title: Ursolic Acid, a Natural Pentacylcic Triterpene fromOchrosia ellipticaand Its Role in The Management of Certain Neglected Tropical Diseases.
abstract: BACKGROUND
  Leishmaniasis and African trypanosomiasis are recognized as the leading causes of mortality and morbidity with the greatest prevalence in the developing countries. They affect more than one billion of the poorest people on the globe.
  
  
  OBJECTIVE
  To find a cheap, affordable, safe, and efficacious antileshmanial and antitrypanosomal natural drug and to elucidate its probable mode of action.
  
  
  METHODS
  Phytochemical investigation of the non-polar fraction of the methanol extract of leaves ofOchrosia ellipticaLabill. (Apocyanaceae) resulted in the isolation of ursolic acid, which was unambiguously determined based on HR-ESI-FTMS, extensive 1D and 2D NMR spectroscopy. It was further tested for its cytotoxicity, antimicrobial, antimalarial, antileishmanial, and trypanocidal potency.in-silicomolecular modeling studies were conducted on six vital parasitic enzymes including farnesyl diphosphate synthase,N-myristoyl transferase, pteridine reductase 1, trypanothione reductase, methionyl-tRNA synthetase, and inosine-adenosine-guanosine nucleoside hydrolase to discover its potential mode of action as antitrypanosomal and antileishmanial agent.
  
  
  RESULTS
  Ursolic acid displayed considerable antitrypanosomal and antileishmanial activities with IC50values ranging between 1.53 and 8.79 μg/mL. It showed superior antitrypanosomal activity as compared to the standard drug difluoromethylornithine (DFMO), with higher binding affinities towards trypanothione reductase and pteridine reductase 1. It displayed free binding energy of -30.73 and -50.08 kcal/mole towards the previously mentioned enzymes, respectively. In addition, ursolic acid exhibited considerable affinities to farnesyl diphosphate synthase,N-myristoyl transferase and methionyl-tRNA synthetase with free binding energies ranging from -42.54 to -63.93 kcal/mole.
  
  
  CONCLUSIONS
  Ursolic acid offers a safe, effective and cheap antitrypanosomal and antileishmanial candidate acting on several key parasitic enzymes.
  
  
  CONCLUSIONS
  The fresh leaves ofOchrosia ellepticaLabill., family Apocyanaceae are a reliable source of ursolic acid.Ursolic acid displayed considerable antitrypanosomal and antileishmanial activities. It showed superior antitrypanosomal activity as compared to difluoromethylornithine (DFMO), potent antitrypanosomal reference drug.In silicomolecular modeling studies revealed that the antileishmanial and antitrypanosomal activities of ursolic acid could be partially explained in view of its multiple inhibitory effects on vital parasitic enzymes with the highest potency exerted in the inhibition of pteridine reductase 1 and trypanothione reductase.Abbreviations used:AHT: African Human Trypanosomiasis, ATCC: American type cell culture, BuOH:n-butanol, DCM: dichloromethane, DFMO: difluoromethylornithine, EtOAc: ethyl acetate, FCS: fetal calf serum, HMBC: Heteronuclear Multiple Bond Correlation, HMQC: Heteronuclear Multiple-Quantum Correlation, HR-ESI-FTMS: High Resolution Electrospray ionozation Mass Spectrometry, MENA: Middle East and North Africa, MeOH: Methanol, MRSA: Methicillin-resistantStaphylococcus aureus, NTDs: Neglected tropical diseases, TLC: Thin layer chromatography, UA: Ursolic acid, UV: Ultra violet, WHO: World Health Organization.
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; National Center for Natural Products Research, MS, USA.
authors.forename: Rola M
authors.initials: RM
authors.lastname: Labib
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Sherif S
authors.initials: SS
authors.lastname: Ebada
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Fadia S
authors.initials: FS
authors.lastname: Youssef
authors.affiliation: Department of Pharmacognosy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt.
authors.forename: Mohamed L
authors.initials: ML
authors.lastname: Ashour
authors.affiliation: National Center for Natural Products Research, MS, USA; Department of BioMolecular Sciences, School of Pharmacy, University of Mississippi, University, MS, USA.
authors.forename: Samir A
authors.initials: SA
authors.lastname: Ross
keywords: Antileishmanial; Ochrosia elliptica; antitrypanosomal; ursolic acid; virtual screening