Development of derivatives of 3, 3'-diindolylmethane as potent Leishmania donovani bi-subunit topoisomerase IB poisons.

Abstract

BACKGROUND: The development of 3, 3'-diindolyl methane (DIM) resistant parasite Leishmania donovani (LdDR50) by adaptation with increasing concentrations of the drug generates random mutations in the large and small subunits of heterodimeric DNA topoisomerase I of Leishmania (LdTOP1LS). Mutation of large subunit of LdTOP1LS at F270L is responsible for resistance to DIM up to 50 µM concentration. METHODOLOGY/PRINCIPAL FINDINGS: In search of compounds that inhibit the growth of the DIM resistant parasite and inhibit the catalytic activity of mutated topoisomerase I (F270L), we have prepared three derivatives of DIM namely DPDIM (2,2'-diphenyl 3,3'-diindolyl methane), DMDIM (2,2'-dimethyl 3,3'-diindolyl methane) and DMODIM (5,5'-dimethoxy 3,3'-diindolyl methane) from parent compound DIM. All the compounds inhibit the growth of DIM resistant parasites, induce DNA fragmentation and stabilize topo1-DNA cleavable complex with the wild type and mutant enzyme. CONCLUSION: The results suggest that the three derivatives of DIM can act as promising lead molecules for the generation of new anti-leishmanial agents.