K. S. Rangappa

Synthesis of 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives and evaluation of their cytotoxicity and induction of apoptosis in human leukemia cells.

In order to explore the anticancer effect associated with the thiazolidinone framework, several 2-(5-((5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid derivatives 5(a-l) were synthesized. Variation in the functional group at C-terminal of the thiazolidinone led to set of compounds bearing amide moiety. Their chemical structures were confirmed by (1)H NMR, IR and Mass Spectra analysis. These thiazolidinone compounds containing furan moiety exhibits moderate to strong antiproliferative activity in a cell cycle stage-dependent and dose dependent manner in two different human leukemia cell lines. The importance of the electron donating groups on thiazolidinone moiety was confirmed by MTT and Trypan blue assays and it was concluded that the 4th position of the substituted aryl ring plays a dominant role for its anticancer property. Among the synthesized compounds, 5e and 5f have shown potent anticancer activity on both the cell lines tested. To rationalize the role of electron donating group in the induction of cytotoxicity we have chosen two molecules (5e and 5k) having different electron donating group at different positions. LDH assay, Flow cytometric analysis and DNA fragmentation suggest that 5e is more cytotoxic and able to induce the apoptosis.

Synthesis and in vitro antiproliferative activity against human cancer cell lines of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-diones

SummaryA series of novel 5-(4-methyl-benzylidene)-thiazolidine-2,4-dione derivatives 6 (a–d) and 7 (a–g) were synthesized with different substituted aromatic sulfonyl chlorides (R–SO2–Cl) and alkyl halides (R–X) and were characterized by 1H NMR, LC/MS, FTIR and elemental analyses. All the compounds synthesised were evaluated for their cell antiproliferation activity by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. The antiproliferative effects of the synthesised compounds were tested against viable human skin fibroblast cell line and carcinoma cell lines namely HeLa cells, HT-29 cells, MCF-7 cells, HepG-2 cells by adopting positive and negative control. The importance of the nitro group on thiazolidinone moiety was confirmed and it was concluded that the fourth position of the substituted aryl ring plays a dominant role and was responsible for the antiproliferative activity. Among the synthesized compounds only 6a, 7e and 7g have potent antiproliferative activity on all the carcinoma cell lines tested.

Specific Small-Molecule Activator of Aurora Kinase A Induces Autophosphorylation in a Cell-Free System

Aurora kinases are essential for chromosomal segregation and cell division and thereby important for maintaining the proper genomic integrity. There are three classes of aurora kinases in humans: A, B, and C. Aurora kinase A is frequently overexpressed in various cancers. The link of the overexpression and tumorigenesis is yet to be understood. By employing virtual screening, we have found that anacardic acid, a pentadecane aliphatic chain containing hydroxylcarboxylic acid, from cashew nut shell liquid could be docked in Aurora kinases A and B. Remarkably, we found that anacardic acid could potently activate the Aurora kinase A mediated phosphorylation of histone H3, but at a similar concentration the activity of aurora kinase B remained unaffected in vitro. Mechanistically, anacardic acid induces the structural changes and also the autophosphorylation of the aurora kinase A to enhance the enzyme activity. This data thus indicate anacardic acid as the first small-molecule activator of Aurora kinase, which could be highly useful for probing the function of hyperactive (overexpressed) Aurora kinase A.

Synthesis and xanthine oxidase inhibitory activity of 7-methyl-2-(phenoxymethyl)-5H-[1,3,4]thiadiazolo[3,2-a]pyrimidin-5-one derivatives

An elevated level of blood uric acid (hyperuricemia) is the underlying cause of gout. Xanthine oxidase is the key enzyme that catalyzes the oxidation of hypoxanthine to xanthine and then to uric acid. Allopurinol, a widely used xanthine oxidase inhibitor is the most commonly used drug to treat gout. However, a small but significant portion of the population suffers from adverse effects of allopurinol that includes gastrointestinal upset, skin rashes and hypersensitivity reactions. Moreover, an elevated level of uric acid is considered as an independent risk factor for cardiovascular diseases. Therefore use of allopurinol-like drugs with minimum side effects is the ideal drug of choice against gout. In this study, we report the synthesis of a series of pyrimidin-5-one analogues as effective and a new class of xanthine oxidase inhibitors. All the synthesized pyrimidin-5-one analogues are characterized by spectroscopic techniques and elemental analysis. Four (6a, 6b, 6d and 6f) out of 20 synthesized molecules in this class showed good inhibition against three different sources of xanthine oxidase, which were more potent than allopurinol based on their respective IC(50) values. Molecular modeling and docking studies revealed that the molecule 6a has very good interactions with the Molybdenum-Oxygen-Sulfur (MOS) complex a key component in xanthine oxidase. These results highlight the identification of a new class of xanthine oxidase inhibitors that have potential to be more efficacious, than allopurinol, to treat gout and possibly against cardiovascular diseases.

Chemistry and Structural Evaluation of Different Phospholipase A2 Inhibitors in Arachidonic Acid Pathway Mediated Inflammation and Snake Venom Toxicity

PLA2 inhibitors specific to Group I and II PLA2 isoforms are therapeutically important as anti-inflammatory molecules and against venom toxicity. From various natural sources diversified molecules with PLA2 inhibition and concomitant neutralization of inflammatory reactions and venom toxicity were characterized. Using these molecules, lead compounds are generated in several laboratories. Analogues of lead molecules were generated by substituting different types of functional groups in order to obtain a molecule with optimal PLA2 inhibition. The lead molecules characterized as PLA2 inhibitors are indoles, azetidinones, piperazines, isoxazolidines, isoxazolines, diazepinones, acenaphthenes and several substrate analogues. The lead optimization involves relative hydrophobicity and substitution of functional groups, such as electron withdrawing or donating. Many such groups are placed on hydrophobic moiety and their positional bioisosters are characterized. Among these analogue piperazine derivatives on optimization with respect to hydrophobicity and electronegativity showed inhibition at nanomolar levels. Structural analysis of many lead molecules indicated that a PLA2 inhibitor should have both hydrophobic moiety and polar functional groups. Each lead molecule requires optimization in this regard for effective inhibition.

