Education

• NIH Postdoctoral Fellow 1994-1996, Johns Hopkins University.
• Ph.D.1993, University of Virginia.
• B.S. 1988, State University of New York at Binghamton.

---

Areas of Interest

Parasitic diseases have a devastating effect on public health in developing areas of the world. Our group's research efforts focus on approaches toward the discovery and development of new agents for the treatment of leishmaniasis, trypanosomiasis, and malaria, the protozoal parasitic diseases targeted for control or eradication by the World Health Organization. We are currently working on three major projects in this area:

Selective antiparasite antimitotic agents. Tubulin is an established target for cancer chemotherapy. Since this protein plays a critical cellular role in all eukaryotes, tubulin should also be an attractive antiparasitic drug target. Leishmanial tubulin possesses differences in drug susceptibility compared to the corresponding mammalian protein in that colchicine site mammalian microtubule inhibitors are ineffective against the parasite protein. Starting with the antimitotic herbicide oryzalin as a lead compound, which has mediocre activity against leishmanial tubulin and against parasite growth in vitro, our lab has made systematic functional group modifications to oryzalin and has synthesized compounds with potent and selective antimitotic activity against Leishmania and trypanosomes. Both N 1-phenyl-3,5-dinitro-N4,N4-di-n-propylsulfanilamide (GB-II-5) and N1-phenyl-3,5-dinitro-N4,N4-di-n-butylsulfanilamide (GB-II-150) possess selectivity for leishmanial tubulin compared to mammalian tubulin in vitro and cause a striking accumulation of Leishmania and Trypanosoma brucei in the G 2M cell cycle phases at concentrations that block parasite growth. GB-II-5 and GB-II-150 are thus exciting lead molecules against kinetoplastid parasites that selectively target tubulin in these organisms. Current work on this project aims to increase the potency of these compounds, increase their stability to in vivo metabolism, and characterize their binding to parasite tubulin.

Antiparasitic compounds from plants. Natural products continue be an important source of chemotherapeutic agents, and several find application in the treatment of parasitic disease. For instance, quinine and artemisinin are plant constituents used clinically as antimalarials in both their native form and as derivatives, and amphotericin B is a natural product from Streptomyces that is widely used for the treatment of visceral leishmaniasis. In an effort to identify natural products with antikinetoplastid activity, we have screened ethanol extracts from over 300 plants against Leishmania donovani axenic amastigote-like forms. Active extracts were further evaluated for activity against bloodstream form Trypanosoma brucei brucei and for toxicity to mammalian cell lines. Based on these results, we have thus far focused our work on two plants from the genus Psorothamnus. Bioactivity guided fractionation of an extract from P. polydenius led to the isolation of two chalcones and the red pigment dalrubone as compounds with promising antileishmanial activity. These compounds display selectivity for axenic L. donovani over Vero cells and reduce parasite burdens in L. mexicana-infected macrophages by at least 95% at concentrations of 25 m g/mL or less. Several bioactive compounds have also been isolated from the root extract of P. arborescens . Of these, a new isoflavone displays modest selectivity for L. donovani axenic amastigotes over Vero cells, and the isoflavone calycosin shows 8-fold selectivity for T. brucei over Vero cells. Our ongoing work in this area will seek to identify compounds from other plants with higher potency against parasites and to prepare analogues of promising leads in order to optimize antiparasitic activity.

Diamidines as antileishmanial drug candidates. Pentamidine is currently used for the chemotherapy of African trypanosomiasis and leishmaniasis, but its clinical utility is limited by pentamidine's route of administration (injection) and toxicity. Dicationic compounds related to pentamidine possess potent antimicrobial activity, and one such candidate is currently undergoing advanced clinical trials as an oral treatment for African trypanosomiasis. Our lab is currently involved in a collaborative effort to identify dications with improved antiparasitic activity. Antileishmanial evaluation of a broad variety of dications synthesized by our collaborators at Georgia State University and the University of North Carolina has revealed that several dicationic compounds (such as DB351 and DB702) are more active against L. donovani amastigote-like forms than pentamidine. Future roles for our lab on this project will be to identify novel dications as antileishmanial drug candidates through in vitro and in vivo assays and to elucidate the mechanism(s) of action of promising dications against the parasites.

---

Courses Taught

Pharmacy 410: Introduction to Medicinal Chemistry (team-taught course, B.S.P.S. students)

Pharmacy 411: Medicinal and Natural Products Chemistry Laboratory (team-taught course, B.S.P.S. students)

Pharmacy 462: Biomedicinal Chemistry II (B.S.P.S. students)

Pharmacy 735: Advanced Medicinal Chemistry (team-taught course, Ph.D. students)

Pharmacy 837: Chemotherapy of Infectious Diseases (Ph.D. students)

Recipient of the 2004-2005 Distinguished Teaching Award for the Bachelor of Science in the Pharmaceutical Sciences (B.S.P.S) program, The Ohio State University College of Pharmacy

---

Professional Experience

• Oct 2007 – present: Associate Professor, College of Pharmacy, The Ohio State University, Columbus, Ohio.

  Oct 2000 – 2007: Assistant Professor, College of Pharmacy, The Ohio State University, Columbus, Ohio.

  Jan 1997 – Aug 2000: Principal Investigator, Walter Reed Army Institute of Research

---