Models for the Diastereoselective Synthesis of Indolizidine Alkaloids:

Faculty of Science; School of Chemistry; PhD ThesisThe synthesis of nitrogen containing ring systems has been one of the interests of this research group at the University of the Witwatersrand for a long time. These systems form part of a group of compounds called alkaloids, whose structural diversity is rivalled only by their distribution in nature. A small sub-set of the alkaloids is the fused 5 and 6 membered bicyclic frames with nitrogen at one bridgehead. Having developed a unique method of synthesising these indolizidine alkaloids, we examined various aspects of this methodology and there remained one crucial question – what is the best way to control the stereochemical outcome of the ring-forming steps? This project looks at this question from the view of a model natural product, the indolizidine alkaloids (+)- and (–)-tashiromine. The synthesis of tashiromine and related compounds was examined using chiral auxiliaries such as the Oppolzer sultam and the Evans oxazolidinone, as well as the use of chirally modified reductants. The efficacies of the chiral auxiliaries were studied using molecular modelling techniques, and certain modifications were suggested from these results

General Perception of Liposomes: Formation, Manufacturing and Applications

Liposomes are currently part of the most reputed carriers for various molecular species, from small and simple to large and complex molecules. Since their discovery, liposomes have been subject to extensive evolution, in terms of composition, manufacturing and applications, which led to several openings in both basic and applied life sciences. However, most of the advances in liposome research have been more devoted to launching new developments than improving the existing technology for potential implementation. For instance, the evolution of the conventional lipid hydration methods to novel microfluidic technologies has permitted upscale production, but with increase in manufacturing cost and persistent use of organic solvents. This chapter intends to present general concepts in liposome technology, highlighting some longstanding bottlenecks that remain challenging to the preparation, characterization and applications of liposomal systems. This would enhance the understanding of the gaps in the field and, hence, provide directions for future research and developments

Cationic cyclodextrin/alginate chitosan nanoflowers as 5-fluorouracil drug delivery system

Cyclodextrins (CDs) have widely been used as component of drug delivery systems. However unmodified cyclodextrins are associated with cytotoxicity and poor water solubility thus limiting their use in pharmaceutical industry. The cationic-β-cyclodextrin (Cat-β-CD) polymer cores were synthesized using β-CD, epichlorohydrin and choline chloride via a one-step polycondensation process. The main aim of this study was to synthesize hierarchical nanoflowers composed of cationic-β-CD as polymeric core along with alginate and chitosan “petals” (Cat-β-CD/Alg-Chi nanoflowers) as carriers for oral delivery of 5-Fluorouracil (5-FU) via an ionic-gelation technique. The drug loading capacity, particle size, zeta potential and surface morphology of the synthesized nanoflowers were determined. The prepared nanoflowers were formed with an average size of 300 nm and a zeta potential of + 9.90 mV with good encapsulation efficiency of up to 77.3%. In vitro release of 5-FU from the loaded nanoflowers showed controlled and sustained release compared to the inclusion complex alone. Cat-β-CD/Alg-Chi nanoflowers were assessed against L929 cells and found to be effectively inhibiting the growth of L929 cells in a concentration dependent manner

Biological activities of plant extracts from Ficus elastica and Selaginella vogelli: an antimalarial, antitrypanosomal and cytotoxity evaluation

The cytotoxic, antiplasmodial, and antitrypanosomal activities of two medicinal plants traditionally used in Cameroon were evaluated. Wood of Ficus elastica Roxb. ex Hornem. aerial roots (Moraceae) and Selaginella vogelii Spring (Selaginellaceae) leaves were collected from two different sites in Cameroon. In vitro cell-growth inhibition activities were assessed on methanol extract of plant materials against Plasmodium falciparum strain 3D7 and Trypanosoma brucei brucei, as well as against HeLa human cervical carcinoma cells. Criteria for activity were an IC50 value 10 μg/mL. The extract of S. vogelii did not significantly reduce the viability of P. falciparum at a concentration of 25 μg/mL but dramatically affected the trypanosome growth with an IC50 of 2.4 μg/mL. In contrast, at the same concentration, the extract of F. elastica exhibited plasmodiacidal activity (IC50 value of 9.5 μg/mL) and trypanocidal (IC50 value of 0.9 μg/mL) activity. Both extracts presented low cytotoxic effects on HeLa cancer cell line. These results indicate that the selected medicinal plants could be further investigated for identifying compounds that may be responsible for the observed activities and that may represent new leads in parasitical drug discovery

Comprehensive Assessment of Biomolecular Interactions of Morpholine-Based Mixed Ligand Cu(II) and Zn(II) Complexes of 2,2′-Bipyridine as Potential Anticancer and SARS-CoV-2 Agents: A Synergistic Experimental and Structure-Based Virtual Screening

