Synthesis and functionalization of novel meso-substituted tetrabenzotriazaporphyrins

Phthalocyanine derivatives have seen many important developments since their discovery in 1907 by Braun and Tcherniac. These interesting materials are one of the most significant classes of macroheterocyclic organic materials owing to their remarkable electrical and physical properties which can be tuned by suitable derivatization of their rigid inner core. A brief summary of the syntheses, properties and applications of these complexes is clarified in Chapter 1. The work described in this thesis concerns the synthesis of phthalocyanine (Pc)/tetrabenzoporphyrin (TBP) hybrids – intermediates between the widely studied Pc and TBP parents. Such hybrids have received a very little attention, mainly because they have previously proved difficult to synthesise. Among the series of the phthalocyanine/tetrabenzoporphyrin hybrids, tetrabenzotriazaporphyrins (TBTAPs) are the most widely studied and they are the focus of this thesis. They have a single meso-carbon linkage which can offer an additional site for the attachment of various functional groups, thus would provide a wide range of functionalized TBTAP derivatives. The syntheses of the phthalonitriles have been achieved successfully through the investigation of different strategies. Phthalonitriles have been constructed by the nickel or palladium catalysed Kumada cross-coupling reaction using 1,2-dichlorobenzene as precursor, followed by electrophilic bromination and Rosenmund von Braun cyanation reaction in the last step. An alternative route towards the formation of the phthalonitriles was used in order to synthesise alternative target phthalonitriles in good yield; the method employed Kumada cross-coupling reaction using 4,5-dibromoveratrole as precursor followed by a sequence of synthetic steps and finally cyanation reaction following the procedure described by Hanack and Drechsler. A series of meso-phenyl substituted tetrabenzotriazaporphyrins (TBTAPs) bearing different functional groups has been prepared successfully via the investigation of various approaches. The traditional synthetic methods and their new modified versions via Grignard reagents have been developed as well as the modern technique via aminoisoindoline that was discovered recently by our group. Most importantly, synthesis of functionalised TBTAPs has been achieved. Expansion of the π-conjugated system of TBTAPs has been attempted as first experimental examinations in this field through several chemical and photochemical cyclisation methods, but the desired products were not isolated. Finally, transformations of the functionalised meso-phenyl TBTAP macrocycles through the palladium-catalysed Suzuki and copper-free Sonogashira cross-coupling reactions have been accomplished successfully resulting in the formation of a new series of materials. The new strategies combine to open up the potential for many new hybrid structures

First examples of functionalisation of meso-aryl tetrabenzotriazaporphyrins (TBTAPs) through cross-coupling reactions

Recent synthetic advances have given convenient access to tetrabenzotriazaporphyrins (TBTAPs) functionalised with meso-aryl substituents. In this paper we report the first examples of further functionalization of the meso-sites through Suzuki-Miyaura and copper-free Sonagashira cross-coupling reactions of the meso-(bromophenyl)TBTAPs, demonstrating the breadth of new materials design now possible in the hybrid macrocycles

A biochemical, theoretical and immunohistochemical study comparing the therapeutic efficacy of curcumin and taurine on T-2 toxin induced hepatotoxicity in rats

Introduction: Foodborne trichothecene T-2 Toxin, is a highly toxic metabolite produced by Fusarium species contaminating animal and human food, causing multiple organ failure and health hazards. T-2 toxins induce hepatotoxicity via oxidative stress causing hepatocytes cytotoxicity and genotoxicity. In this study, curcumin and taurine were investigated and compared as antioxidants against T-2-provoked hepatotoxicity.Methods: Wistar rats were administrated T-2 toxin sublethal oral dose (0.1 mg/kg) for 2 months, followed by curcumin (80 mg/kg) and taurine (50 mg/kg) for 3 weeks. Biochemical assessment of liver enzymes, lipid profiles, thiobarbituric acid reactive substances (TBARs), AFU, TNF-α, total glutathione, molecular docking, histological and immunohistochemical markers for anti-transforming growth factor-β1 (TGFβ1), double-strand DNA damage (H2AX), regeneration (KI67) and apoptosis (Active caspase3) were done.Results and Discussion: Compared to T-2 toxin, curcumin and taurine treatment significantly ameliorated hepatoxicity as; hemoglobin, hematocrit and glutathione, hepatic glycogen, and KI-67 immune-reactive hepatocytes were significantly increased. Although, liver enzymes, inflammation, fibrosis, TGFβ1 immunoexpressing and H2AX and active caspase 3 positive hepatocytes were significantly decreased. Noteworthy, curcumin’s therapeutic effect was superior to taurine by histomorphometry parameters. Furthermore, molecular docking of the structural influence of curcumin and taurine on the DNA sequence showed curcumin’s higher binding affinity than taurine.Conclusion: Both curcumin and taurine ameliorated T-2 induced hepatotoxicity as strong antioxidative agents with more effectiveness for curcumin

