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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.

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.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.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.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.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.

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.

International audience; Like much of the developing world, sub-Saharan Africa (SSA) is facing a major challenge. This challenge is due to noncommunicable diseases (NCDs) whose rates are rising dramatically in SSA. Two conditions that frequently coexist head the list of NCDs as either established disease entities or risk factors for NCDs. These are hypertension and diabetes. Hypertension is the foremost cardiovascular condition. The objective of this scoping review is to examine peer-reviewed publications for the period 2009–2019 related to the detection and management of hypertension in SSA. We seek to define the issues confronted in managing hypertension in SSA, what measures have been implemented and evaluated, and what barriers and facilitators have been found. By mapping the complex, heterogeneous literature, we aim to identify the key concepts that underpin a major public health issue in SSA. The central question that this review addresses is how to control hypertension in SSA.

Background Cardiovascular disease (CVD) is the leading cause of mortality in India. Social and behavioural factors are strongly interrelated in the prevention and control of CVD. The ability to make lifestyle changes to control hypertension and diabetes (major risk factors for CVD) is determined by factors such as education, gender, caste, poverty, and urbanicity. This study aimed to improve our understanding of the inter-relationship of social and behavioural factors in the management of elevated serum glucose and high blood pressure and co-morbid mental health conditions. Methods A population-based catchment area cross sectional survey was conducted in Kerala, India. Data were collected from residents aged over 30 years (n = 997) using standardized tools and clinical measures. We performed latent class analysis incrementally to extract homogeneous latent classes of individuals based on their responses to social and behavioural risk factors in the survey. Using structural equation models, we assessed the mediating effect of depression and anxiety, and social or behavioural risk factors, on management of high blood pressure and raised serum glucose levels. Results The prevalence of high blood pressure and blood glucose in the sample was 33 and 26% respectively. Latent class analysis found three clusters of risk factors. One had a predominance of behavioural characteristics, another of social risk factors and the third was a low risk group. Age, female sex, and marital status had an effect on high blood pressure and high glucose, though were mediated by mental health, social and behavioural risk factors. Conclusions Interventions to improve the management of risk factors for CVD need to address social risk factors and be sensitive to the needs of population sub-groups that may require additional support to access health services. An integration of social and health services may be required to achieve this.

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.

This article belongs to the Special Issue Molecular Simulations Applications in Biochemistry and Molecular Biology., 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 11β-HSD1 enzyme, which is implicated in obesity and diabetes. Self- and cross-docking experiments revealed that a number of non-native 11β-HSD1 inhibitors were able to accurately dock within the 11β-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 11β-HSD1 binding affinity scores as well as interactions to a known potent 11β-HSD1 inhibitor., This research was funded by the Deanship of Scientific Research at Princess Nourah bint Abdulrahman University through the Research Groups Program (Grant No. RGP-1442-0010-4).

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.

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.

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.

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.

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&ndash, 50 &micro, M concentrations. At 10 &micro, M, all compounds significantly attenuated MPP+-induced neurotoxicity as evident by the enhancement in cell viability between 23.05 &plusmn, 3.45% to 53.56 &plusmn, 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.

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.

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

ObjectivesThe purpose of this study is to examine the existing literature of the major social risk factors which are associated with diabetes, hypertension and the comorbid conditions of depression and anxiety in India.DesignScoping review.Data sourcesScopus, Embase, CINAHL Plus, PsycINFO, Web of Science and MEDLINE were searched for through September 2019.Eligibility criteria for selecting studiesStudies reporting data on social risk factors for diabetes or hypertension and depression or anxiety in community-based samples of adults from India, published in English in the 10 years to 2019, were included. Studies that did not disaggregate pooled data from other countries were excluded.Data extraction and synthesisTwo independent reviewers extracted study aims; methods; sample size and description; demographic, social and behavioural risk factors and a summary of findings from each paper. Risk factors were synthesised into six emergent themes.ResultsTen studies were considered eligible and included in this review. Nine presented cross-sectional data and one was a qualitative case study. Six themes emerged, that is, demographic factors, economic aspects, social networks, life events, health barriers and health risk behaviours.ConclusionsLiterature relating to the major social risk factors associated with diabetes, hypertension and comorbid depression and anxiety in India is sparse. More research is required to better understand the interactions of social context and social risk factors with non-communicable diseases and comorbid mental health problems so as to better inform management of these in the Indian subcontinent.

