An insight into tetrahydro-β-carboline-tetrazole hybrids: synthesis and bioevaluation as potent antileishmanial...

A series of 2,3,4,9-tetrahydro-β-carboline tetrazole derivatives (14a-u) have been synthesized utilizing the Ugi multicomponent reaction and were identified as potential antileishmanial chemotypes. Most of the screened derivatives exhibited significant in vitro activity against the promastigote (IC₅₀ from 0.59 ± 0.35 to 31 ± 1.27 μM) and intracellular amastigote forms (IC₅₀ from 1.57 ± 0.12 to 17.6 ± 0.2 μM) of L. donovani, and their activity is comparable with standard drugs miltefosine and sodium stibogluconate. The most active compound 14t was further studied in vivo against the L. donovani/golden hamster model at a dose of 50 mg kg^-1 through the intraperitoneal route for 5 consecutive days, which displayed 75.04 ± 7.28% inhibition of splenic parasite burden. Pharmacokinetics of compound 14t was studied in the golden Syrian hamster, and following a 50 mg kg^-1 oral dose, the compound was detected in hamster serum for up to 24 h. It exhibited a large volume of distribution (651.8 L kg^-1), high clearance (43.2 L h^-1 kg^-1) and long mean residence time (10 h).