Chandana Lakshmi T. Meda

Novel N-indolylmethyl substituted olanzapine derivatives: their design, synthesis and evaluation as PDE4B inhibitors

A new strategy for converting antipsychotic drug olanzapine into PDE4 inhibitors is described via the design and Pd/C mediated synthesis of novel N-indolylmethyl olanzapine derivatives. One compound showed good inhibition (IC50 1.1 μM) and >10 fold selectivity towards PDE4B over D that was supported by docking studies. This compound also showed significant inhibition of TNF-α and no major toxicities in cell lines and a zebrafish embryo model except the teratogenic effects to be re-assessed in rodents.

Novel 1-alkynyl substituted 1,2-dihydroquinoline derivatives from nimesulide (and their 2-oxo analogues): A new strategy to identify inhibitors of PDE4B

A number of novel 1-(3-arylprop-2-ynyl) substituted 1,2-dihydroquinoline derivatives related to nimesulide and their 2-oxo analogues have been designed as potential inhibitors of PDE4. All these compounds were synthesized by using Sonogashira coupling as a key step. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized are presented.

Pyrrolo[2,3-b]quinoxalines as inhibitors of firefly luciferase: Their Cu-mediated synthesis and evaluation as false positives in a reporter gene assay

2-Substituted pyrrolo[2,3-b]quinoxalines having free NH were prepared directly from 3-alkynyl-2-chloroquinoxalines in a single pot by using readily available and inexpensive methane sulfonamide (or p-toluene sulfonamide) as an ammonia surrogate. The reaction proceeded in the presence of Cu(OAc)(2) affording the desired product in moderate yield. The crystal structure analysis of a representative compound and its supramolecular interactions are presented. Some of the compounds synthesized exhibited inhibitory activities against luciferase that was supported by the predictive binding mode of these compounds with luciferase enzyme through molecular docking studies. The key observations disclosed here can alert users of luciferase reporter gene assays for possible false positive results due to the direct inhibition of luciferase.

Yb(OTf)3 mediated MCR: a new and regioselective approach towards polysubstituted pyrroles of pharmacological interest

A regioselective synthesis of 1,2,3,4-tetrasubstituted pyrroles has been achieved via Yb(OTf)3-mediated 3-component reaction of amines, a 1,3-diketone and phenacyl bromide in a single pot. Yb(OTf)3 was identified as a reusable catalyst and a number of pyrrole derivatives were prepared by using this strategy. Single crystal X-ray diffraction study of a representative compound confirmed the substitution pattern on the central pyrrole ring. The crystal structure analysis of the same compound indicated the presence of a sheet-like molecular arrangement along the bc-plane present in the molecule. A possible mechanism for the regioselective formation of 1,2,3,4-tetrasubstituted pyrrole rings is discussed. A number of compounds synthesized showed PDE4 inhibitory properties when tested in vitro and two of them were identified as inhibitors of further interest.

Novel thieno[2,3-d]pyrimidines: their design, synthesis, crystal structure analysis and pharmacological evaluation.

Novel thieno[2,3-d]pyrimidines containing a cyclohexane ring fused with a six- or five-membered heterocyclic moiety along with a benzylic nitrile were designed as potential inhibitors of PDE4. Expeditious synthesis of these compounds was carried out via a multi-step sequence consisting of a few key steps such as Gewald reaction, Dieckmann type cyclisation and Krapcho decarboxylation. This newly developed strategy involved construction of the thienopyrimidine ring followed by the cyclohexanone moiety and subsequently the fused heterocyclic ring. A number of thieno[2,3-d]pyrimidine based derivatives were synthesized using this method some of which showed promising PDE4B inhibitory properties. One of them was tested for PDE4D inhibition in vitro and dose dependent inhibition of TNF-α. A few selected molecules were docked into the PE4B protein the results of which showed good overall correlations to their observed PDE4B inhibitory properties in vitro. The crystal structure analysis of representative compounds along with hydrogen bonding patterns and molecular arrangement present within the molecule is described.

Pd-mediated functionalization of polysubstituted pyrroles: Their evaluation as potential inhibitors of PDE4

Novel polysubstituted pyrroles have been designed and accessed via a one-pot multicomponent reaction followed by Pd-mediated C-C bond forming reactions. All the compounds synthesized were tested for their PDE4B inhibitory properties in vitro and two of them obtained via Heck reaction showed significant inhibition. The docking results suggested that these alkenyl derivatives containing ester moiety interact well with the PDE4B protein in silico where the ester carbonyl oxygen played a key role. The pyrrole framework presented here could be a new template for the identification of small molecule based novel inhibitors of PDE4. The single crystal X-ray data of a representative compound is presented.

Montmorillonite K-10 catalyzed green synthesis of 2,6-unsubstituted dihydropyridines as potential inhibitors of PDE4.

Montmorillonite K-10 mediated MCR of anilines, arylaldehydes and ethyl-3,3-diethoxypropionate in water afforded 2,6-unsubstituted dihydropyridines depending on the nature of anilines employed. A variety of dihydropyridines were prepared by using this green methodology in good yields and montmorillonite K-10 was found to be an inexpensive and reusable catalyst. The structure elaboration of a representative compound was carried out under Heck conditions. Some of the compounds synthesized showed significant inhibition of PDE4B when tested in vitro. Docking studies indicated that one of the ester moieties of these compounds played a key role in their interactions with the PDE4B protein.

Discovery of novel 1,4-dihydropyridine-based PDE4 inhibitors.

Substituted 1,4-dihydropyridines were discovered as a novel and potent series of phosphodiesterase 4 (PDE4) inhibitors. Structure-activity relationships within this series have been carried out and studies revealed that the dihydropyridine core, with indole moiety and 3,4-dimethoxybenzyl group, is a potent analogue for PDE4 inhibition. These novel series of compounds were prepared via a 3-component reaction in a single pot. In vitro biological activity, modeling studies and crystallography data are also reported.

(Pd/C-mediated)coupling–iodocyclization–coupling strategy in discovery of novel PDE4 inhibitors: a new synthesis of pyrazolopyrimidines

Pyranones fused with a pyrazolopyrimidine moiety were prepared via regioselective construction of pyranone ring using (Pd/C-mediated)coupling–iodocyclization followed by Sonogashira/Heck/Suzuki reactions. The pyrazolopyrimidine based reactant required was obtained via a new H3PO3 mediated condensation reaction. This strategy has led to the discovery of a novel and potentially safe PDE4 inhibitor.

Design and synthesis of 4-alkynyl pyrazoles as inhibitors of PDE4: a practical access via Pd/C-Cu catalysis.

The design and synthesis of 4-alkynyl pyrazole derivatives has led to the identification of new class of PDE4 inhibitors. All these compounds were accessed for the first time via a facile Pd/C-CuI-PPh(3) mediated C-C bond forming reaction between an appropriate pyrazole iodide and various terminal alkynes. In vitro PDE4B inhibitory properties and molecular modeling studies of some of the compounds synthesized indicated that 4-alkynyl pyrazole could be a promising template for the discovery of novel PDE4 inhibitors.