title: Identification of Leishmania donovani Topoisomerase 1 inhibitors via intuitive scaffold hopping and bioisosteric modification of known Top 1 inhibitors.
abstract: A library of arylidenefuropyridinediones was discovered as potent inhibitors of Leishmania donovani Topoisomerase 1 (LdTop1) where the active molecules displayed considerable inhibition with single digit micromolar EC50 values. This molecular library was designed via intuitive scaffold hopping and bioisosteric modification of known topoisomerase 1 inhibitors such as camptothecin, edotecarin and etc. The design was rationalized by molecular docking analysis of the compound prototype with human topoisomerase 1 (HTop1) and Leishmania donovani topoisomerase 1(LdTop1). The most active compound 4 displayed no cytotoxicity against normal mammalian COS7 cell line (~100 fold less inhibition at the EC50). Similar to camptothecin, 4 interacted with free LdTop1 as observed in the preincubation DNA relaxation inhibition experiment. It also displayed anti-protozoal activity against Leishmania donovani promastigote. Crystal structure investigation of 4 and its molecular modelling with LdTop1 revealed putative binding sites in the enzyme that could be harnessed to generate molecules with better potency.
authors.affiliation: Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500085, Telangana, India.|GVK Bioscience, 28A IDA Nacharam, Hyderabad, Telengana, India.
authors.forename: Rajinikanth
authors.initials: R
authors.lastname: Mamidala
authors.affiliation: Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India.
authors.forename: Papiya
authors.initials: P
authors.lastname: Majumdar
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar 201314, Uttar Pradesh, India.
authors.forename: Kunal Kumar
authors.initials: KK
authors.lastname: Jha
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar 201314, Uttar Pradesh, India.
authors.forename: Chandramohan
authors.initials: C
authors.lastname: Bathula
authors.affiliation: Department of Life Sciences, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar 201314, Uttar Pradesh, India.
authors.forename: Rahul
authors.initials: R
authors.lastname: Agarwal
authors.affiliation: Department of Chemistry, Jawaharlal Nehru Technological University, Kukatpally, Hyderabad 500085, Telangana, India.
authors.forename: M Thirumala
authors.initials: MT
authors.lastname: Chary
authors.affiliation: Institute of Chemical Biology, 4 Raja S.C. Mullick Road, Kolkata 700032, West Bengal, India.
authors.forename: Hemanta K
authors.initials: HK
authors.lastname: Majumder
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar 201314, Uttar Pradesh, India.
authors.forename: Parthapratim
authors.initials: P
authors.lastname: Munshi
authors.affiliation: Department of Chemistry, School of Natural Sciences, Shiv Nadar University, Chithera, Dadri, Gautam Buddha Nagar 201314, Uttar Pradesh, India.
authors.forename: Subhabrata
authors.initials: S
authors.lastname: Sen
mesh_terms: D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D018360:Crystallography, X-Ray; D004264:DNA Topoisomerases, Type I / Q000737:chemistry / Q000378:metabolism; D007893:Leishmania donovani / Q000201:enzymology* / Q000235:genetics; D007898:Leishmaniasis, Visceral / Q000188:drug therapy / Q000201:enzymology; D008958:Models, Molecular; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D059004:Topoisomerase I Inhibitors / Q000737:chemistry / Q000494:pharmacology
chemical_list: D015800:Protozoan Proteins; D059004:Topoisomerase I Inhibitors; D004264:DNA Topoisomerases, Type I