Investigation Into Novel Mukanadin B, Mukanadin D and Mukanadin F Derivatives as Antagonists of 5-HT1A Signalling.

Marine bromopyrrole alkaloids are a diverse family of natural products with a large array of biological applications. The mukanadin family is a group of molecules consisting of seven members (mukanadin A-G) that possess a range of biological activities. Inhibition of serotonergic signaling has been demonstrated by mukanadin B derivatives, presenting this chemical scaffold as a candidate for further SAR exploration. A library of thirteen novel mukanadin B and D derivatives with structural variation targeted at the pyrrole ring, central linker and hydantoin ring, were synthesized. These analogues were subsequently assessed for serotonergic antagonism, in addition to natural products, mukanadin B, D, F and 9-hydroxy mukanadin B. A collection of compounds exhibited significant 5-HT1A signaling, including five of the novel derivatives and two of the naturally occurring bromopyrroles, mukanadin B and F. Particular SAR information could be determined from these results, such as modification of the pyrrole ring being a well-tolerated strategy for improving serotonergic inhibition. Other changes to the pharmacophore led to significant reduction in activity such as saturation of the linker region, or no conclusive improvement in inhibitory activity such as a 9-OH group or replacement of the hydantoin ring with a triazole moiety.

Corrigendum: Retention of service users on opioid substitution therapy in the City of Tshwane, South Africa.

No abstract available.

Methadone use for acute opioid withdrawal in Tshwane shelters during the COVID-19 lockdown.

BACKGROUND: Temporary shelters were established for street-based people during the national level 5 coronavirus disease 2019 (COVID-19) lockdown. However, street-based substance users' need to access substances was not addressed, resulting in large numbers of people experiencing withdrawal. The Community Oriented Substance Use Programme (COSUP) in Tshwane provided methadone to manage opioid withdrawal. METHODS: A cross-sectional, descriptive study was conducted using the daily methadone dosing records from shelters in Tshwane between March 2020 and September 2020. RESULTS: The final analysis included 495 participants, of which 64 (12.9%) were initiated on 20 mg - 30 mg of methadone, 397 (80.2%) on 40 mg - 50 mg, and 34 (6.9%) on 60 mg - 70 mg. A total of 194 (39.2%) participants continued their initiation dose for 1-2 months, after which 126 (64.9%) had their doses increased, and 68 (35.1%) had their doses decreased. Approximately 12 (2.4%) participants were weaned off methadone after 1-3 months and 46 (9.3%) after 4-6 months. In all, 100 (20.2%) participants left the shelter prematurely and did not continue with methadone. A total of 126 (25.5%) participants continued to stay in the shelters and received methadone for 6 months, with 125 (25.3%) participants leaving the shelter with continued follow-up at a COSUP site. CONCLUSION: This study demonstrates variability in methadone dosing regimens among shelter residents. As the lockdown measures eased, many chose to leave the shelters, while others remained to receive methadone and other services. The COSUP appears to be effective during periods of increased vulnerability, since a large number of participants were successfully followed up.Contribution: Opioid dependence is a persistent, lifelong disease. It is multifaceted with complex environmental and individual determinants. This study highlighted the use of opioid substitution therapy during a period of increased vulnerability.

Mental health symptoms among homeless shelter residents during COVID-19 lockdown in Tshwane, South Africa.

