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The design, synthesis and antiplasmodial activity of a series of halogenated fosmidomycin analogues and hybrid drugs

- Afolayan, Anthonia Folake

Authors: Afolayan, Anthonia Folake
Date: 2012
Subjects: Uncatalogued
Language: English
Type: text , Thesis , Doctoral , PhD
Identifier: http://hdl.handle.net/10962/64370 , vital:28538
Description: Malaria continues to be a devastating disease and a major cause of death in sub-Saharan Africa. With resistance against most of the available antimalarial drugs, there is a need for ongoing research and development of antimalarial agents. Fosmidomycin and its acetyl analogue FR900098 have been identified as potent inhibitors of Plasmodium falciparum, the causative agent of the most deadly form of malaria. Clinical trials of these agents have revealed poor absorption due to their high hydrophilicity. In the present studies the effect of halogenation of the acyl chain as well as the biological effect of extending the acyl sidechain was explored. This provided the basis on which fosmidomycin hybrids were designed to investigate the feasibility of hybrid extending into NADPH binding pocket. Synthesis of a series of halogenated FR900098 analogues was carried out in three stages. This included i) The introduction of the phosphonate group by reaction with 1,3dibromopropane in an Arbuzov reaction, ii) The introduction of a hydroxamate group by reaction of the propyl phosphonate by means of a nucleophilic substitution reaction with BocNHOBn and iii) The introduction of a halogenated acyl side chain on a protected fosmidomycin backbone. The synthesis of fosmidomycin-hybrids for which chloroquinefosmidomycin hybrids were used as the prototype, involved convergence of the two separately constructed moieties i.e. fosmidomycin and the quinoline moieties in a covalent linkage. The quinoline moiety was easily synthesized from the reaction of 4,7dichloroquinoline with 1,2-diamino ethane. The aminoquinoline so formed resulted in chloroquine-fosmidomycin hybrids 3.8 and 3.9 when reacted with halogenated FR900098 analogues. Antiplasmodial assays were conducted on the chloroquine-fosmidomycin hybrids and the halogenated fosmidomycin derivatives against the chloroquine resistant Gambian FCR-3 strain of P. falciparum. The most potent iodoacetyl fosmidomycin analogues 2.21 gave an IC50 value of 5.54 µM which is eight times more potent than the known antiplasmodial FR900098 which gave an IC50 value of 41.67 µM. All the halogenated FR900098 analogues showed better antiplasmodial activity than their non-halogenated derivatives. This indicated that the presence of halogens in the FR900098 analogues contributes to their biological Chapter 1 Literature review activity. The acetyl and propyl linked hybrids 3.8 and 3.9 showed potent antiplasmodial activity with IC50 values of 0.18 and 0.82 µM respectively. These were by far the most potent hybrids synthesized and provided leads for a new class of promising antimalarial agents. Preliminary E. coli DXR enzyme inhibition assays were carried out on the halogenated fosmidomycin analogues. The results showed good inhibition of the enzyme by the phosphonic acids of the chloroacetyl and chloropropyl analogues 2.1 and 2.2 respectively. Molecular modelling of the compounds on E. coli (PDB code: 2EGH) and P. falciparum (PDB code: 3AUA) DXR showed strong binding of the halogenated fosmidomycin analogues while the hybrids in the absence of docked NADPH showed minimum binding to the enzymes.
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Gender activity report to the NEC of the 12th-14th November 1998

- National Union of Metalworkers of South Africa

Authors: National Union of Metalworkers of South Africa
Date: 1998-11-12
Subjects: Uncatalogued
Language: English
Type: text , pamphlet
Identifier: http://hdl.handle.net/10962/106370 , vital:32645
Description: As per our Congress Resolution on Women Empowerment, the main objective for this year (1998) was to implement some of these resolutions. It is obvious that not all the resolutions could be realized this year, however, this department managed to execute the following as per our year plan: mechanisms to empower women in the union, develop education and training programmes on women’s needs, encourage male comrades to take part in gender activities/programmes to raise understanding of gender issues. The above issues were going to be actualized in the following way: national gender schools and gender workshops.
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Sex work: discussion document 27-29 March 2012

