title: Diversity-oriented synthesis and activity evaluation of substituted bicyclic lactams as anti-malarial against Plasmodium falciparum.
abstract: BACKGROUND
  Malaria remains the world's most important devastating parasitic disease. Of the five species of Plasmodium known to infect and cause human malaria, Plasmodium falciparum is the most virulent and responsible for majority of the deaths caused by this disease. Mainstream drug therapy targets the asexual blood stage of the malaria parasite, as the disease symptoms are mainly associated with this stage. The prevalence of malaria parasite strains resistance to existing anti-malarial drugs has made the control of malaria even more challenging and hence the development of a new class of drugs is inevitable.
  
  
  METHODS
  Screening against different drug resistant and sensitive strains of P. falciparum was performed for few bicyclic lactam-based motifs, exhibiting a broad spectrum of activity with low toxicity generated via a focussed library obtained from diversity oriented synthesis (DOS). The synthesis and screening was followed by an in vitro assessment of the possible cytotoxic effect of this class of compounds on malaria parasite.
  
  
  RESULTS
  The central scaffold a chiral bicyclic lactam (A) and (A') which were synthesized from (R)-phenylalaninol, levulinic acid and 3-(2-nitrophenyl) levulinic acid respectively. The DOS library was generated from A and from A', by either direct substitution with o-nitrobenzylbromide at the carbon α- to the amide functionality or by conversion to fused pyrroloquinolines. Upon screening this diverse library for their anti-malarial activity, a dinitro/diamine substituted bicyclic lactam was found to demonstrate exceptional activity of >85% inhibition at 50 μM concentration across different strains of P. falciparum with no toxicity against mammalian cells. Also, loss of mitochondrial membrane potential, mitochondrial functionality and apoptosis was observed in parasite treated with diamine-substituted bicyclic lactams.
  
  
  CONCLUSIONS
  This study unveils a DOS-mediated exploration of small molecules with novel structural motifs that culminates in identifying a potential lead molecule against malaria. In vitro investigations further reveal their cytocidal effect on malaria parasite growth. It is not the first time that DOS has been used as a strategy to identify therapeutic leads against malaria, but this study establishes the direct implications of DOS in scouting novel motifs with anti-malarial activity.
authors.forename: Vijeta
authors.initials: V
authors.lastname: Sharma
authors.forename: Shalini
authors.initials: S
authors.lastname: Agarwal
authors.forename: Sanjay M
authors.initials: SM
authors.lastname: Madurkar
authors.forename: Gaurav
authors.initials: G
authors.lastname: Datta
authors.forename: Poonam
authors.initials: P
authors.lastname: Dangi
authors.forename: Ramu
authors.initials: R
authors.lastname: Dandugudumula
authors.affiliation: Shiv Nadar University, Gautam Budh Nagar, UP 203207, India. subhabrata.sen@snu.edu.in.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Sen
authors.forename: Shailja
authors.initials: S
authors.lastname: Singh
mesh_terms: D000962:Antimalarials / Q000138:chemical synthesis* / Q000494:pharmacology*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000138:chemical synthesis / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology*; D007982:Levulinic Acids / Q000138:chemical synthesis / Q000494:pharmacology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000254:growth & development / Q000502:physiology
chemical_list: D000962:Antimalarials; D019086:Bridged Bicyclo Compounds, Heterocyclic; D007769:Lactams; D007982:Levulinic Acids