OpenUCT :: Browsing by Author "Caira, Mino R"

Browsing by Author "Caira, Mino R"

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Open Access
Anti-cancer and anti-malarial 4-aminoquinoline derivatives : synthesis and solid-state investigations
(2006) Melo, Candice Soares de; Chibale, Kelly; Caira, Mino R
The work presented in this thesis is two-fold: (i) development of single agents that provide inhibition of both the growth of malaria parasites and of tumour cells in vitro, and (ii) inclusion of these potential novel inhibitors in cyclodextrin host molecules in an attempt to render these dual drugs water-soluble. Of all the current clinically established antimalarials, the 4-aminoquinolines haveproven to be the most significant and efficacious for the treatment and prophylaxis of malaria. However, their efficacy has decreased by the spread of drug resistant strains of the causative agent Plasmodium Jalciparum. Future research into 4-aminoquinoline derivatives as antimalarial agents is still warranted and justified on the basis of several considerations. The quinoline moiety has also been shown to be a substructure in multi-drug resistance reversal agents against certain cancer cell lines and antitumour agents which have demonstrated the ability to act as differentiation-inducing agents. The strategy employed for this project was to hybridize chalcone moieties and their Mannich base derivatives with the 4-aminoquinoline moiety. This dual drug concept uses the basic structure of the chalcone scaffold, which has a wide range of known antimalarial and anticancer activities, and is hybridised with the 4-aminoquinoline moiety, in order to exert maximal biological activity and overcome or prevent drug resistance. Structural variation on the aromatic rings of the chalcone scaffold allowed preliminary structure-activity relationship studies to be undertaken.
Open Access
Antimycobacterial 2-aminoquinazolinones and benzoxazole-based oximes: synthesis, biological evaluation, physicochemical profiling and supramolecular derivatization
(2017) Njaria, Paul Magutu; Chibale, Kelly; Caira, Mino R
Tuberculosis (TB) is a life-threatening infectious disease caused by Mycobacterium tuberculosis (Mtb). Globally, TB is a major public health burden with an estimated 10.4 million new cases and 1.8 million deaths reported in 2015. Although TB is curable, the treatment options currently available are beset by numerous shortcomings such as lengthy and complex treatment regimens, drug-drug interactions, drug toxicities, as well as emergence of widespread multi-drug resistance. Therefore, there is an urgent and compelling need to develop new, more effective, safer drugs with novel mechanisms of action, and which are capable of shortening treatment duration. This study focused on hit-to-lead optimization of two new classes of compounds with potential anti-TB properties: 2-aminoquinazolinones (AQZs) and benzoxazole-based oximes (BZOs). A hit compound for each of these classes with low micromolar antimycobacterial activity had previously been identified through phenotypic whole-cell in vitro screening.
Open Access
Beneficiation of selected pesticides and an antihyperlipidemic agent via cyclodextrin complexation and co-crystallization
(2016) Maurel, Vaughan Jean; Caira, Mino R; Bourne, Susan A
The applications of many bioactive molecules are limited by their undesirable physicochemical properties, such as poor aqueous solubility and low thermal stability. The agrochemicals methyl- 2,5-dichlorobenzoate (fungicide, DCB) and fenthion (insecticide), as well as the medicinal compound acipimox (lipid-lowering agent) were selected for study in this context. The cyclodextrin (CD) complexes γ-CD/DCB, 2,6-dimethylated-β-CD/DCB, β-CD/fenthion, permethylated α-CD/fenthion and permethylated β-CD/fenthion, were synthesised. 1H-NMR spectroscopy, thermogravimetric analysis (TGA), differential scanning calorimetry (DSC) and hot stage microscopy (HSM) were used to assess their stoichiometries and thermal behaviours. The complexes 2,6-dimethylated-β-CD/DCB, permethylated α-CD/fenthion and permethylated β-CD/fenthion have 1:1 host-guest stoichiometries, while those for γ-CD/DCB and β-CD/fenthion are 3:4 and 2:1 respectively. Single crystal X-ray structures were elucidated to investigate the modes of DCB inclusion and crystal packing. All of the solid complexes displayed higher thermal stabilities than those of the untreated pesticides. Furthermore, the volatility of the insecticide fenthion (a liquid at 25 ᵒC) was significantly reduced by its transformation to a solid on CDcomplex formation. The solution-state behaviour of fenthion was qualitatively evaluated using UV-visible spectrophotometry and induced circular dichroism. Phase solubility profiles at 25 ᵒC were of type Bs for solubilisation of DCB by β-CD and (2-hydroxypropyl)-β-CD, and for solubilisation of fenthion by β-CD, the respective 1:1 association constants being 737 ± 108 M⁻¹, 412 ± 53 M⁻¹ and 789 ± 170 M⁻¹. For solubilisation of fenthion