1,721,185 research outputs found
Utilization of the Baylis-Hillman and related reactions in antiparasitic drug discovery
No full textBibliography: leaves 81-83.Baylis-Hillman adducts and compounds containing quinoline moieties have been previously utilized extensively in the search for antiparasitic agents. Work in this dissertation describes a series of compounds based on the Baylis-Hillman and the related three-component aza Baylis-Hillman reactions synthesised for biological evaluation as potential inhibitors of two parasitic cysteine proteases (cruzain and Falcipain-2) and as antiparasitic agents. The utilization of polymer-supported bases in the Baylis-Hillman reaction is described. The use of ultrasound in combination with Lewis acids is also described in an attempt to improve the reaction rate
Exploring the potential of xanthene derivatives as inhibitors of trypanothione reductase and resistance reversal agents
No full textIncludes bibliographical references
Synthesis of activity-based protein profiling probes for malaria and hypertension disease models & potential novel ACE inhibitors with an attenuated zinc binding group
No full textIncludes bibliographical references.Angiotensin-converting enzyme (ACE) and P. falciparum A M1 (PfA-M1) are both zinc metalloproteases implicated in hypertension and malaria, respectively. Hypertension affects approximately 26 % of the world’s population while each year over 300 million cases of malaria occur worldwide resulting in between 1.5 and 2.7 million deaths annually. Hypertension treatment with current ACE inhibitors is marred by unpleasant side effects, such as cough and angioedema. In malaria, the parasites continuously develop resistance to anti-malarial drugs where the disease is endemic. There is therefore a need for continuous research into the application of new techniques as well as the design of new small molecule chemical entities as probes or chemotherapeutic agents
Structure-activity and structure-property relationships of antimalarial pyrimido[1,2-a]benzimidazoles, imidazo[1,2-a]pyridines, and imidazo[1,2-a]pyrimidines
No full textMalaria is an infectious disease that continues to cause significant morbidity and mortality in countries with poor infrastructure, with the African region being the most heavily affected. An estimated 241 million malaria cases were recorded in 2020, with 627,000 deaths. Of these, 77% occurred in children under the age of 5 years. Due to the widespread rise of parasite resistance, current treatments may no longer be effective. Furthermore, artemisinin-based combination treatments (ACTs), which are the first-line antimalarial medications currently recommended by the World Health Organization (WHO), are restricted in availability, prohibitively expensive, and have undesirable side effect profiles. Resistance to ACTs (albeit partial) has been reported in some Asian regions and in East Africa. Hence, there is an urgent need for new antimalarial agents with novel mechanisms of action and structural diversity. In 2011, pyrido[1,2-a]benzimidazoles (PBI) were reported as a promising novel antimalarial chemical series. However, one of the shortcomings of these compounds, which present a barrier to achieving optimal in vivo efficacy, is their poor aqueous solubility and suboptimal in vivo pharmacokinetics. In this study, the aim was to improve the physicochemical properties of previously identified PBI derivatives towards identifying new analogs able to address the aforementioned shortcomings. 1, 2 Three scaffolds were proposed based on their envisaged improved physicochemical properties, namely pyrimidino[1,2-a]benzimidazoles, imidazo[1,2-a]pyrimidines, and imidazo[1,2-a]pyrimidines. Compounds based on these scaffolds showed high in vitro antiplasmodium activity, with pyrimidino[1,2- a]benzimidazoles showing superior antiplasmodium activity and cytotoxicity profiles
Antimalarials based on the arylpiperazine privileged substructure
No full textIncludes bibliographical references (leaves 118-124).Based on a previous study, arylpiperazines (2-chlorophenylpiperazine, 2-ethoxyphenylpiperazine and phenylpiperazine) were found to be significantly more potent against the chloroquine-resistant (K1) strain than against the chloroquine-sensitive(DIO) strain. In other studies, 8-hydroxy-2-(di-n-propylamino)tetralin (8-0H-DPAT) has been identified as a potential antimalarial agent for the inhibition of the 5-hydroxytryptamine type 1A receptor in Plasmodium falciparum. A number of arylpiperazines are also known to target this receptor in other systems. Coupled with the potential role of arylpiperazines as replacements for the antimalarial 8-OH-OPA T, these results prompted a further investigation into the antiplasmodial properties of a broader range of simple un substituted and substituted arylpiperazines against a broader range of chloroquine-sensitive and chloroquine-resistant strains of PlasmodiumJalciparum
Bioactive chloroquine-based ligands and their gold complexes as potential novel antimalarial agents
No full textIncludes bibliographical references.Includes bibliographical references.Chloroquine(CO)-derived 4-aminoquinolines have proven to be the most efficacious antimalarial drugs for both the treatment and prophylaxis of malaria. However, with the advent of drug resistance, their ability to treat the disease has been significantly hindered. Future research into the synthesis of new 4-aminoquinoline derivatives is warranted, since it has been found that the resistance is based on the identity of the side chain and not on the aminoquinoline ring, the functionality by which these compounds derive their activity. Consequently, the synthesis of CO derivatives with a modified side chain attached to a substituted quinoline ring is a reasonable approach in the search of novel antimalarial compounds that are active against drug-resistant parasite strains
Antiprotozoal quinolines containing electrophilic moieties
