3-Aminobenzenesulfonamides incorporating acylthiourea moieties selectively inhibit the tumor-associated carbonic anhydrase isoform IX over the off-target isoforms I, II and IV.

We describe the synthesis of a series of novel 1-aroyl/acyl-3-(3-aminosulfonylphenyl) thioureas (4a-k) acting as human carbonic anhydrase (hCA, EC 4.2.1.1) inhibitors. Reaction of alkyl/aryl isothiocyanates with 3-aminobenzenesulfonamide afforded a series of the title compounds incorporating a variety of short as well as highly lipophilic long tails. The newly synthesized sulfonamides were evaluated against 4 physiologically relevant CA isoforms (hCA I, II, IV, and IX). Several compounds showed interesting inhibitory activity. The tumor-associated hCA IX was the most sensitive isoform to inhibition with these compounds, with KIs in the range of 21.5-44.0 nM and selectivity ratios over the major cytosolic isoform hCA II in the range of 3.35-37.3. The sulfonamides incorporating the phenylacetylthioureido and pentadecanoylthioureido moieties were the most hCA IX-selective inhibitors detected in this work, making them of interest for further investigations.

Synthesis of sulfadiazinyl acyl/aryl thiourea derivatives as calf intestinal alkaline phosphatase inhibitors, pharmacokinetic properties, lead optimization, Lineweaver-Burk plot evaluation and binding analysis.

To seek the new medicinal potential of sulfadiazine drug, the free amino group of sulfadiazine was exploited to obtain acyl/aryl thioureas using simple and straightforward protocol. Acyl/aryl thioureas are well recognized bioactive pharmacophore containing moieties. A new series (4a-4j) of sulfadiazine derived acyl/aryl thioureas was synthesized and characterized through spectroscopic and elemental analysis. The synthesized derivatives 4a-4j were subjected to calf intestinal alkaline phosphatase (CIAP) activity. The derivative 4a-4j showed better inhibition potential compared to standard monopotassium phosphate (MKP). The compound 4c exhibited higher potential in the series with IC50 0.251 ±â€¯0.012 µM (standard KH2PO4 4.317 ±â€¯0.201 µM). Lineweaver-Burk plots revealed that most potent derivative 4c inhibition CIAP via mixed type pathway. Pharmacological investigations showed that synthesized compounds 4a-4j obey Lipinsk's rule. ADMET parameters evaluation predicted that these molecule show significant lead like properties with minimum possible toxicity and can serve as templates in drug designing. The synthetic compounds show none mutagenic and irritant behavior. Molecular docking analysis showed that compound 4c interacts with Asp273, His317 and Arg166 amino acid residues.

Synthesis, computational studies and enzyme inhibitory kinetics of substituted methyl[2-(4-dimethylamino-benzylidene)-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates as mushroom tyrosinase inhibitors.

The present article describes the synthesis and enzyme inhibitory kinetics of methyl[2-(arylmethylene-hydrazono)-4-oxo-thiazolidin-5-ylidene]acetates 5a-j as mushroom tyrosinase inhibitors. The title compounds were synthesized via cyclocondensation of thiosemicarbazones 3a-j with dimethyl but-2-ynedioate (DMAD) 4 in good yields under solvent-free conditions. The synthesized compounds were evaluated for their potential to inhibit the activity of mushroom tyrosinase. It was unveiled that compounds 5i showed excellent enzyme inhibitory activity with IC50 3.17µM while IC50 of standard kojic acid is 15.91µM. The presence of heterocyclic pyridine ring in compound 5i play important role in enzyme inhibitory activity as rest of the functional groups are common in all synthesized compounds. The enzyme inhibitory kinetics of the most potent derivative 5i determined by Lineweaver-Burk plots and Dixon plots showed that it is non-competitive inhibitor with Ki value 1.5µM. It was further investigated that the wet lab results are in good agreement with the computational results. The molecular docking of the synthesized compounds was performed against tyrosinase protein (PDBID 2Y9X) to delineate ligand-protein interactions at molecular level. The docking results showed that the major interacting residues are His244, His85, His263, Val 283, His 296, Asn260, Val248, His260, His261 and Phe264 which are located in active binding site of the protein. The molecular modeling demonstrates that the oxygen atom of the compound 5i coordinated with the key residues in the active site of mushroom tyrosinase contribute significantly against inhibitory ability and diminishing the human melanin synthesis. These results evident that compound 5i is a lead structure in developing most potent mushroom tyrosinase inhibitors.

Synthesis and Molecular Docking Studies of (E)-4-(Substituted-benzylideneamino)-2H-Chromen-2-one Derivatives: Entry to New Carbonic Anhydrase Class Of Inhibitors.

The present article illustrated the synthesis and characterization of a novel series of (E)-4-(substituted-benzylideneamino)-2H-chromen-2-one derivatives 4A-4J: in good to excellent yields. The target compounds were synthesized by refluxing 4-aminocoumarin with aromatic aldehydes in ethanol. The structural confirmation was achieved by spectroscopic techniques such as (1H, 13C-NMR and FT-IR) and elemental analysis. The synthesized compounds were evaluated for carbonic anhydrase II (CA-II) inhibition and free radical scavenging activity. All the compounds showed CA-II inhibition in the micro molar range. The compound 4C: exhibited higher potential in the series with IC50=0.0928±0.00545 µM (standard Acetazolamide IC50=0.997±0.0586 µM). Pharmacological investigations showed that the synthesized compounds 4A-4J: obey Lipinsk's rule. Compound 4C: elicited drug likeness and showed drug score value of 0.05. Molecular docking analysis showed that compound 4C: interacts with Asn66 and Gln91 amino acid residues. Graphical Abstract.

Enzyme inhibitory activities an insight into the structure-Activity relationship of biscoumarin derivatives.

Biscoumarin derivatives, a dimeric form of coumarin, are well known derivatives of coumarin, occurred in the bioactive metabolites of marine and terrestrial organisms. On account of pharmacological and biological applications, biscoumarins have long been the subject of innumerable enzyme inhibition studies. In this review the pros and cons of enzyme inhibition studies of biscoumarins as urease inhibitors, aromatase inhibitors, NPPs, α-glucosidase inhibitors, α-amylase inhibitors, HIV-1 integrase inhibition, steroid sulfatase inhibitors and c-Met inhibitors are discussed in a systematic way. Moreover, the review discusses the structure activity relationship of biscoumarin scaffold with enzyme inhibitory potency which would unleash new avenues for further development. The purpose of the current review is to disclose the value of biscoumarins as potent and efficient enzyme inhibitor. This review provides a guideline to elaborate the diversity of biscoumarin inhibitors by exploring the effects of electronic groups linked with biscoumarin nucleus.