Novel Synthesis of Lipoxine A4 Analogues. Towards Allostric Modulators for Human Cannabinoid Receptor Type 1

The synthesis of the benzoid-based lipoxine A4 (LXA4) is the focus of this study specifically, the para substituted benzoid system. LXA4 is an endogenous agonist binding with high affinity to (ALXR) receptor that initiate it to display anti-inflammatory and antioxidant activities. Arachidonic acid is the cascade of LXA4 and its derivatives. These compounds belong to the biological active eicosanoids, which are characterized by its consistent of 20 C-atoms. Based on structure activity relationship (SAR) of LXA4, several studies postulated wide range of modification and functionalization. Benzoid based LXA4 analogues have studied by several research groups where the focus was on the O- and M-substituted benzoids. Herein, a total synthesis approach towards some structural mimics of LXA4 was conducted. Where, the target was the benzoid based LXA4. Specifically, the p-substituted benzoid suggesting that these analogues could cover the same conformational space as the native LXA4. The project approach is based on using commercially available starting materials such as 2-deoxy-D-ribose, toluene and p-cresol to assemble the desired molecules. Important reactions in the course of the synthesis includes: C1-C8 building block: Wittig reaction, Parikh-Doering oxidation, hydrogenation of the alkene, protecting group operations. C15-C21 building block: Friedel-Craft acylation, O-alkylation, reduction by sodium borohydride. Key reaction of the synthesis is the Wittig reaction between the two coupling partners. This reaction leads to the selective formation of the trans-olefin. The formation of the lactone ring intermediates 17 and 16 during the de-protection of 1, 2-diol moiety has been studied in details with the help of computational chemistry. The last part of the thesis reveals an initial trial of another suggested approach based on “Ullmann type” reaction. The total synthetic strategy was successfully applied within 14 steps out of 17 were successfully performed obtaining intermediates 16 and 17 in a good yield. The compliment of the steps includes short reactions of lactone ring hydrolysis in basic medium in addition to reduction of the ketone moiety in intermediate 16

ASSOCIATION OF MOLECULAR STRUCTURE SPECTRAL FEATURES WITH NUTRIENT PROFILES AND AVAILABILITY AND MILK PRODUCTION PERFORMANCE OF NEWLY DEVELOPED BLEND-PELLETED PRODUCTS IN HIGH PRODUCING DAIRY COWS

The main objectives of this study were to: (1) study the association between the molecular structural features related to the amide region and protein utilization of blend-pelleted products based on canola meal or carinata meal, and (2) evaluate the effects of feeding newly developed blend-pelleted products based on carinata meal or canola meal on production efficiency, ruminal fermentation characteristics, ruminal degradability, and intestinal digestion in high-producing dairy cows. Result from the first study showed that the moleclar structural related to amide region were detected using fourier transform infrared (FTIR) vibration spectroscopy in which, increasing the level of canola or carinata meal in the blend-pelleted products (BPPs) significantly increased (P 0.10) of dietary treatments on milk yield, milk composition, and milk components yield. All dietary treatments exhibited the same income over feed cost (P > 0.10). The total-tract digestibility of nutrients and nitrogen balance were not (P > 0.10) affected by treatments. Third study was carried out to assess the effect of the dietary treatments on ruminal fermentation and ruminal digestion in dairy cows. The control diet exhibited a higher rumen total volatile fatty acid concentration (P 0.10) of treatments on ruminal ammonia concentration. Furthermore, all diets exhibited the same (P > 0.10) ruminal degradation kinetics, intestinal digestion of nutrients, and metabolizable protein supply in dairy cows. In conclusion, the blend-pelleted products based on new co-product (carinata meal) from bio-fuel processing industry is similar to the other pelleted products based on canola meal without affecting the production efficiency or the ruminal fermentation features in dairy cows. Molecular spectroscopy can be used to determine the inherent structural characteristics in relation to protein profile, energy values, protein digestion (rumen and intestine), and the metabolizable protein supply in the blend-pelleted products based on different bio-energy co-products