Synthesis and in vivo anticancer and antiangiogenic effects of novel thioxothiazolidin-4-one derivatives against transplantable mouse tumor

A series of novel thioxothiazolidin-4-one derivatives 5(a–g) were synthesized by the coupling of different amines containing aliphatic, substituted aromatic, and heterocyclic moieties, such as oxadiazol, pyrazole, isoxazole, and piperazine with 2-(5-(4-chlorophenyl)furan-2-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl)acetic acid. All compounds were characterized by 1H NMR, LCMS, FTIR and elemental analysis. In this study, we investigated the possibility that these novel thioxothiazolidin-4-one derivatives 5(a–g) inhibits tumor growth and tumor induced angiogenesis using mouse Ehrlich Ascites Tumor (EAT) as a model system. Our results demonstrated that the compounds significantly reduced ascites tumor volume, cell number, and increased the life span of EAT-bearing mice. In addition, the compounds manifested strong antiangiogenic effects and suppressed tumor induced endothelial proliferation in the mice peritoneum. From our findings, it is noted that the derivatives 5(a–e) may be possible candidates for anticancer therapy with the ability to inhibit tumor angiogenesis and tumor cell proliferation.

Synthesis and antimicrobial studies of novel 1-benzhydryl-piperazine sulfonamide and carboxamide derivatives

A series of novel substituted 1-benzhydryl-piperazine sulfonamide 8(a–f) and benzamides 9(a–h) were synthesized and their antimicrobial activities evaluated in vitro by paper disc diffusion and micro dilution method against standard strains of Gram-positive (Staphylococcus aureus ATCC 25953, Staphylococcus epidermis 25212, Bacillus cereus 11778, Bacillus substilis 6051) and Gram-negative (Escherichia coli ATCC 25922, Pseudomonas aeruginosa ATCC 2853, Proteus vulgaris ATCC 2853 and Salmonella typhi ATCC 9484) bacteria. Among the synthesized new compounds 8d, 8e, 9c, 9e, 9f and 9 h showed potent antimicrobial activities compared to the standard drug streptomycin.

Muscarinic receptor 1 agonist activity of novel N-aryl carboxamide substituted 3-morpholino arecoline derivatives in Alzheimer's presenile dementia models

Earlier we have reported the effect of arecoline thiazolidinone and morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimers presenile dementia models. To elucidate further our Structure-Activity Relationship (SAR) studies on the chemistry and muscarinic receptor 1 binding efficacy, a series of novel carboxamide derivatives of 2-(1-methyl-1,2,5,6-tetrahydropyridin-3-yl)morpholine molecule have been designed and synthesized as a new class of M1 receptor agonists with a low toxicity effect profile that enhances memory function in animal models of Alzheimers presenile dementia and also modulates the APP secretion from rat brain cerebrocortical slices by activating M1 receptor in vitro. Results suggest that compound 9b having methyl group at the para position of the aryl group attached to the carboxamide of morpholino arecoline could emerge as a potent molecule having antidementia activity.

Synthesis and identification of a new class of antileukemic agents containing 2-(arylcarboxamide)-(S)-6-amino-4,5,6,7-tetrahydrobenzo[d]thiazole.

Recently we have reported the effect of (S)-6-aryl urea/thiourea substituted-2-amino-4,5,6,7-tetrahydrobenzo[d]thiazole derivatives as potent anti-leukemic agents. To elucidate further the Structure Activity Relationship (SAR) studies on the anti-leukemic activity of (S)-2,6-diamino-4,5,6,7-tetrahydrobenzo[d]thiazole moiety, a series of 2-arlycarboxamide substituted-(S)-6-amino-4,5,6,7-tetrahydrobenzo[d]thiazole were designed, synthesized and evaluated for their anti-leukemic activity by trypan blue exclusion, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), lactate dehydrogenase (LDH) assays and cell cycle analysis. Results suggest that the position, number and bulkiness of the substituent on the phenyl ring of aryl carboxamide moiety at 2nd position of 6-amino-4,5,6,7-tetrhydrobenzo[d]thiazole play a key role in inhibiting the proliferation of leukemia cells. Compounds with ortho substitution showed poor activity and with meta and para substitution showed good activity.

Effect of novel N-aryl sulfonamide substituted 3-morpholino arecoline derivatives as muscarinic receptor 1 agonists in Alzheimer’s dementia models

A series of novel, potent, and selective muscarinic receptor 1 agonists (M1 receptor agonists) that employ a key N-substituted morpholine Arecoline moiety has been synthesized as part of research effort for the therapy of Alzheimers diseases. The ester group of arecoline (which is reported as muscarinic agonist) has been replaced by N-substituted morpholine ring. The structure-activity relationship reveals that the electron donating 4-substituted sulfonyl derivatives (9a, 9b, 9c, and 9e) on the nitrogen atom of the morpholine ring increases the affinity of M1 receptor binding 50- to 80-fold greater than the corresponding arecoline. Other derivatives also showed considerable M1 receptor binding affinity.