Sonal Bhandari - Academia.edu (original) (raw)
Papers by Sonal Bhandari
Chemical Biology & Drug Design, 2020
Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and ... more Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and a potential antileishmanial target for its role in N‐terminal methionine processing. As an effort towards new inhibitor discovery against methionine aminopeptidase 1 from Leishmania donovani (LdMetAP1), we have synthesized a series of quinoline‐based hybrids, that is (Z)‐5‐((Z)‐benzylidine)‐2‐(quinolin‐3‐ylimino)thiazolidin‐4‐ones (QYT‐4a‐i) whose in vitro screening led to the discovery of a novel inhibitor molecule (QYT‐4h) against LdMetAP1. The compound QYT‐4h showed nearly 20‐fold less potency for human MetAP1 and had drug‐like features. Time–course kinetic assays suggested QYT‐4h acting through a competitive mode by binding to the metal‐activated catalytic site. Notably, QYT‐4h was most potent against the physiologically relevant Mn(II) and Fe(II) supplemented forms of LdMetAP1 and less potent against Co(II) supplemented form. Surface plasmon resonance and fluorescence spectroscopy demonstrated high affinity of QYT‐4h for LdMetAP1. Through molecular modelling and docking studies, we found QYT‐4h binding at the LdMetAP1 catalytic pocket occupying both the catalytic and substrate binding sites mostly with hydrogen bonding and hydrophobic interactions which provide structural basis for its promising potency. These results demonstrate the feasibility of employing small‐molecule inhibitors for selective targeting of LdMetAP1 which may find use to effectively eliminate leishmaniasis.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
RSC Advances, 2020
Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrrolo... more Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrroloindolines and benzofurano-pyrrolidines via a Lewis acid-catalyzed domino ring-opening annulation using activated spiro-aziridines and heteroarenes.
European Journal of Medicinal Chemistry, 2020
The development of new small molecules from known structural motifs through molecular hybridizati... more The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 μM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.
Tetrahedron Letters, 2020
Abstract An efficient one-pot method for the construction of C–C and C–N bond has been establishe... more Abstract An efficient one-pot method for the construction of C–C and C–N bond has been established from activated spiro-aziridine oxindoles using different substituted 2-naphthols by employing BF3‧OEt2 as a catalyst. This method features spiro-aziridine ring-opening (Friedel-Crafts type C–C bond formation) with concomitant dehydrative formal [3+2] cycloaddition leading to the formation of a complex and diverse benzoindoline fused spiro-oxindoles in moderate to good yields with wide substrate scope. Moreover, this protocol provides an avenue for the generation of a library of bioactive spiro-cyclic fused heterocyclic motifs which may prove to be of therapeutic interest.
Organic & Biomolecular Chemistry, 2021
Herein, we report the first dithiocarbamation of spiro-aziridine oxindoles involving regiospecifi... more Herein, we report the first dithiocarbamation of spiro-aziridine oxindoles involving regiospecific ring-opening by in situ generated nucleophilic dithiocarbamates as an instant source of sulfur. This approach afforded C3-functionalised-3-thiooxindoles in good...
Journal of Diabetes Science and Technology, 2011
Chemical Biology & Drug Design, 2020
Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and ... more Methionine aminopeptidase 1 (MetAP1) is a target for drug discovery against many adversaries and a potential antileishmanial target for its role in N‐terminal methionine processing. As an effort towards new inhibitor discovery against methionine aminopeptidase 1 from Leishmania donovani (LdMetAP1), we have synthesized a series of quinoline‐based hybrids, that is (Z)‐5‐((Z)‐benzylidine)‐2‐(quinolin‐3‐ylimino)thiazolidin‐4‐ones (QYT‐4a‐i) whose in vitro screening led to the discovery of a novel inhibitor molecule (QYT‐4h) against LdMetAP1. The compound QYT‐4h showed nearly 20‐fold less potency for human MetAP1 and had drug‐like features. Time–course kinetic assays suggested QYT‐4h acting through a competitive mode by binding to the metal‐activated catalytic site. Notably, QYT‐4h was most potent against the physiologically relevant Mn(II) and Fe(II) supplemented forms of LdMetAP1 and less potent against Co(II) supplemented form. Surface plasmon resonance and fluorescence spectroscopy demonstrated high affinity of QYT‐4h for LdMetAP1. Through molecular modelling and docking studies, we found QYT‐4h binding at the LdMetAP1 catalytic pocket occupying both the catalytic and substrate binding sites mostly with hydrogen bonding and hydrophobic interactions which provide structural basis for its promising potency. These results demonstrate the feasibility of employing small‐molecule inhibitors for selective targeting of LdMetAP1 which may find use to effectively eliminate leishmaniasis.