Renewable Solvents for Palladium-Catalyzed Carbonylation Reactions

Solvents constitute the largest component for many chemical processes and substitution of nonrenewable solvents is a longstanding goal for green chemistry. Here, we show that Pd-catalyzed carbonylative couplings, such as carbonylative cross-couplings, aminocarbonylations, and alkoxycarbonylations, can be successfully realized using renewable solvents. The present research covers not only well-established renewable solvents, such as 2-methyltetrahydrofuran (2MeTHF), limonene, and dimethyl carbonate, but also recently introduced biomass-derived 1,1-diethoxyethane, isosorbide dimethyl ether, eucalyptol, rose oxide, γ-terpinene, and α-pinene. The carbonylative coupling of boronic acids and aryl bromides works well in limonene. Aminocarbonylation gave excellent results in dimethyl carbonate, α-pinene, and limonene, while alkoxycarbonylation was successful in 2MeTHF, α-pinene, γ-terpinene, and dimethyl carbonate. The developed methods based on renewable solvents can be used for the synthesis of commercial drug Trimetozine and an analogue of Itopride

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Method development towards synthesis of carbapenemase inhibitors

Carbapenemases are enzymes able to hydrolyze the last resort b-lactam antibiotics (carbapenems), which are used for the treatment of infections caused by resistant bacteria. Carbapenemases are structurally and mechanistically classified into serine-b-lactamases (SBLs) and metallo-b-lactamases (MBLs). In order to combat the hydrolytic activity of these enzymes, combination therapy of b-lactam with b-lactamase inhibitor have been clinically successful. Nevertheless, clinically approved inhibitors for a number of important carbapenemases are still missing and resistance against some of the clinically successful combinations have been already reported. Therefore, there is an urgent need to find new effective inhibitors that could potentially reach clinical use. The approach targeted in this thesis is to design new inhibitors against carbapenemases that could be used in the combination therapy with a carbapenem antibiotic to restore its effect. The goal of my work was to develop synthetic methods for the synthesis of inhibitors targeting two clinically relevant carbapenemases - the serine-b-lactamase oxacillinase 48 (OXA-48) and the metallo-b-lactamase Verona integron-encoded metallo-b-lactamase (VIM-2). For the design and development of inhibitors, a fragment-based approach based on previously discovered inhibitory fragments and structural data of the fragments in complex with the target enzymes was choosen. In this thesis I discuss the developed synthetic strategy towards unsymmetrical 3,5-disubstituted benzoic acids using selective Suzuki-Miyaura cross-coupling. Applying the developed method, I synthesized a small extended fragment library of both symmetrical and unsymmetrical 3,5-disubstituted benzoic acids targeting OXA-48. The aim of synthesizing these extended fragments was to target two directions in the binding pocket as suggested by overlaying structural data of smaller fragments in complex with OXA-48. I also developed a synthetic strategy towards 2-aroylbenzoic acid analogues via carbonylative Suzuki coupling using CO in a safe fashion. 2-Aroylbenzoic acids were known to inhibit the carbapenemase VIM-2. Through my investigations about a general synthetic strategy towards 2-aroylbenzoic acid, I found some limitations about substrates with ionizable functional groups and sterically hindered substrates. I then extended my investigation to find better reaction conditions for carbonylative coupling reactions. I also introduced sustainability to the project by using renewable solvents aiming for better reactivity in palladium-catalyzed C-C, C-O, C-N bond forming carbonylative couplings. In summary, through the presented work a range of carbapenemase (OXA-48 and VIM-2) inhibitors have been synthesized. Additionally, the developed synthetic strategies are considered to be a starting point to build a general approach to synthesize a wide range of potent inhibitors against carbapenemases. The work resulted in three publications (Paper I, II, III).

Novel Synthesis of Lipoxine A4 Analogues. Towards Allostric Modulators for Human Cannabinoid Receptor Type 1

