Scalable Preparation of 4,4-Disubstituted Six-Membered Cyclic Sulfones.

We provide an account of synthetic strategies aimed at the efficient preparation of 4-amino-4-methyltetrahydro-2H-thiopyran 1,1-dioxide (3), an important cyclic sulfone building block for medicinal chemistry. A practical and scalable protocol has been developed that readily gives access to the title compound from commercially available and inexpensive starting materials. In addition, this novel approach has enabled the synthesis of various related 4,4-disubstituted cyclic sulfone derivatives that serve as valuable structural motifs for drug discovery.

Synthesis of novel cytotoxic tetracyclic acridone derivatives and study of their molecular docking, ADMET, QSAR, bioactivity and protein binding properties.

Acridone based synthetic and natural products with inherent anticancer activity advancing the research and generating a large number of structurally diversified compounds. In this sequence we have designed, synthesized a series of tetracyclic acridones with amide framework viz., 3-(alkyloyl/ aryloyl/ heteroaryloyl/ heteroaryl)-2,3-dihydropyrazino[3,2,1-de]acridin-7(1H)-ones and screened for their in vitro anti-cancer activity. The in vitro study revealed that compounds with cyclopropyl-acetyl, benzoyl, p-hydroxybenzoyl, p-(trifluoromethyl)benzoyl, p-fluorobenzoyl, m-fluorobenzoyl, picolinoyl, 6-methylpicolinoyl and 3-nicotinoyl groups are active against HT29, MDAMB231 and HEK293T cancer cell lines. The molecular docking studies performed for them against 4N5Y, HT29 and 2VWD revealed the potential ligand-protein binding interactions among the neutral aminoacid of the enzymes and carbonyl groups of the title compounds with a binding energy ranging from - 8.1394 to - 6.9915 kcal/mol. In addition, the BSA protein binding assay performed for them has confirmed their interaction with target proteins through strong binding to BSA macromolecule. The additional studies like ADMET, QSAR, bioactivity scores, drug properties and toxicity risks ascertained them as newer drug candidates. This study had added a new collection of piperazino fused acridone derivatives to the existing array of other nitrogen heterocyclic fused acridone derivatives as anticancer agents.

Synthesis, molecular modeling and evaluation of α-glucosidase inhibition activity of 3,4-dihydroxy piperidines.

Biological evaluation of 3,4-dihydroxy piperidines as α-glucosidase inhibitors is being reported for the first time. Forty-five derivatives (amides, di-amides and sulfonamides) were made using cis and trans 3,4-dihydroxy piperidines to evaluate their α-glucosidase inhibition activity. Polar groups (-OH, -NH2) on phenyl ring having derivatives 5i, 5l, 7g, 7i &12j showed excellent activity compared to standard references. Acarbose, Voglibose and Miglitol were used as standard references. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.

Synthesis and α-glucosidase inhibition activity of dihydroxy pyrrolidines.

A new series of Deacetylsarmentamide A and B derivatives, amides and sulfonamides of 3,4-dihydroxypyrrolidines as α-glucosidase inhibitors were designed and synthesized. The biological screening test against α-glucosidase showed that some of these compounds have the positive inhibitory activity against α-glucosidase. Saturated aliphatic amides were more potent than the olefinic amides. Among all the compounds, 5o/6o having polar -NH2 group, 10f/11f having polar -OH group on phenyl ring displayed 3-4-fold more potent than the standard drugs. Acarbose, Voglibose and Miglitol were used as standard references. The promising compounds 6i, 5o, 6o, 10a, 11a, 10f and 11f have been identified. Molecular docking simulations were done for compounds to identify important binding modes responsible for inhibition activity of α-glucosidase.

Synthesis, molecular modeling and biological evaluation of aza-flavanones as α-glucosidase inhibitors.

An efficient acid catalyzed methodology has been employed to synthesize a variety of aza-flavanones and their α-glucosidase inhibitory activity is evaluated using acarbose, miglitol and voglibose as reference standards. Molecular modeling studies were performed for all compounds to identify the important binding modes responsible for the inhibition activity of α-glucosidase which helped find key interactions between the enzyme and the active compounds. Among all the compounds 5g, 5r and 5w have shown high α-glucosidase inhibition activity compared to standard reference drugs and have been identified as promising potential antidiabetic agents. This study is the first biological evaluation of aza-flavanones as α-glucosidase inhibitors.

Biological activity of some monocyclic- and bicyclic beta-lactams with specified functional groups.

This Review contains our recent studies on evaluation of biological activities associated with monocyclic beta-lactams and bicyclic beta-lactam antibiotics containing various heteroatoms. A series of bicyclic beta-lactams was synthesized, which possessed electron-withdrawing groups, such as an ester, mesylate, and triflate functionality. These beta-lactams exhibited enhanced antibacterial activity.

Reactions of purines-containing butenolides with L-cysteine or N-acetyl-L-cysteine as model biological nucleophiles: a potent mechanism-based inhibitor of ribonucleotide reductase caused apoptosis in breast carcinoma MCF7 cells.

Thiols are the most reactive nucleophilic reagents among the biological models investigated. The reactivity of butenolides 1a-c, 2-4, and 6-8 toward L-cysteine, a model biological nucleophile, was studied spectrophotometrically. The rates of the reactions were measured and correlated with antitumour activity of these molecules. N-Acetylcysteine addition product 5, resulting from the treatment of butenolide 4 with glutathione precursor, N-acetyl-L-cysteine, was isolated. Unlike purine-containing gamma-(Z)-ethylidene-2,3-dimethoxybutenolides 1a-c, 4, 6, and 7, adduct 5 and butenolides 10-12 did not exhibit inhibitory activity against murine leukemias (L1210 and P388), breast carcinoma (MCF7), and human T-lymphoblasts (Molt4/C8 and CEM/0) cell lines. As such, the biological activity of purine-containing butenolides can be attributed to their adenine moiety as a recognition site as well as their reactivity towards the cysteine residues of functional proteins forming covalent bond via reverse Michael type addition. Adenine-containing phosphonothioanhydride derivative 8 was also synthesised. Its reaction with N-acetyl-L-cysteine produced N,S-diacetylcysteine and thiophosphonate 9. Compound 9 did not exhibit anticancer activity; yet its precursor 8 displayed the most pronounced inhibition on all the examined malignant tumour cell lines. In the presence of L-cysteine, cytotoxicity of 4 and 8 was decreased, whereas glutathione addition more influenced on the cytotoxicity of 8. It was found that adenine-containing phosphonothioanhydride 8 functions as a significant irreversible inactivator of the Escherichia coli ribonucleoside diphosphate reductase. After treatment of MCF7 cells with compound 8, fluorescence microscopy demonstrated the presence of nucleus shrinkage or segmentation. This apoptotic morphology, however, was not pronounced in the presence of glutathione or dithiotheritol.