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Importance/Unique Salient Feature

Amongst this series, compound CDRI 98-288 was found to display in vitro antileishmanial activity against promastigotes and amastigotes with good SI index. The compound also exhibted potential antileishmanial activity under in vivo condition against L. donovani in hamster model. This generated interest towards carrying out the SAR for the identified series of compounds. During the process, another compound S-012-552 was also found to be equally effective both under in vitro and in vivo system against L. donovani. Consequently, an Indian patent was filed for this series of compounds as antileishmanial agents. But as S-012-552 was relatively more hydrophobic than 98-288, further in vivo pharmacokinetic investigations were performed with 98-288. During these studies it was found that 98-288 was a prodrug and it metabolised during the first pass metabolism to a metabolite which was possibly responsible for the in vivo antileishmanial effect. Synthesis of this metabolite (A) revealed that it was highly insoluble but still had significant in vivo antileishmanial effect. It was discovered that this compound too resulted in a metabolite which was identified as B. Subsequently the metabolite B was synthesized and the in vivo evaluation of this compound is underway.

In a simultaneous study the process for the preparation of similar analogue (metabolite B) that may originate from S-012-552 was initiated and a new compound S-015-2344 was prepared. The in vitro and in vivo evaluation of this compound would be taken up. It may be noted that these metabolites has better solubility as compared to their parent compounds and therefore are more suited for further studies.

Needless to mention that based on the in vivo evaluation of the metabolite more optimisation studies shall be carried out.