by (2-hydroxypropyl)-β-CD and randomlymethylated β-CD, AN- and AP-type behaviours were recorded respectively, with association constants 1863 ± 26 M⁻¹ and 3582 ± 106 M⁻¹ respectively. Eight multi-component crystalline systems (co-crystals and salts) of acipimox were isolated via its reaction with co-formers 4-aminobenzamide, 4-aminopyridine, benzamide, isonicotinamide, tranexamic acid and urea. NMR spectroscopy revealed 1:1 stoichiometries for all products. Their designation as salts or co-crystals was based on unequivocal evidence gleaned from single crystal X-ray structural studies, these assignments being confirmed by infrared spectroscopy. The melting points and decomposition temperatures of the products containing the coformers 4- aminobenzamide, 4-aminopyridine, isonicotinamide and tranexamic acid were significantly higher than those of untreated acipimox. Equilibrium aqueous solubilities of the multicomponent systems ranged from 0.31 to 2.77 times those of untreated acipimox.
Open Access
Complexation between cyclodextrins and phenylurea herbicides in solution and in the solid state
(2009) Smith, Vincent Joseph; Caira, Mino R; Bourne, Susan A
The author undertook the preparation of cyclodextrin inclusion complexes of four phenylurea herbicides (metobromuron, monolinuron, monuron and fenuron) using the kneading and co-precipitation methods in the solid state while also determining complex formation of the same phenylureas in solution with selected cyclodextrins. The kneading experiments were carried out first to determine whether the phenylureas would complex in the solid-state. The phenylureas were then subjected to complexation by means of co-precipitation under different conditions of crystallisation such as temperature and solvent medium in order to isolate more than one CD complex containing the same host and guest. The solution-state experiments were performed to see if the phenylurea complexes exist in solution and if so, to determine their nature.
Open Access
The crystal and molecular structures of some bioinorganic compounds
(1975) Caira, Mino R; Nassimbeni, Luigi R
In this thesis are presented the results of X-ray structural studies of seven metal-containing crystalline compounds. In some cases, the ligands associated with the metals are themselves biologically active; in other cases, the compound as an entity, rather than any constituent, is of direct or indirect biological significance. Detailed motivations for the individual structural analyses are described in the separate introductions in the body of this work. The compounds studied are generally dissimilar and present different facets of metal-ligand interaction. For this reason, the paragraphs which follow serve to introduce each compound by reviewing the pertinent areas of metal-binding.
Open Access
Crystal isostructurality and X-ray diffraction studies of cyclodextrin inclusion compounds
(2005) Lubhelwana, Siyanda; Caira, Mino R
The first part of this dissertation is an update on the isostructurality method of PXRD analysis (lsoPXRD), the last update having been published in 2001 The scope of the isostructurality part of this dissertation includes organic inclusion complexes of all three natural cyclodextrins (a-,
Open Access
The crystal structure of the Adduct [VO(ACA)₂.4-Phenylpyridine]
(1971) Caira, Mino R; Nassimbeni, Luigi R; Li
Open Access
Crystallization of two forms of a cyclodextrin inclusion complex containing a common organic guest
(Royal Society of Chemistry, 2003) Caira, Mino R; De Vries, Elise J C; Nassimbeni, Luigi R
The isolation and structural elucidation by single crystal Xray diffraction of triclinic and monoclinic modifications of an inclusion complex of b-cyclodextrin with the same guest, methylparaben, are reported.
Open Access
Enhancing the helical distortion in pyrrolo[1,2-a]phenanthrolines
(2010) Dumitraşcu, Florea; Caira, Mino R; Drăghici, Constantin; Căproiu, Miron Teodor; Barbu, Loredana; Dumitrescu, Dan G
The International Society for Burns Injuries (ISBI) has published guidelines for the management of multiple or mass burns casualties, and recommends that 'each country has or should have a disaster planning system that addresses its own particular needs.' The need for a national burns disaster plan integrated with national and provincial disaster planning was discussed at the South African Burns Society Congress in 2009, but there was no real involvement in the disaster planning prior to the 2010 World Cup; the country would have been poorly prepared had there been a burns disaster during the event. This article identifies some of the lessons learnt and strategies derived from major burns disasters and burns disaster planning from other regions. Members of the South African Burns Society are undertaking an audit of burns care in South Africa to investigate the feasibility of a national burns disaster plan. This audit (which is still under way) also aims to identify weaknesses of burns care in South Africa and implement improvements where necessary.