Improved syntheses of meso-aryl tetrabenzotriazaporphyrins (TBTAPs)

New tetrabenzotriazaporphyrins are reported that are functionalised at the meso-position. The derivatives functionalised with meso-bromophenyl substituents are synthesised using an improved variation on the traditional reaction between phthalonitriles and Grignard reagents. For all other new derivatives, a modern protocol is employed that gives convenient access to these challenging materials by template co-macrocyclisation between phthalonitriles and aryl-aminoisoindoline derivatives like 15. The newly developed procedure allows design and synthesis of elaborate, functional composites and this is demonstrated by synthesis of meso-pyrenylTBTAP 24, a linked double chromophore in which the two complementary units lie perpendicular to each other and therefore have minimal ground state interaction

Clinical and economic evaluations of natalizumab, rituximab, and ocrelizumab for the management of relapsing-remitting multiple sclerosis in Saudi Arabia

Abstract Introduction The advent of new disease-modifying therapies (DMTs), such as monoclonal antibodies (mAbs), resulted in significant changes in the treatment guidelines for Multiple sclerosis (MS) and improvement in the clinical outcomes. However, mAbs, such as rituximab, natalizumab, and ocrelizumab, are expensive with variable effectiveness rates. Thus, the present study aimed to compare the direct medical cost and consequences (e.g., clinical relapse, disability progression, and new MRI lesions) between rituximab and natalizumab in managing relapsing-remitting multiple sclerosis (RRMS) in Saudi Arabia. Also, the study aimed to explore the cost and consequence of ocrelizumab in managing RRMS as a second-choice treatment. Methods The electronic medical records (EMRs) of patients with RRMS were retrospectively reviewed to retrieve the patients’ baseline characteristics and disease progression from two tertiary care centers in Riyadh, Saudi Arabia. Biologic–naïve patients treated with rituximab or natalizumab or those switched to ocrelizumab and treated for at least six months were included in the study. The effectiveness rate was defined as no evidence of disease activity (NEDA-3) (i.e., absence of new T2 or T1 gadolinium (Gd) lesions as demonstrated by the Magnetic Resonance Imaging (MRI), disability progression, and clinical relapses), while the direct medical costs were estimated based on the utilization of healthcare resources. In addition, bootstrapping with 10,000 replications and inverse probability weighting based on propensity score were conducted. Results Ninety–three patients met the inclusion criteria and were included in the analysis (natalizumab (n = 50), rituximab (n = 26), ocrelizumab (n = 17)). Most of the patients were otherwise healthy (81.72%), under 35 years of age (76.34%), females (61.29%), and on the same mAb for more than one year (83.87%). The mean effectiveness rates for natalizumab, rituximab, and ocrelizumab were 72.00%, 76.92%, and 58.83%, respectively. Natalizumab mean incremental cost compared to rituximab was $35,383 (95$25,401.09– $49,717.92), and its mean effectiveness rate was 4.92% lower than rituximab (95% CI: -30–27.5) with 59.41% confidence level that rituximab will be dominant. Conclusions Rituximab seems to be more effective and is less costly than natalizumab in the management of RRMS. Ocrelizumab does not seem to slow the rates of disease progression among patients previously treated with natalizumab

MmpL3 Inhibition as a Promising Approach to Develop Novel Therapies against Tuberculosis: A Spotlight on SQ109, Clinical Studies, and Patents Literature

