Lida Tang

Design, synthesis and antibacterial activity of novel actinonin derivatives containing benzimidazole heterocycles

A series of novel actinonin derivatives containing a benzimidazole heterocycle linked as amide isostere have been designed and synthesized. The structures of all the synthesized compounds were confirmed by analytical and spectroscopic methods. All the compounds were evaluated in vitro against Staphylococcus aureus, Klebsiella pneumoniae, and Sarcina lutea. Among them, compound 1a with unsubstituted benzimidazole ring exhibited potent antibacterial activities.

Synthesis and preliminary antibacterial evaluation of 2-butyl succinate-based hydroxamate derivatives containing isoxazole rings

Two series of novel 2-butyl succinate-based Hydroxamate derivatives containing isoxazole rings were synthesized, characterized and evaluated for antibacterial activity. The synthesized compounds were found to exhibit weak to moderate inhibitory activity against Staphytlococcusaureu and Klebsiellar pneumonia in vitro. All the compounds synthesized were found to be more effective against Klebsiellar pneumonia compared to Staphytlococcus aureu.

Docking and Molecular Dynamics Simulations of Peroxisome Proliferator Activated Receptors Interacting with Pan Agonist Sodelglitazar

PPAR (peroxisome proliferator-activated receptor) pan agonists play a critical role in treating metabolic diseases, especially the Type-2 diabetes mellitus (T2DM). GlaxoSmithKlines sodelglitazar (GW677954) is one of the potent PPAR pan agonists, which is currently being investigated in Phase II clinical trials for the treatment of T2DM and its complications. The present study was aimed at investigation into the effect of sodelglitazar at the binding pockets of PPARs. The Schrodinger Suite program (2009) was used for the molecular docking, while the GROMACS program used for the molecular dynamics (MD) simulations. The results thus obtained showed that sodelglitazar being docked well in the active site of PPARs. It was revealed by the MD simulations that the structures of the receptors remained quite stable during the simulations and that the important AF-2 helix showed less flexibility after binding with sodelglitazar. Also, it was observed that sodelglitazar could periodically form hydrogen bonds with the AF-2 helix of PPARs to stabilize the AF-2 helix in an active conformation. Our findings have confirmed that GlaxoSmithKlines sodelglitazar can activate the PPARs, which is quite consistent with the previous biological studies.

Synthesis, Resolution, and Enantiomeric Purity Assay of 2-n-Butylbutanedioic Acid 4-t-Butyl Esters

Racemic 2- n -butylbutanedioic acid 4- t -butyl esters were synthesized from methyl hexanoate and t -butyl α-iodoacetate via alkylation and subsequently selective hydrolyzation. The ( R )-and ( S )-2- n -butylbutanedioic acid 4- t -butyl esters were obtained by the resolution of the above-mentioned racemic compounds with ( S )-(-) or ( R )-(+)-α-methylbenzylamine, respectively. The e.e. values of the two optical active products were determined to be above 99% by HPLC after the formation of two pairs of diastereoisomers with ( R )-(+)-α-methylbenzylamine and ( S )-phenylalanine methyl ester.

Design, synthesis and biological activity of tetrazole-bearing uric acid transporter 1 inhibitors

Systematic structure-activity relationship(SAR) exploration of a moderately active tetrazole-bearing lesinurad-based hit 1f led to the discovery of a potent uric acid transporter 1(URAT1) inhibitor 1i, which possessed a novel molecular skeleton and was 11-fold more potent than the parent lesinurad against human URAT1 in-vitro (IC50=0.66 μmol/L for 1i vs. 7.18 μmol/L for lesinurad).

