Hummera Rafique

Design, synthesis, molecular docking studies and in vitro screening of ethyl 4-(3-benzoylthioureido) benzoates as urease inhibitors

Thioureas are exceptionally versatile building blocks towards the synthesis of wide variety of heterocyclic systems, which also possess extensive range of pharmacological activities. The substituted benzoic acids were converted into corresponding acid chlorides, these acid chlorides were then treated with potassium thiocyanate in acetone and then the reaction mixture was refluxed for 1-2h afford ethyl 4-(3-benzoylthioureido)benzoates thioureas in good yields. All the newly synthesized compounds were evaluated for their urease inhibitory activities and were found to be potent inhibitors of urease enzyme. Compounds 1f and 1g were identified as the most potent urease inhibitors (IC50 0.21 and 0.13 μM, respectively), and was 100-fold more potent than the standard inhibitors. Further molecular docking studies were carried out using the crystal structure of urease to find out the binding mode of the inhibitors with the enzyme.

SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF SOME NEW 1-AROYL-3-(SUBSTITUTED-2-BENZOTHIAZOLYL)THIOUREAS

An efficient, synthesis of some new 1-aroyl-3-(substituted-2-benzothiazolyl)-thioureas is reported. Substituted anilines were treated with potassium thiocyanate and bromine in acidic medium to afford the corresponding 2-amino-benzothiazoles (2a–e). Treatment of the latter with suitably substituted aroyl isocyanates, produced in situ by reaction of corresponding aroyl chlorides with thiocyanate in acetone, afforded the 1-aroyl-3-(substituted-2-benzothiazolyl)thioureas (3a–k). The structures were confirmed by physical, IR, NMR, and mass spectral data. The synthesized compounds (2a–d, 3a–k) were assayed in vitro for their antimicrobial activity against Gram positive and Gram negative bacteria and were found to exhibit moderate to potent activity towards the tested microorganisms, as compared to the standard drugs.

Benzothiazolyl substituted iminothiazolidinones and benzamido-oxothiazolidines as potent and partly selective aldose reductase inhibitors

Two new series of oxothiazolidine benzoate and acetate derivatives were synthesized and evaluated as aldehyde reductase (ALR1) and aldose reductase (ALR2) inhibitors. Methyl 2-[2-benzamido-3-(benzo[d]thiazol-2-yl)-4-oxothiazolidin-5-ylidene]acetates (2a–k) and ethyl 4-[2-benzamido-5-(2-methoxy-2-oxyethylidene)-4-oxothiazolidin-3-yl]benzoates (4a–j) were obtained in good to excellent yield by the heterocyclization of 1-aroyl-3-(2-benzothiazolyl) thioureas (1a–j) and ethyl 4-(3-aroylthioureido)benzoates (3a–j), respectively, with dimethyl acetylenedicarboxylate (DMAD) in dry methanol. Among the tested compounds, 2d, 2g, 2h, 2i, 2j, 4b, 4f and 4h showed a potent inhibitory activity on ALR1, whereas 2a, 2g, 2h, 4d, 4f, 4h and 4j exhibited potent inhibition on ALR2. Docking analysis suggested the likely binding modes of the inhibitors within the active site of ALR2. The new aldose reductase inhibitors are believed to represent useful lead structures for the generation of candidate compounds to target a number of pathological conditions, most notably long-term diabetic complications. FTIR, 1H NMR, 13C NMR, GC-MS and elemental analyses confirmed the assigned structures to the synthesized compounds. Further, the structure and geometry of compound ethyl 4-((2Z,5Z)-22,4-di-(2,4-dichlorobenzoylimino)-5-(2-methoxy-2-oxoethylidene)-4-oxothiazolidin-3-yl)benzoate (4c) was unequivocally confirmed by single crystal X-ray diffraction.

Synthesis and antibacterial evaluation of typharin analog: 6,8-dihydroxy-7-methyl-3-styryl-3,4-dihydroisocoumarin

Synthesis of the 6-hydroxy-7-methyl analog of typharin (8-dihydroxy-3-styryl-3,4-dihydroisocoumarin) isolated from the rhizomes of Typha capensis has been described. Direct condensation of 3,5-dimethoxy-4-methylhomophthalic acid (1) with cinnamoyl chloride at elevated temperature under inert conditions afforded 6,8-dihydroxy-7-methyl-3-styrylisocoumarin (2). Hydrolysis of isocoumarin to keto acid (3) followed by reduction and cyclodehydration of hydroxy acid analog (4) afforded ( ± )-6,8-dimethoxy-3-(4-methoxyphenyl)-3,4-dihydroisocoumarin (5). Demethylation of the latter using anhydrous aluminum chloride/ethane thiol furnished the title isocoumarin (6). Compounds (1–6) were screened for in vitro antibacterial activity against a representative panel of Gram-positive and Gram-negative bacteria using levofloxacin as the reference drug.