Date: 2012
Subjects: Uncatalogued
Type: book , text
Identifier: http://hdl.handle.net/10962/68748 , http://vital.seals.ac.za8080/10962/85260 , vital:29311
Description: The aim of this paper is to resuscitate the debate on the need for decriminalization of sex work and ensure that COSATU and its affiliates further engage within structures, alliance, non -governmental organizations and with the Government in terms of the need for law reform and identify alternative policy framework. However, whatever outcome of the legal processes pertaining to sex work, should be abide by the spirit of the Constitution which is committed to advancing human rights and social justice. Sex work in South Africa is currently criminalised and is restricted by the Sexual Offences Act of 1957 (an un-amended apartheid-era law) which prohibits all activities associated with it. The criminal offences related to sex work include amongst them the keeping or participating in the management of a brothel, procuring someone to become a sex worker, soliciting or selling sex or living of the earnings of a sex worker. In 2007 through the Sexual Offences Act their clients were also criminalised In 2007, the Act was amended to criminalise buyers of sexual services too (SALRC 2009). We therefore argue that the existing laws on sex work are nothing but hypocrisy of the conservatives and elites. They do not improve the conditions of women; instead they worsen the miserable conditions that women in the sex trade already find themselves in. The missing fact is that sex work is a by-product of our patriarchal capitalist society-not something created by some “immoral prostitute” The current oppressive legislation on sex work has stimulated a lot of debates and has led to an upsurge in advocacy work by individuals and organizations around the need to either legalise or decriminalize sex work. Likewise, Cosatu as a key civil society player has also played a leading role in its endeavor to unite the working class and to defend workers from exploitation as well as finding workable solutions to the plight of the most vulnerable people in our society who find themselves with no choice but to engage in sex work. The sex industry is by nature exploitative and inherently dangerous. Women in the industry experience different degrees of abuse, coercion and violence, but all of them are harmed physically and psychologically. As a trade union movement, COSATU has an interest in the debate about sex work, from the point of view that sex work targets mainly the working class and the poor, predominantly black women. High levels of unemployment, poverty and gender inequality are key factors driving sex work. The global economic crisis has aggravated the situation for the poor majority through job losses, casualisation and ultimately increased feminization of poverty. Cosatu has already started some debates and campaigns aimed at devising ways of protecting sex workers through collective workers struggles. As such, the sex work discourse and campaign among Cosatu affiliates for decriminalization was tabled at the Federation’s 10th Congress though it was deferred because of contestation and opposition amongst delegates. However, affiliates had the responsibility to go back and make further consultations, sensitization with their structures and open up a discussion at the level of the COSATU Central Executive Committee. Indeed, it is high time that the debate on decriminalization should be concluded and that sex work be recognized as work as Arnott and Crago (2009) argue that: “The criminalisation of sex work has precluded the enforcement and protection of sex workers’ Labour rights. This disregard for sex workers as workers has left many of those employed in brothels in South Africa vulnerable to labor abuses such as withheld wages, arbitrary fines, restrictions on mobility, and confiscation of belongings including medication. Sex workers on the street or working in brothels and other agencies have no recourse if customers refuse to pay them’’1 The decriminalization of sex work should take the course of a rights- based approach which means that sex workers would be able to enjoy their basic human & labour rights and be protected against sexual harassment, violence, rape and unfair working conditions. By so doing, sex workers would be able to access non-discriminatory health care services, be more empowered and operate within the ambit of protective labour and occupational health & safety laws.
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The FAWU Research Unit

- Food and Allied Workers' Union

Authors: Food and Allied Workers' Union
Subjects: Uncatalogued
Language: English
Type: text , pamphlet
Identifier: http://hdl.handle.net/10962/106408 , vital:32649
Description: The FAWU research unit has been operating in the Head Office since 1998. It has established a resource centre and has two people working in it at this time - Thandi Yoli and Viva Mtai. The unit was jointly conceived in 1996/97 by FAWU and the Labour Research Service (LRS). The relationship between the two organisations continues presently, and will last until the research unit is properly established and resourced within FAWU's head office. The LRS successfully applied for funding for the project in 1996/97 from the FNV-Holland. This money goes to paying the salaries and overhead costs incurred by the LRS for providing a senior researcher (Reza Daniels) to supervise and establish the research unit in FAWU. It is a three-year project and we are currently in the third year of the project. We are, however, going to apply for an extension of the project (to the FNV-Holland) so that it is completed by the end of the year 2000. The original aim of the project in 1996 was to assist FAWU to increase its bargaining capacity by developing a research unit that was targeted to producing sectoral reports that could assist the bargaining department. It was felt that FAWU lacked the research capacity to fully support its bargaining structures because of several factors.
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