The neuroprotective effects of closed polycyclic cage molecules such as NGP1-01, memantine and amantadine have been extensively explored. These effects are mostly linked to the antagonism of the N-methyl-d-aspartate (NMDA) receptor- and the blockage of voltage gated calcium channels (VGCC). The synthesis of structurally related open and rearranged cage derivatives has been studied in depth. However, very little is known on their neuroprotective effects. In this study, a series of open and rearranged polycyclic cage molecules containing a norbornane derived scaffold were synthesised and evaluated for cytotoxicity, neuroprotection and calcium blocking effects via the NMDA receptor and VGCC on neuroblastoma cells at a 10 μM concentration. All compounds showed negligible cytotoxicity and were able to significantly attenuate MPP

Butyrylcholinesterase (BuChE) is considered a promising drug target as it plays an important role in the progression of late stage Alzheimer’s disease (AD). Two compound libraries were selected and 64 124 amine containing moieties were screened using a hierarchical virtual screening protocol to discover new selective BuChE inhibitors. From these and subsequent docking experiments, 9-phenylacridinedione (9-PAD) was identified as a promising scaffold for selective inhibition of BuChE. Selected top dock scored 9-PADs were assayed and compounds 3 and 6 exhibited potent and highly selective human BuChE inhibition (IC50: 98 nM and 142 nM, respectively). Both molecules were also predicted to show sufficient brain permeability, not have any substantial toxicities, especially hepatotoxicity, and no significant in vitro cytotoxicity against SH-SY5Y neuroblastoma cells at concentrations up to 100 µM. These findings indicate that 9-PAD is a promising lead structure for the development of agents able to treat late stage AD.

Introduction: Neurodegenerative diseases commonly present misfolding and aggregation of one or more proteins, including α-synuclein, β-amyloid, and tau. Several research efforts have been made to d...

A series of indole derivatives was designed and synthesised to improve on activity and circumvent pharmacokinetic limitations experienced with the structurally related compound, ladostigil. The compounds consisted of a propargylamine moiety (a known MAO inhibitor and neuroprotector) at the N1 position and a ChE inhibiting diethyl-carbamate/urea moiety at the 5 or 6 position of the indole ring. In order to prevent or slow down the in vivo hydrolysis and deactivation associated with the carbamate function of ladostigil, a urea moeity was incorporated into selected compounds to obtain more metabolically stable structures. The majority of the synthesised compounds showed improved MAO-A inhibitory activity compared to ladostigil. The compounds possessing the propargylamine moiety showed good MAO-B inhibitory activity with 6 and 8 portraying IC50 values between 14-20 fold better than ladostigil. The ChE assay results indicated that the compounds have non-selective inhibitory activities on eeAChE and eqBuChE regardless of the type or position of substitution (IC50: 2-5 μM). MAO-A and MAO-B docking results showed that the propargylamine moiety was positioned in close proximity to the FAD cofactor suggesting that the good inhibitory activity may be attributed to the propargylamine moiety and irreversible inhibition as confirmed in the reversibility studies. Docking results also indicated that the compounds have interactions with important amino acids in the AChE and BuChE catalytic sites. Compound 6 was the most potent multifunctional agent showing better inhibitory activity than ladostigil in vitro on all enzymes tested (hMAO-A IC50 = 4.31 μM, hMAO-B IC50 = 2.62 μM, eeAChE IC50 = 3.70 μM, eqBuChE IC50 = 2.82 μM). Chemical stability tests confirmed the diethyl-urea containing compound 6 to be more stable than its diethyl-carbamate containing counterpart compound 8. Compound 6 also exerted significant neuroprotection (52.62% at 1 μM) against MPP+ insult to SH-SY5Y neural cells and has good in silico predicted ADMET properties. The favourable neuronal enzyme inhibitory activity, likely improved pharmacokinetic properties in vivo and the potent neuroprotective ability of compound 6 make it a promising compound for further development.

C22H28N2O2S, monoclinic, P21/n (no. 14), a = 9.2516(7) Å, b = 10.5122(8) Å, c = 19.7782(15) Å, β = 98.9530(10)°, V = 1900.1(2) Å3, Z = 4, R gt(F) = 0.0356, wR ref(F 2) = 0.1004, T = 100(2) K.

