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.

The global preponderance of diabetes mellitus has prompted the medical community to opt for various therapeutic solutions to curb the menace. One of the means involved controlling the post prandial hyperglycemia. α-glucosidase inhibitors are known to be excellent agents of controlling postprandial hyperglycemia. Different classes of α-glucosidase inhibitors has been discovered.In this context, a diverse library of substituted furopyridinediones (12a-v) was designed as potential inhibitors of α-glucosidase, using an intuitive scaffold hopping approach (which was further rationalized by molecular docking). They were synthesized in one step via an aldol condensation reaction of furopyridinedione scaffold and appropriate aldehydes. The compounds were screened against α-glucosidase using acarbose as the reference inhibitor. Among the screened compounds, 12p transpired to be the lead candidate with an IC 50 of 0.24 µM.Lineweaver Burke analysis of 12p indicated it to be a mixed inhibitor. X-ray crystallography of 12p further confirmed its structure. Molecular modelling studies and molecular dynamic simulation experiments were performed against a homology model of α-glucosidase to observe the binding interaction of 12p with the enzymes.

A versatile stereoselective diversity oriented synthetic pathway to the possible spiro and fused diverse heterocyclic small molecules is described. The strategy involved the "build-couple-pair" approach involving an S N Ar, Michael addition and Mannich reaction on chiral acyl bicyclic lactams 2a/b, followed by a cyclization onto the inbuilt scaffold electrophile, thereby leading to asymmetric fused and spirocyclic nitrogen heterocycles. A "post-pair" phase has been incorporated to generate more polar compounds. We used Principal Component Analysis (PCA) and polar moment of inertia to evaluate the shape-space diversity of our scaffolds with respect to a commercial database and observed extraordinary diversity within the scaffold network. We further calculated the polar surface area (PSA) of our molecules which is an indicator for drug cell permeability.

Scientific Reports 6: Article number: 26603; published online: 25 May 2016; updated: 20 June 2016 The original version of this Article contained errors in the spelling of the author Hemanta K. Majumder which was incorrectly given as H. K. Mazumdar. This has now been corrected in the PDF and HTML versions of the Article.

The presented “build‐couple‐pair”‐approach involves an SNAr, Michael addition as well as Mannich reaction.