BACKGROUND: In order to contain the spread of COVID-19 in South Africa during the national state of emergency, the Gauteng Department of Social Development established temporary shelters and activated existing facilities to provide basic needs to street-homeless people in Tshwane, which facilitated primary health care service-delivery to this community. AIM: This study aimed to determine and analyse the prevalence of mental health symptoms and demographic characteristics among street-homeless people living in Tshwane's shelters during lockdown. SETTING: Homeless shelters set up in Tshwane during level 5 of the COVID-19 lockdown in South Africa. METHODS: A cross-sectional, analytical study was conducted using a Diagnostic and Statistical Manual of Mental Disorders (DSM-5)-based questionnaire that looked at 13 mental health symptom domains. RESULTS: Presence of moderate-to-severe symptoms were reported among the 295 participants as follows: substance use 202 (68%), anxiety 156 (53%), personality functioning 132 (44%), depression 85 (29%), sleep problems 77 (26%), somatic symptoms 69 (23%), anger 62 (21%), repetitive thoughts and behaviours 60 (20%), dissociation 55 (19%), mania 54 (18%), suicidal ideation 36 (12%), memory 33 (11%) and psychosis 23 (8%). CONCLUSION: A high burden of mental health symptoms was identified. Community-oriented and person-centred health services with clear care-coordination pathways are required to understand and overcome the barriers street-homeless people face in accessing health and social services.Contribution: This study determined the prevalence of mental health symptoms within the street-based population in Tshwane, which has not previously been studied.

Retention of service users on opioid substitution therapy in the City of Tshwane, South Africa.

BACKGROUND: Opioid substitution therapy (OST) is evidence-based treatment for opioid use disorders and, when taken as maintenance therapy, has proven health and social benefits. The benefits of OST are achieved through the retention of service users in the treatment programme. AIM: To identify factors that affected retention of service users who had OST interrupted in less than 6 months of being in an OST programme. SETTING: This qualitative study was conducted with 19 service users from eight Community-Oriented Substance Use Programme (COSUP) sites in the City of Tshwane, Gauteng, South Africa. METHODS: Participants were COSUP service users who had interrupted OST in less than 6 months since initiation and were purposefully selected from all COSUP sites. Demographic information was obtained and four focus group discussions covered challenges of OST retention. Discussions were recorded, transcribed and qualitatively analysed using Attride-Stirling's thematic networks framework. RESULTS: The 19 participants were all male, mostly black African, with a mean age of 26 years. Facilitators of retention in OST were individual readiness to change OST accessibility, positive family and peer support, treatment monitoring, understanding and managing expectations of service users, contribution in society and meaningful opportunities for engagement. Barriers were the cost of OST, bureaucracy within the programme, inability to communicate challenges timeously and effectively to treatment providers, boredom, cravings and poverty. CONCLUSION: Opioid substitution therapy programmes can ensure a holistic approach to prevent and treat harms related to illicit opioid use if they remain person-centred and are well-funded.Contribution: Understanding the barriers to, and facilitators of retention on OST can contribute to improved community-based service delivery.

A Qualitative Study of Occupational Therapists' Understanding of Spirituality in South Africa.

Occupational therapy is a holistic profession that assists clients to restore meaning to their lives-a vital spiritual task. Spirituality is a multifaceted and multidimensional construct that occupational therapists need to integrate into everyday practice. In this study, Occupational Therapy educators' and clinicians' understanding of spirituality in their practice was qualitatively explored by purposively selecting 24 participants who attended a workshop based on an appreciative approach, in Gauteng, South Africa. Data were collected through self-report interview schedules and focus group inquiries and were analysed using the creative hermeneutic method. Participants expressed spirituality in occupational therapy as connectedness, meaning of life and client-centred practice.

Validating TDP1 as an Inhibition Target for the Development of Chemosensitizers for Camptothecin-Based Chemotherapy Drugs.

Cancer chemotherapy sensitizers hold the key to maximizing the potential of standard anticancer treatments. We have a long-standing interest in developing and validating inhibitors of the DNA repair enzyme tyrosyl-DNA phosphodiesterase 1 (TDP1) as chemosensitizers for topoisomerase I poisons such as topotecan. Herein, by using thieno[2,3-b]pyridines, a class of TDP1 inhibitors, we showed that the inhibition of TDP1 can restore sensitivity to topotecan, results that are supported by TDP1 knockout cell experiments using CRISPR/Cas9. However, we also found that the restored sensitivity towards topoisomerase I inhibitors is likely regulated by multiple complementary DNA repair pathways. Our results showed that one of these pathways is likely modulated by PARP1, although it is also possible that other redundant and partially overlapping pathways may be involved in the DNA repair process. Our work thus raises the prospect of targeting multiple DNA repair pathways to increase the sensitivity to topoisomerase I inhibitors.