Tuberculosis (TB) is accountable for considerable global morbidity and mortality. Effective TB therapy with multiple drugs completes in about six months. The longer duration of TB therapy challenges patient compliance and contributes to treatment collapse and drug resistance (DR) progress. Therefore, new medications with an innovative mechanism of action are desperately required to shorten the TB therapy’s duration and effective TB control. The mycobacterial membrane protein Large 3 (MmpL3) is a novel, mycobacteria-conserved and recognized promiscuous drug target used in the development of better treatments for multi-drug resistance TB (MDR-TB) and extensively drug-resistant TB (XDR-TB). This article spotlights MmpL3, the clinical studies of its inhibitor (SQ109), and the patent literature. The literature on MmpL3 inhibitors was searched on PubMed and freely available patent databases (Espacenet, USPTO, and PatentScope). SQ109, an analog of ethambutol (EMB), is an established MmpL3 inhibitor and has completed Phase 2b-3 clinical trials. Infectex and Sequella are developing orally active SQ109 in partnership to treat MDR pulmonary TB. SQ109 has demonstrated activity against drug-sensitive (DS) and drug-resistant (DR) Mycobacterium tuberculosis (Mtb) and a synergistic effect with isoniazid (INH), rifampicin (RIF), clofazimine (CFZ), and bedaquiline (BNQ). The combination of SQ109, clofazimine, bedaquiline, and pyrazinamide (PZA) has been patented due to its excellent anti-TB activity against MDR-TB, XDR-TB, and latent-TB. The combinations of SQ109 with other anti-TB drugs (chloroquine, hydroxychloroquine, and sutezolid) have also been claimed in the patent literature. SQ109 is more potent than EMB and could substitute EMB in the intensive stage of TB treatment with the three- or four-drug combination. Developing MmpL3 inhibitors is a promising approach to fighting the challenges associated with DS-TB and DR-TB. The authors foresee MmpL3 inhibitors such as SQ109 as future drugs for TB treatment

PREVALENCE OF SICKLE-CELL DISEASE IN SAUDI ARABIA: A SYSTEMATIC REVIEW

Background: A series of hemoglobinopathies known collectively as sickle cell disease (SCD) contain abnormalities in the gene encoding the beta component of haemoglobin. There are other subcategories that fall under the SCD umbrella, including sickle cell disease (SCD), haemoglobin SC disease (HbSC), and haemoglobin sickle-beta thalassemia (beta-thalassemia positive or beta-thalassemia negative). The prevalence of SCD varies greatly across Saudi Arabia, with the Eastern province having the greatest frequency and the southern regions having the second-highest prevalence. The reported sickle-cell prevalence ranges from 2% to 27%, and in some regions, up to 2.6% of people will have SCD. Objectives: The study aims to summarize current evidences regarding Prevalence of Sickle-Cell Disease in Saudi Arabia. Methods: For article selection, the PubMed database and EBSCO Information Services were used. All relevant articles relevant with our topic and other articles were used in our review. Other articles that were not related to this field were excluded. The data was extracted in a specific format that was reviewed by the group members. Conclusion: Although the prevenance of sickle cell anemia is relatively high due to multiple reasons such as consanguinity, the prevalence of genetic diseases in Saudi Arabia may be significantly lowered during the following decades as a result of premarital screening there. Also, acute chest syndrome in SCD patients is relatively infrequent in Saudi Arabia's Eastern Province, it nonetheless has a major impact on morbidity and death. If patients with African haplotypes are compared, it has a low prevalence and recurrence

The effect of bariatric surgery on dietary Behaviour, dietary recommendation Adherence, and micronutrient deficiencies one year after surgery

Bariatric surgery (BS) is associated with vitamin and mineral deficiencies, which might be augmented by low adherence to dietary guidelines and inappropriate dietary behaviours. The aim of this study was to determine the influence of BS on eating behaviour, prevalence of nutrient deficiency, level of commitment to diet, and lifestyle recommendations one-year post-BS.A cross-sectional study was conducted among adult patients who underwent BS in 2019 and had follow-up for a year. Age, gender, and clinical data were collected from the hospital system and other information was obtained from questionnaires during phone interviews. A total of 160 patients participated in the study.At 12 months, a significant increase from the baseline values in plasma levels of vitamin B12, folate, vitamin D, iron, corrected calcium, albumin, CRP, and MCV, as well as a significant decrease in BMI was observed. Adherence to dietary and lifestyle recommendations was moderate to high. Emotional, and restrained eating behaviours were moderate with 64.4%, and 77.5%, respectively. External eating was low at 58.1%.The study concluded that pre-and post-bariatric surgery nutrients should be closely monitored