Medicinal Chemistry: The Design of Oxamniquine

So guys, I was struggling these few days to find a pharmacophore identification of this drug *ghez* But then I realized oxamniquine is such an interesting topic to talk about…so this is what I’ve summarized from an amazing book , check it out!

Oxamniquine is an important drug in developing countries, and is used in the treatment of schistosomiasis (Bilharzia). The disease is caused by small flatworms called schistosomes which are contracted by swimming or wading in infected water. The parasites can rapidly penetrate human skin in the larval form and once they are in the blood supply, the larvae develop into adult flatworms. The females then produce eggs that become trapped in organs and tissues, leading inflammation and a long debilitating disease that can last up 20 years. 

How oxamniquine are made?

In 1964 Pfizer initiated a project initiated a project aimed at developing an orally active, non-toxic that would be effective as a single dose against all three pathogenic strains. Lucanthone was chosen as the lead compound because it was orally active and it was decided to try simplifying the structure to see whether  the tricyclic system was necessary. Several compound were made-the most interesting structure wa one where two rings had been removed (Figure below).

This gave a compound called mirasan which retained the right-hand aromatic ring containing the methyl and β-aminoethylamino side chains para to each other. Varying subtituents showed that an electronegative chloro substituent, positioned where the sulphur atom had been was beneficial to activity. By now, the structure of the compound had been altered significantly from mirasan. When this is the case it is advisable to check whether past result still hold true. Therefore mirasan’s bicyclic structure are modified by varying substituents and substitution  pattern on the aromatic ring and by varying alkyl subtituents on the amino group. Chains were also extended to search for other possible binding regions.

The results and possible conclusions were as follows:

• It was possible to vary substituents on the aromatic ring, but the substitution pattern itself could not be altered and was essential for activity

•  Replacing the chloro substituent with more electronegative substituents improved activity, with the nitro group being the best substituents. A strongly electron-deficient aromatic ring would pull the cyclic nitrogen’s lone pair of electrons into the ring, thus reducing its basicity and might alter the pka of the drug.

• The best activities were found if the amino group on the side chain was secondary rather than primary or tertiary

• The alkyl group on this nitrogen could be increased up to four carbon units with a corresponding increase in activity

• Branching of the alkyl chain increased activity because its increases van der Waals interaction to a hydrophobic region of the binding sit. Alternatively, the lipophilicity of the drug might be increased

• Putting a methyl group on the side chain eliminated activity (Conformational blocking)

• Extending the length of the side chain by an extra methylene group eliminated activity

The optimum structure based on these result was structure III. It has one asymmetric center and as one might expect, the activity was much greater for one enantiomer than it was for other. Therefore, the methyl group on III was replaced by a hydroxymethylene group to give oxamniquine. It was proposed that the new hydroxyl group may be involved in an extra hydrogen bonding interaction with the binding site. 

 How oxamniquine are work?

Oxamniquine inhibit nucleic acid synthesis in schistosomal cells. The mechanism of action is thought to involve prior activation of the drug by a sulphotransferase enzyme that is present in parasitic cells, but not in mammalian cells. Once oxamniquine is bound to the active site of the schistosomal enzyme, the hydroxyl is converted to a sulphate ester. The ester is a much better leaving group than the originally hydroxyl group, and so the molecule is now set up to dissociate. The structure that is formed is an alkylating agent which alkylated the DNA of the parasite and prevents DNA replication. Therefore, oxamniquine is acting as a prodrug which is activated by the parasitic sulphotransferase enzyme.

Reference:

Patrick, G.L., 2017. An introduction to medicinal chemistry, sixth edition. United Kingdom: Oxford University Press. 

QUESTION BOX:

1.    Apa itu lead compound? 2.    Berdasarkan artikel diatas sintesis oxamniquine didasarkan pada obat lama yang dimodifikasi strukturnya, lantas apakah pada dasarnya oxamniquine dapat dimodifikasi lagi? 3.    Bagaimana pengaruh lipofilitas terhadap absorbsi obat ini?

Submit your answer below!