The synthesis of the benzoid-based lipoxine A4 (LXA4) is the focus of this study specifically, the para substituted benzoid system. LXA4 is an endogenous agonist binding with high affinity to (ALXR) receptor that initiate it to display anti-inflammatory and antioxidant activities. Arachidonic acid is the cascade of LXA4 and its derivatives. These compounds belong to the biological active eicosanoids, which are characterized by its consistent of 20 C-atoms. Based on structure activity relationship (SAR) of LXA4, several studies postulated wide range of modification and functionalization. Benzoid based LXA4 analogues have studied by several research groups where the focus was on the O- and M-substituted benzoids. Herein, a total synthesis approach towards some structural mimics of LXA4 was conducted. Where, the target was the benzoid based LXA4. Specifically, the p-substituted benzoid suggesting that these analogues could cover the same conformational space as the native LXA4. The project approach is based on using commercially available starting materials such as 2-deoxy-D-ribose, toluene and p-cresol to assemble the desired molecules. Important reactions in the course of the synthesis includes: C1-C8 building block: Wittig reaction, Parikh-Doering oxidation, hydrogenation of the alkene, protecting group operations. C15-C21 building block: Friedel-Craft acylation, O-alkylation, reduction by sodium borohydride. Key reaction of the synthesis is the Wittig reaction between the two coupling partners. This reaction leads to the selective formation of the trans-olefin. The formation of the lactone ring intermediates 17 and 16 during the de-protection of 1, 2-diol moiety has been studied in details with the help of computational chemistry. The last part of the thesis reveals an initial trial of another suggested approach based on “Ullmann type” reaction. The total synthetic strategy was successfully applied within 14 steps out of 17 were successfully performed obtaining intermediates 16 and 17 in a good yield. The compliment of the steps includes short reactions of lactone ring hydrolysis in basic medium in addition to reduction of the ketone moiety in intermediate 16

Using HLA-E Expression and CREB1 Modulation to Study the Regulation of NK Cell-Mediated Cytotoxicity in Multiple Myeloma

Multiple myeloma (MM) develops in the bone marrow from normal plasma cells, reshaping the bone marrow microenvironment to survive. Several MM treatments, such as immunomodulatory drugs and proteasome inhibitors, are available as therapeutic options for patients; however, MM remains largely incurable. While patients undergoing treatment may notice improvement in their symptoms, many patients still experience relapse. For that reason, personalized therapeutic options that consider genetic and environmental factors may facilitate improved patient health outcomes. While the immune system’s surveillance is equipped with the necessary mechanisms to ward off infections and diseases, cancer cells have novel ways to evade detection. The innate immune system utilizes natural killer (NK) cells to prevent the spread of viruses and growth of tumor cells. NK cells display both activating and inhibitory receptors in which, upon ligand interaction, leads to downstream signaling to elicit the proper cellular response. HLA-E, a non-classical major histocompatibility complex, is a ligand that binds to the NKG2A/CD94 inhibitory surface receptor on NK cells where it can regulate cell-mediated cytotoxicity. In healthy cells, HLA-E functions to prevent NK cell-mediated cytotoxicity upon interaction as a means of recognizing “self” cells from aberrant cells. However, as our study emphasizes, MM cells express abnormally high amounts of HLA-E to bypass the immune system and escape NK cell-mediated lysis. Our study aims to investigate immune escape via modulation of the HLA-E antigen both at the mRNA and protein level through IFN-gamma expression, proteins involved in the JAK-STAT pathway, and the CREB1 gene wherein inhibition of CREB1 has demonstrated downregulation in HLA-E and consequently restored NK cell-mediated lysis.No embargoAcademic Major: BiologyAcademic Major: Biochemistr

Retracted: Fabrication-ready self-learning PID controller: a comparison study with classical PID

This article was withdrawn and retracted by the Journal of Fundamental and Applied Sciences and has been removed from AJOL at the request of the journal Editor in Chief and the organisers of the conference at which the articles were presented (www.iccmit.net). Please address any queries to [email protected]

Carbonylative Suzuki-Miyaura couplings of sterically hindered aryl halides: Synthesis of 2-aroylbenzoate derivatives

We have developed a carbonylative approach to the synthesis of diversely substituted 2-aroylbenzoate esters featuring a new protocol for the carbonylative coupling of aryl bromides with boronic acids and a new strategy to favour carbonylative over non-carbonylative reactions. Two different synthetic pathways – (i) the alkoxycarbonylation of 2-bromo benzophenones and (ii) the carbonylative Suzuki–Miyaura coupling of 2-bromobenzoate esters – were evaluated. The latter approach provided a broader substrate tolerance, and thus was the preferred pathway. We observed that 2-substituted aryl bromides were challenging substrates for carbonylative chemistry favouring the non-carbonylative pathway. However, we found that carbonylative Suzuki–Miyaura couplings can be improved by slow addition of the boronic acid, suppressing the unwanted direct Suzuki coupling and, thus increasing the yield of the carbonylative reaction