Open Access
Fluorescent ajoenes as a mechanistic probe for cancer
(2010) Cotton, Jonathan; Hunter, Roger; Caira, Mino R; Parker, Iqbal
This thesis describes the development and synthesis of several novel ajoene mimics. The first of which, (E/Z)-1,8-(Bis-p-methoxyphenyl)-2,3,7-trithia-octa-4-ene 7-oxide 17, was developed as a continuation of SAR studies performed by our group, involved the placing p-methoxyphenly groups on the termini of the ajoene pharmacophore.
Open Access
Inclusion of alkylparabens in cyclodextrins
(2003) De Vries, Elise Janine Christl; Caira, Mino R; Nassimbeni, Luigi R
The aim of this thesis was to prepare crystalline inclusion complexes with cyclodextrins (CDs), as hosts, and drugs, as guests, characterise them using various methods and attempt to elucidate their structures by X-ray diffraction methods to establish the detailed mode of drug inclusion in the solid state. Cyclodextrins and their derivatives have a low polarity central void formed by linked glucose residues of varying numbers. This annular cavity is able to encapsualte low molecular weight molecules and is therefore responsible for the great interest in CDs in host-guest chemistry. In addition, inclusion of drug molecules in cyclodextrins can significantly improve aspects of their performance, such as increased aqueous solubility and dissolution rates which lead to their increasing application in the pharmaceutical industry.
Open Access
New crystalline forms of permethylated β-cyclodextrin
(Royal Society of Chemistry, 2004) Caira, Mino R; Bourne, Susan A; Mhlongo, Welcome T; Dean, Pamela M
Two new crystalline forms of permethylated β-cyclodextrin are reported that contain methylglucose residues exclusively in the 4C1 conformation, in contrast to the known monohydrate, in which a single methylglucose residue adopts the 1C4 conformation.
Open Access
New tri- and tetra-substituted pyrroles via quinazolinium N1-ylides
(2011) Caira, Mino R; Georgescu, Emilian; Barbu, Loredana; Georgescu, Florentina; Dumitraşcu, Florea
New tri-and tetra-substituted N-arylpyrroles were synthesized by one-pot reaction of 3,7-disubstituted quinazolinonium bromides with substituted alkynes having at least one electron-withdrawing substituent in 1,2-epoxybutane acting both as solvent and hydrogen bromide scavenger. Structural characterization of the new compounds was based on IR and NMR spectroscopy as well as on single crystal X-ray analysis.
Open Access
The optical resolution of albuterol
(1998) Stevens, Anne Theresa; Caira, Mino R; Hunter, Roger; Nassimbeni, Luigi R
The acetonide derivative of (rac)-albuterol has been prepared and used as a substrate in cocrystallisation experiments with several acidic resolving agents~ Successful resolution of the acetonide was achieved with both di-0-benzoyl- and di-0-toluoyltartaric acid, with the (2S,3S)enantiomer of the acid selectively co-crystallising with the desired (R)-albuterol acetonide. High performance liquid chromatography on a chiral stationary phase, and 1H NMR experiments using a chiral shift reagent were used to assess the optical purity of the resolved material. Acid hydrolysis of the resolved acetonide gave rise to the target, (R)-albuterol, which was isolated as an acetate salt. The inferred absolute configuration of the resolved acetonide was assessed by 1H NMR analysis of its (R)-Mosher ester, and confirmed by an X-ray structural determination of its (R)-phenylethylurea derivative. The acetonide derivative of (rac)-albuterol has been prepared and used as a substrate in cocrystallisation experiments with several acidic resolving agents~ Successful resolution of the acetonide was achieved with both di-0-benzoyl- and di-0-toluoyltartaric acid, with the (2S,3S)enantiomer of the acid selectively co-crystallising with the desired (R)-albuterol acetonide. High performance liquid chromatography on a chiral stationary phase, and 1H NMR experiments using a chiral shift reagent were used to assess the optical purity of the resolved material. Acid hydrolysis of the resolved acetonide gave rise to the target, (R)-albuterol, which was isolated as an acetate salt. The inferred absolute configuration of the resolved acetonide was assessed by 1H NMR analysis of its (R)-Mosher ester, and confirmed by an X-ray structural determination of its (R)-phenylethylurea derivative.
