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

A series of 2,3,4,9-tetrahydro-ß-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).

Hydroxypropyl- ß -cyclodextrin: A Novel Transungual Permeation Enhancer for Development of Topical Drug Delivery System for Onychomycosis.

The treatment of onychomycosis is a challenging task because of unique barrier properties of the nail plate which hampers the passage of antifungal drugs in a concentration required to eradicate the deeply seated causative fungi in the nail bed. In present investigation, application of hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was established as an effective and nail friendly transungual drug permeation enhancer especially for poorly water soluble drugs using terbinafine hydrochloride as a poorly soluble drug. HP-ß-CD significantly improves hydration of nail plates and increases solubility of terbinafine hydrochloride in the aqueous environment available therein, which leads to uninterrupted drug permeation through water filled pores of hydrogel-like structure of hydrated nail plates. A nail lacquer formulation was designed with an objective to deliver the drug in an effective concentration across nail plates, using HP-ß-CD as a permeation enhancer. The formulations containing HP-ß-CD showed higher flux than the control formulation in in vitro drug permeation study. The formulation containing 10% w/v of HP-ß-CD showed maximum flux of 4.586 ± 0.08 µg/mL/cm(2) as compared to the control flux of 0.868 ± 0.06 µg/mL/cm(2). This finding supports application of HP-ß-CD as an effective permeation enhancer for transungual delivery of terbinafine hydrochloride and possibly other poorly water soluble drugs where HP-ß-CD can act as a solubilizer.