An entry from the Cambridge Structural Database, the world's repository for small molecule cr... more An entry from the Cambridge Structural Database, the world's repository for small molecule crystal structures. The entry contains experimental data from a crystal diffraction study. The deposited dataset for this entry is freely available from the CCDC and typically includes 3D coordinates, cell parameters, space group, experimental conditions and quality measures.
RSC Advances, 2020
Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrrolo... more Herein, we report a facile tandem approach for the synthesis of both spiro-oxindole-fused pyrroloindolines and benzofurano-pyrrolidines via a Lewis acid-catalyzed domino ring-opening annulation using activated spiro-aziridines and heteroarenes.
European Journal of Medicinal Chemistry, 2020
The development of new small molecules from known structural motifs through molecular hybridizati... more The development of new small molecules from known structural motifs through molecular hybridization is one of the trends in drug discovery. In this connection, we have combined the two pharmacophoric units (pyrimidine and thioindole) in a single entity via molecular hybridization strategy along with introduction of urea functionality at C2 position of pyrimidine to increase the efficiency of H-bonding interactions. Among the synthesized conjugates 12a-aa, compound 12k was found to exhibit significant IC50 values 5.85, 7.87, 6.41 and 10.43 μM against MDA-MB-231 (breast), HepG2 (liver), A549 (lung) and PC-3 (prostate) cancer cell lines, respectively. All these compounds were further evaluated for their inhibitory activities against VEGFR-2 protein. The results specified that among the tested compounds, 12d, 12e, 12k, 12l, 12p, 12q, 12t and 12u prominently suppressed VEGFR-2, with IC50 values of 310-920 nM in association to the positive control (210 nM). Angiogenesis inhibition was evident by tube formation assay in HUVECs and cell-invasion by transwell assay. The mechanism of cellular toxicity on MDA-MB-231 was found through depolarisation of mitochondrial membrane potential, increased ROS production and subsequent DNA damage resulting in apoptosis induction. Moreover, clonogenic and wound healing assays designated the inhibition of colony formation and cell migration by 12k in a dose-dependent manner. Molecular docking studies also shown that compound 12k capably intermingled with catalytically active residues GLU-885, ASP-1046 of the VEGFR-2 through hydrogen-bonding interactions.
Tetrahedron Letters, 2020
Abstract An efficient one-pot method for the construction of C–C and C–N bond has been establishe... more Abstract An efficient one-pot method for the construction of C–C and C–N bond has been established from activated spiro-aziridine oxindoles using different substituted 2-naphthols by employing BF3‧OEt2 as a catalyst. This method features spiro-aziridine ring-opening (Friedel-Crafts type C–C bond formation) with concomitant dehydrative formal [3+2] cycloaddition leading to the formation of a complex and diverse benzoindoline fused spiro-oxindoles in moderate to good yields with wide substrate scope. Moreover, this protocol provides an avenue for the generation of a library of bioactive spiro-cyclic fused heterocyclic motifs which may prove to be of therapeutic interest.
Organic & Biomolecular Chemistry, 2021
Herein, we report the first dithiocarbamation of spiro-aziridine oxindoles involving regiospecifi... more Herein, we report the first dithiocarbamation of spiro-aziridine oxindoles involving regiospecific ring-opening by in situ generated nucleophilic dithiocarbamates as an instant source of sulfur. This approach afforded C3-functionalised-3-thiooxindoles in good...
Journal of Diabetes Science and Technology, 2011