Improving the solubility of anti-proliferative thieno[2,3-b]quinoline-2-carboxamides.

Thieno[2,3-b]pyridines are a class of compounds known for their potent anti-proliferative activities against a range of human cancer cell lines. In this research, a number of strategies to generate analogues that have improved aqueous solubility whilst retaining the potent anti-proliferative actions, compared to previously-explored compounds in this class, were made. Herein we report the synthesis of 80 novel compounds, comprising two series, all based on the thieno[2,3-b]pyridine core structure. Overall, it was found that introducing alternative heterocycles did not notably improve the solubility or retain anti-proliferative activity seen in previously-reported analogues. However, pleasingly it was discovered, that the best strategy for improving the solubility was the alteration of the appended alkyl ring to introduce polar groups such as alcohols, ketones and substituted amine groups. In addition to this finding, we have discovered a thieno[2,3-b]pyridine, 15e, with greater aqueous solubility that has ever been seen for this class of compounds that is also a potent inhibitor of cancer cell growth, with IC50's in the nanomolar range. This new lead structure will form the basis of future explorations into this class of compounds.

The three-stage assessment to support hospital-home care coordination in Tshwane, South Africa.

BACKGROUND: In complex health settings, care coordination is required to link patients to appropriate and effective care. Although articulated as system and professional values, coordination and cooperation are often absent within and across levels of service, between facilities and across sectors, with negative consequences for clinical outcomes as well as service load. AIM: This article presents the results of an applied research initiative to facilitate the coordination of patient care. SETTING: The study took place at three hospitals in the sub-district 3 public health complex (Tshwane district). METHOD: Using a novel capability approach to learning, interdisciplinary, clinician-led teams made weekly coordination-of-care ward rounds to develop patient-centred plans and facilitate care pathways for patients identified as being stuck in the system. Notes taken during three-stage assessments were analysed thematically to gain insight into down referral and discharge. RESULTS: The coordination-of-care team assessed 94 patients over a period of six months. Clinical assessments yielded essential details about patients' varied and multimorbid conditions, while personal and contextual assessments highlighted issues that put patients' care needs and possibilities into perspective. The team used the combined assessments to make patient-tailored action plans and apply them by facilitating cooperation through interprofessional and intersectoral networks. CONCLUSION: Effective patient care-coordination involves a set of referral practices and processes that are intentionally organised by clinically led, interprofessional teams. Empowered by richly informed plans, the teams foster cooperation among people, organisations and institutions in networks that extend from and to patients. In so doing, they embed care coordination into the discharge process and make referral to a link-to-care service.

Synthesis and Antibacterial Analysis of Analogues of the Marine Alkaloid Pseudoceratidine.

In an effort to gain more understanding on the structure activity relationship of pseudoceratidine 1, a di-bromo pyrrole spermidine alkaloid derived from the marine sponge Pseudoceratina purpurea that has been shown to exhibit potent biofouling, anti-fungal, antibacterial, and anti-malarial activities, a large series of 65 compounds that incorporated several aspects of structural variation has been synthesised through an efficient, divergent method that allowed for a number of analogues to be generated from common precursors. Subsequently, all analogues were assessed for their antibacterial activity against both Gram-positive (Staphylococcus aureus) and Gram-negative (Escherichia coli) bacteria. Overall, several compounds exhibited comparable or better activity than that of pseudoceratidine 1, and it was found that this class of compounds is generally more effective against Gram-positive than Gram-negative bacteria. Furthermore, altering several structural features allowed for the establishment of a comprehensive structure activity relationship (SAR), where it was concluded that several structural features are critical for potent anti-bacterial activity, including di-halogenation (preferable bromine, but chlorine is also effective) on the pyrrole ring, two pyrrolic units in the structure and with one or more secondary amines in the chain adjoining these units, with longer chains giving rise to better activities.