Discovery of a Flexible Triazolylbutanoic Acid as a Highly Potent Uric Acid Transporter 1 (URAT1) Inhibitor

In order to systematically explore and understand the structure–activity relationship (SAR) of a lesinurad-based hit (1c) derived from the replacement of the S atom in lesinurad with CH2, 18 compounds (1a–1r) were designed, synthesized and subjected to in vitro URAT1 inhibitory assay. The SAR exploration led to the discovery of a highly potent flexible URAT1 inhibitor, 1q, which was 31-fold more potent than parent lesinurad (IC50 = 0.23 μM against human URAT1 for 1q vs 7.18 μM for lesinurad). The present study discovered a flexible molecular scaffold, as represented by 1q, which might serve as a promising prototype scaffold for further development of potent URAT1 inhibitors, and also demonstrated that the S atom in lesinurad was not indispensable for its URAT1 inhibitory activity.

[3-(4-Chloro­phen­yl)isoxazol-5-yl]methanol

In the title molxadecule, C10H8ClNO2, the isoxazole ring shows normal values of bond lengths and angles. The mean planes of the benzene and isoxazole rings make a dihedral angle of 16.3u2005(2)°. Interxadmolecular O—H⋯N hydrogen bonds link the molxadecules into chains extended along the b axis. The crystal packing is further stablized by weak C—H⋯O interxadactions and van der Waals forces.

Systematic Structure-Activity Relationship (SAR) Exploration of Diarylmethane Backbone and Discovery of A Highly Potent Novel Uric Acid Transporter 1 (URAT1) Inhibitor

In order to systematically explore and better understand the structure-activity relationship (SAR) of a diarylmethane backbone in the design of potent uric acid transporter 1 (URAT1) inhibitors, 33 compounds (1a–1x and 1ha–1hi) were designed and synthesized, and their in vitro URAT1 inhibitory activities (IC50) were determined. The three-round systematic SAR exploration led to the discovery of a highly potent novel URAT1 inhibitor, 1h, which was 200- and 8-fold more potent than parent lesinurad and benzbromarone, respectively (IC50 = 0.035 μM against human URAT1 for 1h vs. 7.18 μM and 0.28 μM for lesinurad and benzbromarone, respectively). Compound 1h is the most potent URAT1 inhibitor discovered in our laboratories so far and also comparable to the most potent ones currently under development in clinical trials. The present study demonstrates that the diarylmethane backbone represents a very promising molecular scaffold for the design of potent URAT1 inhibitors.

3-Oxodapagliflozin as a potent and highly selective SGLT2 inhibitor for the treatment of type 2 diabetes

Structural modifications of 3-OH in the glucose moiety of dapagliflozin(1), an approved potent sodium-dependent glucose transporter 2(SGLT2) inhibitor, led to 3-oxodapagliflozin(16), a highly potent and more selective SGLT2 inhibitor[IC50(hSGLT1)/IC50(hSGLT2)=2851 for compound 16vs. 843 for compound 1]. 3-Oxodapagliflozin(16) exhibited in vitro(IC50=1.0 nmol/L against hSGLT2 for compound 16vs. 1.3 nmol/L for compound 1) and in vivo activities comparable to those of dapagliflozin(1). The bioactivities of 3-oxodapagliflozin (16) warrant its further evaluation as a promising SGLT2 inhibitor for the treatment of type 2 diabetes.

Facile synthesis of enantiomerically pure 1-(5-bromo-2-chlorophenyl)-1-(4-ethoxyphenyl)ethane

A facile 7-step procedure for the synthesis of enantiomerically pure 1-(5-bromo-2-chlorophenyl)-1-(4-ethoxyphenyl)ethanes[(R)-2 and(S)-2] that started from (5-bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone 3 was developed. The key step was the resolution of 2-(5-bromo-2-chlorophenyl)-2-(4-ethoxyphenyl)acetic acid 6 by crystallizations of its L- and D-menthyl esters 7 and 8 from petroleum ether to give optically pure enantiomers 9 and 10, respectively. The absolute configurations of the products were unambiguously determined by single-crystal X-ray diffractions of four key intermediates, 9, 10, 13 and 14. This procedure is characterized by inexpensiveness, scalability and ability to produce two individual enantiomers of a diarylethane with unambiguously determined absolute configurations and high enantiomeric purities.