title: Novel β-carboline-quinazolinone hybrids disrupt Leishmania donovani redox homeostasis and show promising antileishmanial activity.
abstract: Visceral Leishmaniasis is a deadly parasitic disease caused by Leishmania donovani. Paucity exists in the discovery of novel chemotherapeutics against Leishmaniasis. In this study, we synthesized a natural product inspired Diversity Oriented Synthesis library of L. donovani Trypanothione reductase (LdTR) inhibitor β-carboline-quinazolinone hybrids, which are different in stereochemical architecture and diverse in the bioactive chemical space. It is noteworthy that chirality affects drug-to-protein binding affinity since proteins in any living system are present only in one of the chiral forms. Upon evaluation of the hybrids, one of the chiral forms i.e. Compound 1 showed profound cytotoxic effect in micromolar range as compared to its other chiral form i.e. Compound 2. In-silico docking studies confirmed high binding efficiency of Compound 1 with the catalytic pocket of LdTR. Treatment of L. donovani parasites with Compound 1 inhibits LdTR activity, induces imbalance in redox homeostasis by enhancing ROS, disrupts the mitochondrial membrane potential, modifies actin polymerization and alters the surface topology and architecture. All these cellular modifications eventually led to apoptosis-like death of promastigotes. Furthermore, we synthesized the analogues of Compound 1 and found that these compounds show profound antileishmanial activity in the nanomolar range both in promastigotes and intracellular amastigotes. The enhanced inhibitory potential of these compounds was further supported by in-silico analysis of protein-ligand interactions which revealed high binding efficiency towards the catalytic pocket of LdTR. Taken together, this study reports the serendipitous discovery of β-carboline-quinazolinone hybrids with enhanced antileishmanial activity along with the in-depth structure-activity relationships and mechanism of action of these analogues.
authors.affiliation: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: Dandugudumula
authors.initials: D
authors.lastname: Ramu
authors.affiliation: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: Swati
authors.initials: S
authors.lastname: Garg
authors.affiliation: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: R
authors.initials: R
authors.lastname: Ayana
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: A K
authors.initials: AK
authors.lastname: Keerthana
authors.affiliation: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: Vijeta
authors.initials: V
authors.lastname: Sharma
authors.affiliation: Department of Physics, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: C P
authors.initials: CP
authors.lastname: Saini
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Sen
authors.affiliation: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, India.
authors.forename: Soumya
authors.initials: S
authors.lastname: Pati
authors.affiliation: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, India; Special Centre for Molecular Medicine, Jawaharlal Nehru University, New Delhi, India. Electronic address: shailjasingh@mail.jnu.ac.in.
authors.forename: Shailja
authors.initials: S
authors.lastname: Singh
mesh_terms: D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002243:Carbolines / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D007893:Leishmania donovani / Q000187:drug effects* / Q000378:metabolism; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D010084:Oxidation-Reduction; D052999:Quinazolinones / Q000737:chemistry / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D000981:Antiprotozoal Agents; D002243:Carbolines; D052999:Quinazolinones; D017382:Reactive Oxygen Species; C010262:norharman
keywords: Atomic Force Microscopy; Drug development; In-silico docking; Leishmania donovani; Trypanothione reductase; β-Carboline-quinazolinone hybrid