**Acknowledgements**

*Vector-Borne Diseases - Recent Developments in Epidemiology and Control*

and pharmacological validation of using PDEs as novel drug targets for diseases caused by the kinetoplastid parasites. This study for the first time explores the possibility of using human PDE inhibitors as the starting framework for the design of *Leishmania*selective inhibitors. This proposal is supported by the inhibitory effects of some human PDE inhibitors observed on *T. cruzi* PDEC, e.g., etazolate inhibits human PDE4 and TcrPDEC with the IC50 values of 2 and 0.7 nM [69]. Among the PDE inhibitors used in this study etazolate along with rolipram showed maximum anti-proliferative activity against *Leishmania* parasite with least cytotoxic effect on macrophage cells cultured *in vitro*. Further it was observed that both of them significantly affected the G1 cell cycle arrest and mitochondrial membrane potential of the parasite, therefore we assessed *in vitro* for their ability to clear parasite load within the macrophage cells. Etazolate was found to be more effective in clearing the parasite load when the macrophage cells were pretreated with it compared to rolipram. Etazolate belongs to pyrozopolidine class compound which shows PDE4 enzyme inhibitory activity [70]. Preclinical studies as well as pharmacokinetic and safety profiles in Phase I and Phase IIa of clinical studies revealed that etazolate is a well-established drug of choice with no major side effects reported [70]. Etazolate produced antidepressant like effects in animal models of depression and at the same time it could be used in the treatment of Alzheimer's disease [71]. If through experimentation a minimal dose of etazolate could be determined then etazolate could itself be used as an anti-leishmanial drug. However, if it is not possible to determine the dose concentration which would specifically inhibit parasite PDE, then one can make use of the significant advances made in medicinal chemistry to design compounds which could specifically inhibit parasite PDE but not that of the host. This compound if

*An overview of cAMP signaling in* Leishmania *during stress condition where receptor adenylate cyclase, PDEA, PDED, PKA the effector molecule of cAMP and acidocalcisomal pyrophosphatases play the major roles* 

developed, could act as a potential anti-leishmanial agent in future.

On the other hand, several known PDE inhibitors were tested against *Plasmodium* PDEα, and zaprinast, a known selective inhibitor of human PDE5 which is specific

**148**

**Figure 7.**

*in the maintenance of cAMP homeostasis.*

We thank DST-INSPIRE Project grant (IFA-12 LSBM-22), PRG-University of Kalyani and NASI Senior Scientist Platinum Jubilee Fellowship for this work.