Evaluating community health worker education policy through a National Certificate (Vocational) Primary Health qualification lens.

BACKGROUND: In 2018, the South African National Department of Health (NDoH) published a 5-year policy framework and strategy for Ward-Based Primary Healthcare Outreach teams to improve team management and leadership and support service delivery. In the same year, the World Health Organization (WHO) published guidelines on health policy and system support to optimise Community Health Worker (CHW) programmes. AIM: This article aims to assess the National Certificate (Vocational), or NC(V), Primary Health qualification in terms of the education and training guidelines and recommendations of the 2018 NDoH and WHO policy documents. SETTING: The qualification was initiated in 2013 at 12 Technical and Vocational Education and Training (TVET) colleges across South Africa. The evaluation covered the period 2013-2017. METHODS: Pragmatic qualitative enquiry was used to examine the context, design, implementation and outcomes of the qualification. Data collection involved document reviews, key informant in-depth interviews and focused group discussions, and individual reflections with respondents from one part-time and two full-time offerings at two colleges. Analyses of emergent themes were interpreted using appropriate models and theoretical frameworks. RESULTS: The Department of Higher Education and Training (DHET) created and implemented a standardised, curriculated national programme for CHW education that structured theoretical and practical learning over time to ensure assimilation of content and its application in practice. CONCLUSION: NC(V) Primary Health, as a single, national, quality-assured qualification for CHWs, meets WHO 2018 guidelines and recommendations, NDoH training needs and CHWs learning expectations, especially when offered part-time. Despite the termination of the programme, it remains a relevant option for CHWs in South Africa and elsewhere.

Development, synthesis and biological investigation of a novel class of potent PC-PLC inhibitors.

Phospholipases are enzymes that are involved in the hydrolysis of acyl and phosphate esters of phospholipids, generating secondary messengers that have implications in various cellular processes including proliferation, differentiation and motility. As such inhibitors of phospholipases have been widely studied for their use as anti-cancer therapeutics. Phosphatidylcholine-specific phospholipase C (PC-PLC) is implicated in the progression of a number of cancer cell lines including aggressing triple-negative breast cancers. Most current studies on PC-PLC have utilised D609 as the standard inhibitor however it is known to have multiple failings, including poor stability in aqueous media. 2-Morpholinobenzoic acids were recently identified using vHTS as a potential class of lead compounds, with improvements over D609. In this work 129 analogues in this class were prepared and their PC-PLC inhibitory activity was assessed. It was found that the majority of these novel compounds had improved activity when compared to D609 with the most potent inhibitors completely inhibiting enzyme activity. It was determined that the best compound/s contained a morpholino and 2-substituted N-benzyl moieties with these findings explained using molecular modelling. The compounds reported here will allow for improved study of PC-PLC activity.

Discovery of novel phosphatidylcholine-specific phospholipase C drug-like inhibitors as potential anticancer agents.

Phosphatidylcholine-specific phospholipase C (PC-PLC) is a promising target for new anticancer treatment. Herein, we report our work in the discovery of novel drug-like PC-PLC inhibitors. Virtual screening led to the identification of promising hits from four different structural series that contain the molecular scaffold of benzenesulphonamides (10), pyrido[3,4-b]indoles (22), morpholinobenzoic acid (84) and benzamidobenzoic acid (80). 164 structural analogues were tested to investigate the chemical space around the hit series and to generate preliminary structurally activity relationships (SAR). Two of the pyrido[3,4-b]indoles (22_10 and 22_15) had comparable or better potency as D609, an established but non-drug-like PC-PLC inhibitor. Furthermore, three morpholinobenzoic acids (84, 84_4 and 84_5) had superior potency than D609. Therefore, this study paves the way towards the development of drug-like PL-PLC inhibitors as potential anticancer agents.

Investigation into Improving the Aqueous Solubility of the Thieno[2,3-b]pyridine Anti-Proliferative Agents.

