S. R. Ranganatha

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 cytotoxic evaluation of novel 2-(4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-ylthio)-1H-benzo[d]imidazole derivatives

The present work deals with the anticancer effect of benzimidazole derivatives associated with the pyridine framework. By varying the functional group at N-terminal of the benzimidazole by different L-amino acids, several 2-(4-(2,2,2-trifluoroethoxy)-3-methylpyridin-2-ylthio)-1Hbenzo[d]imidazole derivatives 9(a–j) were synthesized. Their chemical structures were confirmed by 1H NMR, IR and mass spectroscopic techniques. The synthesized compounds were examined for their antiproliferative effects against human leukemia cell lines, K562 and CEM. The preliminary results showed most of the derivatives had moderate antitumor activity. Compound 9j containing cysteine residue exhibited good inhibition compared to other amino acid resides. In addition DNA fragmentation results suggest that 9j is more cytotoxic and able to induce apoptosis.

Evaluation of in vivo wound-healing potential of 2-[4-(2,4-dimethoxy-benzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanone derivatives

Series of 2-[4-(2,4-dimethoxy-benzoyl)-phenoxy]-1-[4-(3-piperidin-4-yl-propyl)-piperidin-1-yl]-ethanone derivatives 9(a-d) and 10(a-d) were synthesized in good yield. The synthesized compounds were characterized by (1)H NMR, LC-MS, FTIR and elemental analysis. All the compounds were screened for in vivo wound-healing activity by incision and dead space wound models on Swiss albino rats. Significant wound healing was observed in 10b and 10d treated groups as also the epithelialization of the incision wound was faster with a high rate of wound contraction in these groups. The tensile strength of the incision wound was significantly increased in 10b and 10d compared to the Nitrofurazone, the standard skin ointment. In dead space wound model also the weight of the granulation was higher indicating increase in collagenation. The SAR correlation studies revealed that the thioamide functional linkage and electron withdrawing groups influence the wound-healing activity.

Synthesis of medicinally important N-trimethylene dipiperidine sulfonamides and carboxamides containing a substituted benzophenone moiety - An antibacterial agents

A series of novel substituted 2-4-(2,4-dimethoxy-benzoyl)-phenoxy]-1- 4-(3-piperidin-4-yl-propyl)-piperidin-1- yl]-ethanone sulfonamide (9a-h) benzamides (10a-h) were synthesized in order to determine their antibacterial activities and possible structure-activity relationships to improve therapeutic efficacy. The synthesized compounds were characterized by H-1-NMR, FTIR and elemental analysis. All the synthesized compounds were evaluated in vitro for their efficacy as antibacterial agents by agar well diffusion and micro dilution method against standard strains of Gram-positive (staphylococcus aureus ATCC 29737, Bacillus substilis NCIM 2010, Streptococcus pyognes NCIM 2608) and Gram-negative (Pseudomonas aeruginosa ATCC 20852, Klebsiella pneumoniae MTCC 618, Escherichia coli ATCC 25922) bacteria. Among the synthesized new compounds (9c), (9d), (9e), (9f), (10a), (10c), (10d), (10e) and (10g) showed potent antibacterial activities compared to the standard drug. In particular, all the tested compounds had potent inhibitory activity against B. subtilis and E. coli.

Synthesis and Antileukemic Activity of Novel 2‐(4‐(2,4‐dimethoxybenzoyl)phenoxy)‐1‐(4‐(3‐(piperidin‐4‐yl)propyl)piperidin‐1‐yl)ethanone Derivatives

A series of novel 2‐(4‐(2,4‐dimethoxybenzoyl)phenoxy)‐1‐(4‐(3‐(piperidin‐4‐yl)propyl) piperidin‐1‐yl)ethanone derivatives 9(a–e) and 10(a–g) were synthesized and characterized by 1H NMR, IR, mass spectral, and elemental analysis. These novel compounds were evaluated for their antileukemic activity against two human leukemic cell lines (K562 and CEM) by using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazoliumbromide assay. Some of the tested compounds showed good antiproliferative activity with IC50 values ranging from 1.6 to 8.0 μm. Compound 9c, 9e, and 10f with an electron‐withdrawing halogen substituent at the para position on the phenyl ring showed excellent in vitro potency against tested human leukemia cells (K562 and CEM).

Synthesis of Novel 1-benzhydryl-4-(3-(piperidin-4-yl)propyl) Piperidine Sulfonamides as Anticonvulsant Agents

A series of novel 1-benzhydryl-4-(3-(piperidin-4-yl)propyl)piperidine sulphonamide derivatives 8(a-j) was synthesized in good yield and met the structural requirements essential for anticonvulsant properties. The structures of the synthesized compounds were confirmed on the basis of their spectral data and elemental analysis. All the compounds were evaluated for their possible anticonvulsant activity by Maximal Electroshock Seizure (MES) test and their neurotoxic effects were determined by rotorod test. Majority of the compounds were active in MES tests. Compounds 8f and 8g have shown a significant and protective effect on seizure, when compared with standard drug phenytoin. Compound 8f and 8g without a fluoro group showed anticonvulsant activity in MES test as compared with compound 8a and 8b with fluoro substituents. From this study, it is quite apparent that there are at least three parameters for the activity of anticonvulsant drugs, that is, a lipophilic domain, a distal hydrophobic center and two-electron donor (-C-N-) system.

Effect of Novel Amino Acids and Dipeptides 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 Alzheimer’s diseases. The ester group of arecoline (which is reported as mucarinic agonist) has been replaced by N-substituted morpholine ring. The structure activity relationship reveals that the increase in lipophilic carbon chain on the nitrogen atom of the morpholine ring increases the affinity of M1 receptor. In the present study, we are reporting N-amino acid substituted 9(a–k) and dipeptides substituted 10(a–j) and 11(a–j) morpholino arecoline derivatives, along with their in vitro muscarinic binding studies by using [3H]QNB and also in vivo evaluation of memory and learning in male Wistar rats (passive avoidance test plus maze studies) as M1 receptor agonist. Some molecules from the dipeptide series (10b, 10c and 10j) showed potent M1 receptor agonist activity. Other derivatives also showed considerable M1 receptor binding affinity.

Novel N-Substituted Thiazolidinones as Proton Pump Inhibitors and Potent Anti-Ulcer Agents: SAR Study

A series of N-substituted thiazolidinone derivatives 5(a-j) was synthesized in good yield. All the compounds were screened for their in vitro H(+), K(+)-ATPase inhibitory activity. The structures of the synthesized compounds were confirmed by the spectral data. Compounds 5d, 5e, 5f and 5c showed potential H(+), K(+)-ATPase blocking activities, when compared to standard drug Lansoprazole. Structure-activity relationship studies, with various chemical groups, revealed that position and nature of the substitution on the N-thiazolidinones are crucial for H(+), K(+)-ATPase inhibitory activity.