Open Access
Physicochemical characterisation of cyclodextrin-drug complexes
(1996) Griffith, Vivienne Jean; Caira, Mino R; Nassimbeni, Luigi R
The cyclodextrins and their derivatives are finding increasing application in the pharmaceutical industry as carrier molecules for many drugs, as complexation can result in improved physical characteristics such as increased aqueous solubility and dissolution rates. The aim of this work was to prepare solid cyclodextrin complexes with selected drugs which have already been shown to interact with cyclodextrins in solution and ultimately to grow crystals of these inclusion complexes of sufficient quality for single crystal X-ray structure determination. The designated drugs included an antibacterial, sulfathiazole; three non-steroidal anti-inflammatory drugs (NSAIDs), (S)-naproxen and the sodium salts of diclofenac and meclofenamic acid; and (L)-menthol, a compound used in many pharmaceutical preparations. The chosen host molecules were ,β-cyclodextrin, γ-cyclodextrin, heptakis(2,6-di-O-methyl)-, β-cyclodextrin (DIMEB) and heptakis(2,3,6-tri-O-methyl)-β-cyclodextrin (TRIMEB). The unit cell parameters of thirteen cyclodextrin-drug complexes and of TRIMEB monohydrate were determined by X-ray photography and the cry tal structures of six of these complexes and of TRIMEB monohydrate were solved. The water content of the complexes was established by thermogravimetric analysis and the host:guest stoichiometries of those complexes whose crystal structures were not solved were determined by UV spectrophotometry or, in one case, by a combination of NMR and thermogravimetric analysis. The complexes were also characterised by differential scanning calorimetry. Hot stage microscopy was a useful method for initial testing for the formation of inclusion complexes of the native cyclodextrins, since their behaviour on heating differs markedly from that of the relevant host alone. The events observed could be correlated with the thermal analyses of the complexes. Complexes which contained alkali metal cations appeared to retain water molecules of crystallisation to higher temperatures, on average, than those which did not. XRD patterns were calculated from the crystal structures which were solved and matched the experimental patterns of the prepared samples well. The calculated patterns serve as the best references for establishing the identity and purity of prepared complexes. Host-guest interactions included hydrogen bonding, van der Waals contacts and hydrophobic interactions. Guest molecules maintained similar conformations on the whole as those observed in other crystal structures containing these particular guests. Conformations of the hosts were akin to those found in known crystal structures, except in TRIMEB monohydrate, where the TRIMEB conformation was distorted to a remarkable extent even in comparison with the distorted conformations observed in its complexes. In addition, one of the methylglucose residues is present in the ¹C₄ inverted chair conformation which has not been observed before in the cyclodextrins or their complexes in the solid state. The invariable occurrence in the TRIMEB host of C(6Gn)-H···0(5Gn-1) hydrogen bonds noted in this study is partly responsible for the uniformity in the conformation of TRIMEB in its complexes. The packing arrangement found in the diclofenac sodium-β-CD complex is unique and is the first example of a β-CD complex crystallising in the hexagonal crystal system. The inclusion by β-CD of meclofenamate sodium (a structural isomer of diclofenac sodium) is similar to that of diclofenac sodium, but the packing arrangement is different and while unique for a complex of unsubstituted β-CD, resembles the packing arrangement found in most of the known TRIMEB complexes.
Open Access
Physicochemical studies of the inclusion of selected agrochemicals in cyclodextrins
(2011) Cruickshank, Dyanne Louise; Caira, Mino R; Bourne, Susan A
Pesticides frequently display adverse properties such as low aqueous solubility, low stability, and high toxicity that limit their applications and render them environmentally hazardous. The possibility of improving these physical properties was attempted by complexing four pesticides with native and derivatised cyclodextrins (CDs). The pesticides studied included: the phenylurea herbicide, cycluron; an organochlorine insecticide, endosulfan; an organophosphorus insecticide, fenitrothion; and the chloroacetanilide herbicide, acetochlor. A study of CD complexation with these pesticides in solution as well as in the solid state was undertaken. A further set of experiments was conducted, whereby the thermal stabilities of three isostructural inclusion complexes were evaluated using thermogravimetric analysis.