It is now established that the thieno[2,3-b]pyridines are a potent class of antiproliferatives. One of the main issues encountered for their clinical application is their low water solubility. In order to improve this, two strategies were pursued. First, a morpholine moiety was tethered to the molecular scaffold by substituting the sulphur atom with nitrogen, resulting in a 1H-pyrrolo[2,3-b]pyridine core structure. The water solubility was increased by three orders of magnitude, from 1.2 µg/mL (1-thieno[2,3-b]pyridine) to 1.3 mg/mL (3-pyrrolo[2,3-b]pyridine), however, it was only marginally active against cancer cells. The second strategy involved loading a very potent thieno[2,3-b]pyridine derivative (2) into a cholesteryl-poly(allylamine) polymer matrix for water solubilisation. Suppression of human pancreatic adenocarcinoma (BxPC-3) viability was observed to an IC50 value of 0.5 µg/mL (1.30 µM) in conjunction with the polymer, which is a five-fold (×5) increase in potency as compared to the free drug alone, demonstrating the utility of this formulation approach.

Thieno[2,3-b]pyridine derivatives are potent anti-platelet drugs, inhibiting platelet activation, aggregation and showing synergy with aspirin.

Drugs which inhibit platelet function are commonly used to prevent blood clot formation in patients with Acute Coronary Syndromes (ACS) or those at risk of stroke. The thieno[3,2-c]pyridine class of therapeutic agents, of which clopidogrel is the most commonly used, target the P2Y12 receptor, and are often used in combination with acetylsalicylic acid (ASA). Six thieno[2,3-b]pyridine were assessed for in vitro anti-platelet activity; all derivatives showed effects on both platelet activation and aggregation, and showed synergy with ASA. Some compounds demonstrated greater activity when compared to clopidogrel. These compounds, therefore, represent potential novel P2Y12 inhibitors for improved treatment for patients.

GPCR Modulation of Thieno[2,3-b]pyridine Anti-Proliferative Agents.

A panel of docking scaffolds was developed for the known molecular targets of the anticancer agents, thieno[2,3-b]pyridines, in order to glean insight into their mechanism of action. The reported targets are the copper-trafficking antioxidant 1 protein, tyrosyl DNA phosphodiesterase 1, the colchicine binding site in tubulin, adenosine A2A receptor, and, finally, phospholipase C-δ1. According to the panel, the A2A receptor showed the strongest binding, inferring it to be the most plausible target, closely followed by tubulin. To investigate whether the thieno[2,3-b]pyridines modulate G protein-coupled receptors (GPCRs) other than A2A, a screen against 168 GPCRs was conducted. According to the results, ligand 1 modulates five receptors in the low µM region, four as an antagonist; CRL-RAMP3 (IC50-11.9 µM), NPSR1B (IC50-1.0 µM), PRLHR (IC50-9.3 µM), and CXCR4 (IC50-6.9 µM). Finally, one agonist, GPRR35, was found (EC50 of 7.5 µM). Molecular modelling showed good binding to all of the receptors investigated; however, none of these surpass the A2A receptor. Furthermore, the newly-identified receptors are relatively modestly expressed in the cancer cell lines most affected by the thieno[2,3-b]pyridines, making them less likely to be the main targets of the mechanism of action for this compound class. Nevertheless, new modulators against GPCRs are of an interest as potential hits for further drug development.

Synthesis and antiproliferative activity of 2-chlorophenyl carboxamide thienopyridines.

3-Amino-2-arylcarboxamide-thieno[2,3-b]pyridines are a known class of antiproliferative compounds with activity against the phospholipase C enzyme. To further investigate the structure activity relationships of these derivatives a series of analogues were prepared modifying key functional groups. It was determined that modification of the 3-amino and 2-aryl carboxamide functionalities resulted in complete elimination of activity, whilst modification at C-5 allowed compounds of greater activity to be prepared.

Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives.

Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC50 values in the 80-250nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.