The versatile biological activities of tacrine, trolox and β-carboline derivatives make them promising lead structures for the development of multifunctional Alzheimer’s disease (AD) agents. Based on the topology of the active site of cholinesterases and other target proteins involved in the pathogenesis of AD, we have designed and synthesized tacrine-trolox and tacrine-tryptoline hybrids with various linker chain lengths. The hybrids containing the trolox moiety (8a-8d) showed moderate to high TcAChE inhibition (IC50: 17.37 - 2200 nM), eqBuChE inhibition (IC50: 3.16 – 128.82 nM) and free radical scavenging activities (IC50: 11.48 – 49.23 µM). The hybrids with longer linker chain lengths in general showed better ChE inhibitory activity. As expected, free radical scavenging activities were not significantly affected by varying linker chain lengths. The hybrid compound containing the tryptoline moiety linked with a 7 carbon spacer to tacrine (14) displayed the best AChE and BuChE inhibitory activity (IC50 = 17.37 and 3.16 nM). Docking experiments exhibited that compounds 8d and 14 were able to bind to both the CAS and PAS of TcAChE and eqBuChE, suggesting that they will be able to inhibit ChE induced Aβ aggregation. Novel multi-target agents that exhibit good ChE inhibition (8d and 14) and anti-oxidant (8d) activity were identified as suitable candidates for further investigation.

A series of 7-substituted coumarin derivatives were designed and synthesised to display ChE and MAO-B inhibitory activity. The compounds consisted out of a coumarin structure (MAO-B inhibitor) and benzyl-, piperidine-, N -benzylpiperidine- or p -bromo- N -benzylpiperizine moiety, resembling the N -benzylpiperidine function of donepezil (ChE inhibitor), connected via an alkyl ether linkage at the 7 position. The biological assay results indicated that all the compounds ( 1 – 25 ) displayed selective inhibition to hMAO-B over hMAO-A, with the benzyloxy series ( 1 – 8 , 10 – 13 ) showing nano-molar hMAO-B inhibition (IC 50 : 0.5–73 nM). Limited ChE inhibitory activity was however observed for the benzyloxy series with the exception of 2 and especially 3 showing selective BuChE inhibition. From this series 3 showed the best multifunctional activity (eqBuChE IC 50 = 0.96 μM, hMAO-A IC 50 = 2.13 μM, hMAO-B IC 50 = 0.0021 μM). Within the N -benzylpiperidine ( 16 – 19 ) and p -bromo- N -benzylpiperizine ( 21 – 24 ) series the compounds in general showed moderate ChE and MAO-B inhibitory activity. Of these compounds 19 was the most potent multifunctional agent showing good eeAChE and eqBuChE inhibition (IC 50 = 9.10 μM and 5.90 μM, respectively), and relatively potent and selective hMAO-B inhibition (IC 50 = 0.30 μM, SI = >33). Molecular modeling revealed that 19 was able to bind simultaneously to the CAS, mid-gorge and PAS sites of AChE and BuChE suggesting that it will be able to inhibit AChE induced Aβ aggregation. From this study, compounds that 3 and 19 can be considered as promising multifunctional lead compounds.

5-(Adamantan-1-yl)-3-[(4-chlorobenzyl)sulfanyl]-4-methyl-4H-1,2,4-triazole (4) was identified as a potential 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) inhibitor and this paper describes the in-depth structural analysis thereof. Compound 4 was synthesized in a 92% yield and its 3D-structure confirmed by single-crystal X-ray diffraction. Hirshfeld surface analysis indicated that H…H, C-H…C, C-H…Cl and especially C-H…N hydrogen bond interactions are the primary contributors to the intermolecular stabilisation in the crystal. In order to explore the properties of 4, free from the influence of the crystal field, density functional theory (DFT) calculations were conducted. Results indicated that the DFT optimized geometry of 4 produced a conformer (4a) that is significantly different from the crystal structure. Further experiments confirmed that the crystal structure is not the absolute minimum conformation. This indicated that the crystal packing forces has significantly influenced the conformation thereof. Frontier molecular orbital energies and net atomic charges were also calculated to elucidate the electronic properties of 4a. These results provided insight into areas of the molecule that may present with the ability to form binding interactions at the 11β-HSD1 active site. Molecular docking experiments revealed important intermolecular interactions between 4a and 11β-HSD1. These results indicate that 4 may be considered for further drug design endeavors.