A new class of pharmacologically active mixed-ligand complexes (1a-2a) [MII(L)2 (bpy)], where L = 2-(4-morpholinobenzylideneamino)phenol), bpy = 2,2′-bipyridine, MII = Cu (1a), and Zn (2a), were assigned an octahedral geometry by analytical and spectral measurements. Gel electrophoresis showed that complex (1a) demonstrated the complete DNA cleavage mediated by H2O2. The overall DNA-binding constants observed from UV-vis, fluorometric, hydrodynamic, and electrochemical titrations were in the following sequence: (1a) > (2a) > (HL), which suggests that the complexes might intercalate DNA, a possibility that is further supported by the biothermodynamic characteristics. The binding constant results of BSA by electronic absorption and fluorometric titration demonstrate that complex (1a) exhibits the highest binding effectiveness among others, which means that all compounds could interact with BSA through a static approach, additionally supported by FRET measurements. Density FunctionalTheory (DFT) and molecular docking calculations were relied on to unveil the electronic structure, reactivity, and interacting capability of all substances with DNA, BSA, and SARS-CoV-2 main protease (Mpro). These observed binding energies fell within the following ranges: −7.7 to −8.6, −7.2 to −10.2, and −6.7 to −8.2 kcal/mol, respectively. The higher reactivity of the complexes compared to free ligand is supported by the Frontier MolecularOrbital (FMO) theory. The in vitro antibacterial, cytotoxic, and radical scavenging characteristics revealed that complex (1a) has the best biological efficacy compared to others. This is encouraged because all experimental findings are closely correlated with the theoretical measurements

Aqua/Mechanochemical Mediated Synthesis of Novel Spiro [Indole–Pyrrolidine] Derivatives

Spirocyclic scaffolds are found in many pharmacologically active natural and synthetic compounds. From time to time, efforts have been made to develop new or better processes for the synthesis of spirocyclic compounds. Spiro [Indole–pyrrolidine] Derivatives are readily synthesized in high to excellent yields by the Michael condensation of 3-dicyanomethylene-2H-indol-2-ones (produced via the Knoevenagel condensation of indole-2,3-dione with malononitrile) with isothiocyanate derivatives under aqueous and mechanochemical conditions. The advantages of this protocol are that the reactions are solvent-free, occur at ambient temperature, require short reaction times, have experimental simplicity, and produce excellent yields. These environmentally friendly reaction media are useful alternatives to volatile organic solvents

Aqua/Mechanochemical Mediated Synthesis of Novel Spiro [Indole–Pyrrolidine] Derivatives

Spirocyclic scaffolds are found in many pharmacologically active natural and synthetic compounds. From time to time, efforts have been made to develop new or better processes for the synthesis of spirocyclic compounds. Spiro [Indole–pyrrolidine] Derivatives are readily synthesized in high to excellent yields by the Michael condensation of 3-dicyanomethylene-2H-indol-2-ones (produced via the Knoevenagel condensation of indole-2,3-dione with malononitrile) with isothiocyanate derivatives under aqueous and mechanochemical conditions. The advantages of this protocol are that the reactions are solvent-free, occur at ambient temperature, require short reaction times, have experimental simplicity, and produce excellent yields. These environmentally friendly reaction media are useful alternatives to volatile organic solvents

A More Sustainable Isocyanide Synthesis from N-Substituted Formamides Using Phosphorus Oxychloride in the Presence of Triethylamine as Solvent

A simple, green, and highly efficient protocol for the synthesis of isocyanides is described. The reaction involves dehydration of formamides with phosphorus oxychloride in the presence of triethylamine as solvent at 0 °C. The product isocyanides were obtained in high to excellent yields in less than 5 min. The method offers several advantages including increased synthesis speed, relatively mild conditions, and rapid access to large numbers of functionalized isocyanides, excellent purity, increased safety, and minimal reaction waste. The new approach of synthesising dehydrative isocyanides from formamides is significantly more environmentally-friendly than prior methods

Synthesis of pH sensitive dual capped CdTe QDs: their optical properties and structural morphology

We herein report five different types of thiol dual capped cadmium tellurite quantum dots (CdTe QDs) namely glutathionemercapto-propanoic acid (QD 1), glutathione-thiolglycolic acid (QD 2), L-cysteine-mercapto-propanoic acid (QD 3), L-cysteinethiol-glycolic acid (QD 4) and mercapto-propanoic acid-thiol-glycolic (QD 5). Dual-capped CdTe QDs were prepared using a one pot synthetic method. Cadmium acetate and sodium tellurite were respectively used as cadmium and tellurium precursors. Photo-physical properties of the synthesized QDs were examined using UV-Vis and photoluminescence spectroscopy while structural characterization was performed by means of transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy

Clinically established biodegradable long acting injectables: An industry perspective

Long acting injectable formulations have been developed to sustain the action of drugs in the body over desired periods of time. These delivery platforms have been utilized for both systemic and local drug delivery applications. This review gives an overview of long acting injectable systems that are currently in clinical use. These products are categorized in three different groups: biodegradable polymeric systems, including microparticles and implants; micro and nanocrystal suspensions and oil-based formulations. Furthermore, the applications of these drug delivery platforms for the management of various chronic diseases are summarized. Finally, this review addresses industrial challenges regarding the development of long acting injectable formulations