNE SA. WO2022/0789711 (2022).Google Scholar19. Siddiqui H, Choudhary M, Wahab A, Rahman A, Rizvi F, Wajid S. WO2021/03631081 (2021).Google Scholar20. Swalley S. Expanding therapeutic opportunities for neurodegenerative diseases: a perspective on the important role of phenotypic screening. Bioorg. Med. Chem. 28, 115239 (2020).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetails Vol. 11, No. 5 Follow us on social media for the latest updates Metrics Downloaded 32 times History Received 4 July 2022 Accepted 7 July 2022 Published online 2 September 2022 Published in print September 2022 Information© 2022 Newlands PressKeywordsaggregated amyloid-betaAlzheimer's diseasehyperphosphorylated tau-neurotherapeutic agentsnew therapeutic targetsFinancial & competing interests disclosureResearch reported in this publication was supported by the South African Medical Research Council (SAMRC) through its division of Research Capacity Development under the Research Capacity development initiative from funding received from South African National Treasury. The content and findings reported are the sole deduction, view and responsibility of the researcher and do not reflect the official position and sentiments of the SAMRC. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download

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.

Ion channels are critically important for the normal function of the brain and excitable tissues. The Research Topic “Channel Modulation in Neurodegeneration and Neuroprotection” focused on the role of ion channel function or dysfunction in neurological and neurodegenerative conditions. Convergent efforts to establish a link between clinical neurology, genetics, loss of function of important proteins and channelopathies in neurological disorders have become an intense area of research interest. Several ion channels have been implicated as important players in these diseases. This research topic therefore includes ten key research articles and two up-todate review papers in the field of ion channels, their structural features and their proposed modes of action, through the analyses of their structural characteristics, structure-function relationship, therapeutic modulation and neuropharmacology. In this collection, several authors focused on exploring and further elaborating on glutamate receptor channels and their role in the development and treatment of neurological disorders. Gale et al. investigated whether glutaminergic N-methyl-D-aspartate (NMDA) receptor channel antagonists, other than memantine, are able to treat patients with GRIN mutations on the GluN2A subunit of the NMDA receptor by attenuating neurotoxicity associated with GluN2AP552R expression. The authors found that treatment with ketamine does not effectively block GluN2A-P552R-mediated dendrotoxicity, despite the fact that both memantine and ketamine act as open NMDA receptor channel blockers binding at the phencyclidine binding site. These findings suggest that GluN2A-P552R induced dendrotoxicity is mediated through two distinct mechanisms that are yet to be elucidated. The group of Sebih et al. synthesised the glutathione (GSH) metabolite gamma-L-glutamyl-L-glutamate (γ-Glu-Glu) and explored its effects on activation of NMDA receptors. They observed that γ-Glu-Glu partially activated NMDA receptors and exhibited better efficacy for NMDA receptors containing the GluN2B subunit. γ-Glu-Glu was also found to potentiate glutamate responses on NMDA receptors. Further experiments revealed that extracellular γ-Glu-Glu concentration was directly linked to GSH metabolism, suggesting that γ-Glu-Glu could exert excitatory effects when GSH production is enhanced, leading to the overactivation of neuronal NMDA receptors. The research article by Dron et al. described the effect of different anticonvulsants on native glutaminergic calciumpermeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptors (CP-AMPARs) and calcium-impermeable AMPA receptors (CI-AMPARs) using a whole cell patch-clamp method. Amongst the ten anticonvulsants evaluated, phenytoin was the only one with significant ability to reversibly inhibit CP-AMPARs and Cl-AMPARs. The authors have Edited by: Giulia Maria Camerino, University of Bari Aldo Moro, Italy

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 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1–3 were determined using in silico techniques. Molecular docking of the compounds into the 11β-HSD1 active site showed comparable binding affinity scores (−7.50 to −8.92 kcal/mol) to the 11β-HSD1 co-crystallized ligand 4YQ (−8.48 kcal/mol, 11β-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.

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 center dot) releasing abilities to cause effective bactericidity. It is believed that their bactericidal activity can be improved by harnessing alternative strategies to increase NO center dot 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 center dot 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 center dot release as well as some applications where NO-donor hybrid drugs have been used with good therapeutic effect.