Discovery of thiazolyl-phthalazinone acetamides as potent glucose uptake activators via high-throughput screening

Agrawal, Madhavi; Kharkar, Prashant S.; Moghe, Sonali; Mahajan, Tushar; Deka, Vaishali; Thakkar, Chandni; Nair, Amrutha; Mehta, Chirag; Bose, Julie; Kulkarni-Almeida, Asha; Bhedi, D. N.; Vishwakarma, Ram A.

doi:10.1016/j.bmcl.2013.07.067

Cited by 23 publications

(12 citation statements)

References 7 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In organic synthesis, N ‐protected amino acids are essential key precursors and have been used in many areas, for example, peptide synthesis, medicinal chemistry, as chiral sources, and polymer materials . And in the recent years, they got interest because of their magnificent pharmacological and therapeutic properties, and phthalazines linked amino acid derivatives as a new class of promising antimicrobial, antitumor, anihypertensive, antidiabetic,anti‐inflammatory, and vesarelaxant activities . The integration of amino acid residues in various oxygen‐,nitrogen‐, and sulfur‐containing heterocycles sometimes enhances the biological profile manifold over that of its parent nucleus .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of novel phthalazine derivatives as pharmacological activities

Wasfy

Aly

Behalo

et al. 2019

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

Phthalazine derivatives attached to amino acid derivatives were synthesized with high yields. The reaction of phthalazine derivatives with different phthalyl and tosylamino acids such as glycine, alanine, phenylalanine, valine, serine, and threonine in the presence of N,N-dicyclo hexylcarbodiimide (DCC) as a dehydrating agent reagent yielded high yields of the afforded compounds.Phthalylamino acids derivatives were obtained by deprotection of phthalazine derivatives, with the latter heating with hydrazine hydrate. The chemical structures of all phthalazine derivatives were affirmed by elemental analysis and spectral data (IR, MS, 1 HNMR, and 13 C NMR). Screening out and estimation of the synthesized derivatives for their cytotoxic and antioxidant activity were done, and most of them showed powerful activity in comparison with standard drugs.We got all chemical reagents from Sigma-Aldrich. Solvents were purchased from El-Nasr Chemicals in analytical grade. Also, we did thin-layer chromatography (TLC) on all products by using silica gel polyester sheets (Kieselgel 60 F254, 0.20 mm, Merck). All melting points are in degree centigrade (uncorrected). We recorded IR spectra (KBr) at the Microanalytical Center (Faculty of S C H E M E 1 Synthesis of phthalazinone derivative 2 S C H E M E 2 Synthesis of phthalazines derivative (4,5) WASFY ET AL.

show abstract

Section: Introductionmentioning

confidence: 99%

Synthesis of novel phthalazine derivatives as pharmacological activities

Wasfy

Aly

Behalo

et al. 2019

Journal of Heterocyclic Chem

View full text Add to dashboard Cite

show abstract

“…14,17 Hydrazine monohydrate (0.47 mL, 9.0 mmol) was added dropwise to a solution of ethyl (E)-2-(3-oxoisobenzofuran-1(3H)ylidene)acetate 18 (1.97 g, 9.03 mmol) in ethanol (10 mL 8, 159.4, 140.9, 133.6, 131.7, 129.4, 127.5, 125.9, 125.5, 60.7, 37.9, 14.0; 1 H NMR spectroscopic data consistent with literature. 17 Oxo-3,4-dihydrophthalazin-1-yl 13 C NMR (100 MHz, (CD3)2SO) 171. 4, 159.5, 141.5, 133.5, 131.6, 129.6, 127.5, 125.9, 125.6, 38.2; 1 H NMR spectroscopic data consistent with literature.…”

Section: Discussionmentioning

confidence: 99%

Targeting of Fumarate Hydratase from Mycobacterium tuberculosis Using Allosteric Inhibitors with a Dimeric-Binding Mode

et al. 2019

View full text Add to dashboard Cite

With the growing worldwide prevalence of antibiotic-resistant strains of tuberculosis (TB), new targets are urgently required for the development of treatments with novel modes of action. Fumarate hydratase (fumarase), a vulnerable component of the citric acid cycle in Mycobacterium tuberculosis (Mtb), is a metabolic target that could satisfy this unmet demand. A key challenge in the targeting of Mtb fumarase is its similarity to the human homolog, which shares an identical active site. A potential solution to this selectivity problem was previously found in a highthroughput screening hit that binds in a non-conserved allosteric site. Optimization of this inhibitor is complicated by its unique dimeric-binding mode, with the two molecules in the allosteric site interacting with each other in addition to holding together two of the protein subunits in an inactive conformation. In this work, a structure-activity relationship study was carried out with the determination of further structural biology on the lead series, affording derivatives with submicromolar inhibition. Further, the screening of this series against Mtb in vitro identified compounds with potent MICs. Together, these results encourage further work on Mtb fumarase as a target for the development of compounds with bactericidal activity.

show abstract

“…Some pthalazinones containing the thiazolidine-2,4-dione pharmacophore (compound 36, Figure 8) were described as potent in vitro PPARγ activators, showing both plasma glucose and triglycerides lowering activity in vivo, in insulin resistant db/db mice [15]. In addition, the Nsubstituted phthalazinone acetamide scaffold was recently identified as potential glucose uptake activator by using a high throughput screening (HTS) assay [75] and several derivatives were synthesized. The in vitro preliminary screening results indicated that the active compounds increased glucose uptake in skeletal muscle cells (L6 rat myotubes) without inducing PPARγ agonist activity.…”

Section: Figure 7 Comes About Herementioning

confidence: 99%