Synthesis, structure–activity relationship and molecular docking of 3-oxoaurones and 3-thioaurones as acetylcholinesterase and butyrylcholinesterase inhibitors

The present study describes efficient and facile syntheses of varyingly substituted 3-thioaurones from the corresponding 3-oxoaurones using Lawessons reagent and phosphorous pentasulfide. In comparison, the latter methodology was proved more convenient, giving higher yields and required short and simple methodology. The structures of synthetic compounds were unambiguously elucidated by IR, MS and NMR spectroscopy. All synthetic compounds were screened for their inhibitory potential against in vitro acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) enzymes. Molecular docking studies were also performed in order to examine their binding interactions with AChE and BChE human proteins. Both studies revealed that some of these compounds were found to be good inhibitors against AChE and BChE.

Total synthesis and cytotoxic activity of stellatin

Stellatin (3,4-dihydro-8-hydroxy-7-hydroxymethyl-6-methoxyisocoumarin) (8), an extrolite of fungal genera Emericella and Aspergillus, was synthesized. Thus, Vilsmeier–Haack formylation of methyl ester of 3,5-dimethoxy-4-methylphenylacetic acid (1) to afford the formyl ester (2) followed sulfamic acid–sodium chlorite oxidation of the aldehydic function to yield the carboxy ester (3). Chemoselective reduction of ester function in the latter using NaBH4/THF/MeOH furnished the corresponding hydroxy acid (4) that on cyclodehydration afforded the 3,4-dihydro-6,8-dimethoxy-7-methylisocoumarin (5). Benzylic bromination of the C-7 methyl in 5 using NBS/benzoyl peroxide to give the 7-bromomethyldihydroisocoumarin (6) followed the nucleophilic substitution using aqueous acetone to provide 7-hydroxymethyl-dihydroisocoumarin (7). Finally, the regioselective demethylation of 8-methoxyl group using anhydrous magnesium iodide furnished the stellatin (8). The dihydroisocoumarins (5–8) were screened for cytotoxic activity against human keratinocyte cell line and were found to exhibit moderate to good activity.

2-Chloro-4-(2-iodobenzenesulfonamido)benzoic acid

In the molecule of the title compound, C13H9ClINO4S, the coordination around the S atom is distorted tetrahedral. The aromatic rings are oriented at a dihedral angle of 74.46 (9)°. Intramolecular C—H⋯O hydrogen bonds result in the formation of two five- and one six-membered rings, which adopt planar, envelope and twisted conformations, respectively. In the crystal structure, intermolecular N—H⋯O and O—H⋯O hydrogen bonds link the molecules to form R 2 2(8) ring motifs, which are further linked by C—H⋯O hydrogen bonds. π–π contacts between the benzene rings [centroid–centroid distances = 3.709 (3) and 3.772 (3) Å] may further stabilize the structure. The I atom is disordered over two positions, refined with occupancies of ca 0.75 and 0.25.

Methyl 3,5-dibromo-4-methyl­benzoate

In the title compound, C9H8Br2O2, the molecule is essentially planar with an r.m.s. deviation of 0.0652 Å from the mean plane through all non-H atoms and a dihedral angle of 7.1 (2)° between the benzene ring plane and the carboxylate substituent. In the crystal structure, weak C—H⋯Br hydrogen bonds and weak intermolecular O⋯Br contacts [3.095 (2) Å], link adjacent molecules into layers parallel to (102). Additional weak intermolecular C—H⋯O hydrogen bond interactions stack the layers above and below the molecular plane and down the a axis.

3,4,5-Trimethoxy­benzohydrazidium chloride

The title compound, C10H15N2O4 +·Cl−, was obtained as an unexpected by-product during the synthesis of 1-[2-(substituted aryl)]-3-methylpyrazol-5-ones. The hydrazide group is essentially planar, with an r.s.m. deviation of 0.020 (2) Å, and is oriented at a dihedral angle of 30.52 (3)° with respect to the benzene ring. In the crystal structure, the cations and anions are linked through N—H⋯O and N—H⋯Cl hydrogen bonds, forming a molecular tape running along the b axis.

Methyl 4-methyl­benzoate

The structure of the title compound, C9H10O2, is related to that of 4-methylphenyl 4-methylbenzoate and ethylene di-4-methylbenzoate showing similar bond parameters. The molecule is planar, the dihedral angle between the aromatic ring and the –COOMe group being 0.95 (6)°. The cystal structure exhibits intermolecular C—H⋯O contacts that link molecules into infinite chains extended in the [001] direction.