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

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