Development of Thiophene Compounds as Potent Chemotherapies for the Treatment of Cutaneous Leishmaniasis Caused by Leishmania major

Molecules. 2018 Jul 4;23(7):1626. doi: 10.3390/molecules23071626.


Leishmania major (L. major) is a protozoan parasite that causes cutaneous leishmaniasis. About 12 million people are currently infected with an annual incidence of 1.3 million cases. The purpose of this study was to synthesize a small library of novel thiophene derivatives, and evaluate its parasitic activity, and potential mechanism of action (MOA). We developed a structure⁻activity relationship (SAR) study of the thiophene molecule 5A. Overall, eight thiophene derivatives of 5A were synthesized and purified by silica gel column chromatography. Of these eight analogs, the molecule 5D showed the highest in vitro activity against Leishmania major promastigotes (EC50 0.09 ± 0.02 µM), with an inhibition of the proliferation of intracellular amastigotes higher than 75% at only 0.63 µM and an excellent selective index. Moreover, the effect of 5D on L. major promastigotes was associated with generation of reactive oxygen species (ROS), and in silico docking studies suggested that 5D may play a role in inhibiting trypanothione reductase. In summary, the combined SAR study and the in vitro evaluation of 5A derivatives allowed the identification of the novel molecule 5D, which exhibited potent in vitro anti-leishmanial activity resulting in ROS production leading to cell death with no significant cytotoxicity towards mammalian cells.

Keywords: Leishmania major; chemotherapy; cutaneous leishmaniasis; drug screening; in silico docking; reactive oxygen species; structure–activity relationship (SAR); thiophene compounds.

MeSH terms

  • Animals
  • Antiprotozoal Agents / chemical synthesis*
  • Antiprotozoal Agents / chemistry
  • Antiprotozoal Agents / pharmacology
  • Cell Line
  • Drug Evaluation, Preclinical
  • Leishmania major / drug effects*
  • Leishmania major / metabolism
  • Leishmaniasis, Cutaneous / drug therapy
  • Mice
  • Mice, Inbred BALB C
  • Models, Molecular
  • Molecular Docking Simulation
  • Molecular Structure
  • NADH, NADPH Oxidoreductases / antagonists & inhibitors*
  • Protozoan Proteins / antagonists & inhibitors
  • Reactive Oxygen Species / metabolism
  • Small Molecule Libraries / chemical synthesis*
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / pharmacology
  • Structure-Activity Relationship
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology


  • Antiprotozoal Agents
  • Protozoan Proteins
  • Reactive Oxygen Species
  • Small Molecule Libraries
  • Thiophenes
  • NADH, NADPH Oxidoreductases
  • trypanothione reductase