Open Access
Physicochemical study of inclusion of drug molecules in cyclodextrins
(1999) Dodds, Devric Reginald; Caira, Mino R
Inclusion of drug molecules in cyclodextrins can significantly improve various aspects of their performance and has resulted in the use of cyclodextrins (CDs) for a wide variety of pharmaceutical applications. Consequently, the cyclodextrin inclusion of drugs has received great interest in the pharmaceutical and chemical fields. For this study the inclusion of nine pharmaceutical drugs with CDs was investigated in the solid state. The objectives of the study were i.) the preparation, ii.) determination of the chemical composition, iii.) analysis of thermal behaviour and iv.) investigation of the solid state features of the complexes. Ultraviolet spectrophotometry, elemental analysis and thermogravimetric analysis were the principal techniques used for determination of composition. Hot stage microscopy, differential scanning calorimetry and thermogravimetric analysis were the principal techniques used for the analysis of thermal behaviour. Single crystal x-ray diffraction and x-ray powder diffraction were the principal techniques used for investigation of structural features. This thesis reports the preparation by crystallisation from solution of eight beta cyclodextrin (β-CD) and four gamma cyclodextrin (γ-CD) inclusion complexes with selected drugs as guests, as well as the determination of their chemical compositions and analysis of their thermal behaviours. Investigation of the structural features of these complexes includes the determination of the crystal structures of five β-CD complexes and one γ-CD complex. The preparation of hydnoxypropyl-β-CD complexes by kneading and co-grinding is also reported.
Open Access
Physicochemical study of solid Cyclodextrin inclusion complexes of the antithrombotic Ajoene
(2004) Smith, Vincent Joseph; Caira, Mino R; Hunter, Roger; Bourne, Susan
This study describes the preparation and physicochemical characterization of inclusion complexes formed between selected cyclodextrins (CDs) and ajoene, an antlthrombotlc found in garlic. The E and Z isomers of ajoene (4,5,9,-trithiadodeca-1,6,11-triene-9-oxide) were reacted with α, β, γ-CD heptakis(2,6-di-O-methyl )-β-CD (DIMEB) and heptakls(2, 3, 6-tri-O-methyl )-β-CD (TRIMEB) to yield inclusion compounds α-CD·(E)-ajoene (1), α-CD·(Z)ajoene (2), β-CD·(E)-ajoene (3), β-CD·(Z)-ajoene (4), y-CD·(E)-ajoene (5), y-CD·(Z)-ajoene (6), DIMEB·(E)-ajoene (7), DIMEB·(Z)-ajoene (6), TRIMEB·(E)-ajoene·05H20 (9) and TRIMEB·(Z)-ajoene (10).
Open Access
The physio-chemical properties of organic inclusion compounds
(2004) Le Roex, Tanya; Nassimbeni, Luigi R; Caira, Mino R
In this thesis the inclusion properties of the host compounds trans-9,10-dihydroxy-9,10-bis(p-tert-butylphenyl)-9, 10-dihydroanthracene (TBDDDA), 9.9'-(Biphenyl-4,4'diyl) difluoren-9-ol (WEB24) and 1â ´ ,1â ¶,5â ´,5â ¶-tetrahydroxy-2,4,6,8-tetrapentyl-3â ´,3â ¶,7â ´,7â ¶-tetra(p-toluenesulfonyl-oxy)-1,3,5, 7(1,3)-tetrabenzenacyclooctaphane (TTRSC) were investigated. Each of these host compounds is bulky and rigid and in addition contains high-affinity functional groups which can engage in specific host-guest interactions, such as hydrogen bonding.
Open Access
Polymorphs, cyclodextrin inclusion complexes and salts of the bronchodilator tulobuterol
(2004) Oliver, Clive Lloyd; Caira, Mino R; Bourne, Susan
The aim of this thesis was to prepare polymorphs, cyclodextrin inclusion complexes and salts of tulobuterol, a drug with bronchodilating properties. Polymorphic drugs are of interest to the pharmaceutical industry because of their varied physical properties, whilst the increase in aqueous solubilities of drugs by their inclusion within cyclodextrins or by salt formation is also an important pharmaceutical consideration. Two polymorphs, four cyclodextrin inclusion complexes and three salts of tulobuterol free base were successfully generated in this study.