No full textIncludes bibliographical references.Compounds containing the quinoline moiety have been the mainstay of antimalarial chemotherapy. However, the emergence of resistant strains of Plasmodium falciparum, the causative agent of malaria, has compromised the efficacy of these antimalarial quinolines. Therefore the development of new efficient drugs is of critical importance. Extensive research has identified the cysteine proteases in malaria and other parasitic diseases as potential targets for new chemotherapy due to their critical roles in the life cycles of the causative agents. Due to their role in the antimalarial activity of clinically available drugs, quinolines were used as scaffolds to which electrophilic groups, such as thiosemicarbazone, a,β-unsaturated ketone and pyrazoline moieties were appended
In vitro metabolism of tetrazole aminoquinolines and derivatives of metergoline and fusidic acid
No full textIncludes bibliographical references.Drug metabolism is recognised as a key component of the drug discovery and development process. It exerts an influence on the action, duration of action and toxicity of a drug in vivo. The integration of drug metabolism studies is therefore crucial to compound progression through the various stages of the development process. This work details the in vitro metabolism work conducted during the early development of aminoquinoline tetrazoles, and derivatives of metergoline and fusidic acid as potential antiplasmodial and/or antimycobacterial agents
Synthesis and Antimalarial evaluation of Gold Thiosemicarbazone Complexes and Polyamine-Thiosemicarbazone Dendrimers
No full textMalaria still remains one of the most dangerous widespread parasitic diseases in developing nations. Reported alarming figures of malaria infections annually highlight the âgapâ that remains to be filled to rid endemic of malaria. As cases of increasing spread of malaria and the emergence of resistance continue to exert pressure on health systems in most affected areas, novel antimalarial compounds are endlessly needed to overcome the problem of malaria infections. This thesis presents research investigating a series of thiosemicarbazones (TSCs) and their novel gold complexes and dendrimers as potential antimalarial agents. A series of TSCs were synthesised in one step using Schiff base chemistry. On the other hand pyrazoline analogues were obtained in two steps using both Mannich and Schiff base chemistries. A range of gold(I) TSC complexes were achieved by reacting TSCs with the starting gold(I) materials, [AuI(PEt3P)Cl] (4.2), [AuI(THT)Cl] (4.3), [AuI(Ph3P)Cl] (4.5), [AuI(PTA)Cl] (4.24), and C6F5AuI(THT) (4.34). Further reaction of TSCs with starting gold(III) complex 2.15 yielded the corresponding series of gold(III) TSC complexes. All the compounds were characterised by multinuclear NMR and FT-IR spectroscopies, mass spectrometry and elemental analysis. Gold(I) complexes 4.15 and 4.16 were further characterised by single X-ray crystallography. The synthesised ligands and complexes were tested for their antiplasmodial activity against chloroquine-sensitive (D10, 3D7) and chloroquine-resistant (W2, K1) strains of the malaria parasite Plasmodium falciparum. These compounds were also evaluated for inhibitory activity against the malarial cysteine protease (falcipain-2). In most cases gold complexes showed enhanced antiplasmodial activities relative to their corresponding ligands. However, no correlation was found between antiplasmodial activities and the inhibition of falcipain-2 in respect of studied compounds. Reaction of TSC thioesters 6.23 with branched dendritic polyamines (PAs) led to two series of polyamine-TSC dendrimers 6.24 and 6.25 whose chemical structures were elucidated using a range of techniques. Similarly, these dendritic TSCs were also tested for their antiplasmodial activity against the W2 strain. Generally, this class of compounds displayed improved antiplasmodial activities in the mid to low micromolar range. The most active compounds were 6.24c (IC50 = 0.79 ïM) and 6.24d (IC50 = 0.67 ïM), respectively
Investigating the chemical space and metabolic bioactivation of natural products and cross-reactivity of chemical inhibitors in CYP450 phenotyping
No full textIncludes bibliographical references.Natural products have been exploited by humans as the most consistently reliable source of medicines for hundreds of years. Owing to the great diversity in chemical scaffolds they encompass, these compounds provide an almost limitless starting point for the discovery and development of novel semi-synthetic or wholly synthetic drugs. In Africa, and many other parts of the world, natural products in the form of herbal remedies are still used as primary therapeutic interventions by populations far removed from conventional healthcare facilities. However, unlike conventional drugs that typically undergo extensive safety studies during development, traditional remedies are often not subjected to similar evaluation and could therefore harbour unforeseen risks alongside their established efficacy. A comparison of the ‘drug-like properties’ of 335 natural products from medicinal plants reported in the African Herbal Pharmacopoeia with those of 608 compounds from the British Pharmacopoeia 2009 was performed using in silico tools. The data obtained showed that the natural products differed significantly from conventional drugs with regard to molecular weight, rotatable bonds and H-bond donor distributions but not with regard to lipophilicity (cLogP) and H-bond acceptor distributions. In general, the natural products were found to exhibit a higher degree of deviation from Lipinski’s ‘Rule-of-Five’. Additionally, these compounds possessed a slightly greater number of structural alerts per molecule compared to conventional drugs, suggesting a higher likelihood of undergoing metabolic bioactivation
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