D. S. Prasanna

Anti-cancer activity of novel dibenzo[b,f]azepine tethered isoxazoline derivatives.

Background Dibenzoazepine (DB) derivatives are important and valuable compounds in medicinal chemistry. The synthesis and chemotherapeutic properties of naturally occurring DBs and different heterocyclic moiety tethered DBs are reported. Herein, we report the DB-fused hybrid structure that containing isoxazolines (DBIs) and their anti-cancer activity, which could throw light on the structural and functional features of new molecules. Results and Conclusion The synthesis and characterization of novel ring DB tethered isoxazoline derivatives (DBIs) were carried out. After the detailed structural characterization using 2D-NMR experiments, the compounds were identified as 5-substituted isoxazolines. The effect of newly synthesized DBIs against the invasion of murine osteosarcoma (LM8G7) cells was studied. Among the tested molecules, compound 4g (5-[−3-(4-chlorophenyl)-4,5-dihydroisoxazol-5-yl-methyl]-5 H-dibenzo[b,f]azepine), was found to inhibit the invasion of LM8G7 cells strongly, when compared to other structurally related compounds. Cumulatively, the compound 4g inhibited the invasion MDA-MB-231 cells completely at 10 μM. In addition to anti-invasion property the compound 4g also inhibited the migration of LM8G7 and human ovarian cancer cells (OVSAHO) dose-dependently. Compound 4g inhibited the proliferation of LM8G7, OVSAHO, human breast cancer cells (MCF-7) and human melphalan-resistant multiple myeloma (RPMI8226-LR5) cells that are comparable to cisplatin and suramin.

Synthesis and Antileukemic Activity of Novel 4-(3-(Piperidin-4-yl) Propyl)Piperidine Derivatives

To explore the anticancer effect associated with the piperidine framework, several (substituted phenyl) {4‐[3‐(piperidin‐4‐yl)propyl]piperidin‐1‐yl} methanone derivatives 3(a–i) were synthesized. Variation in the functional group at N‐terminal of the piperidine led to a set of compounds bearing amide moiety. Their chemical structures were confirmed by 1H NMR, IR and mass spectra analysis. Among these, compounds 3a, 3d and 3e were endowed with antiproliferative activity. The most active compound among this series was 3a with nitro and fluoro substitution on the phenyl ring of aryl carboxamide moiety, which inhibited the growth of human leukemia cells (K562 and Reh) at low concentration. Comparison with other derivative (3h) results shown by LDH assay, cell cycle analysis and DNA fragmentation suggested that 3a is more potent to induce apoptosis.

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.

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.

Synthesis, Characterization and In Vitro Antiproliferative Effects of Novel 5-Amino Pyrazole Derivatives against Breast Cancer Cell Lines

In search of synthetic chemotherapeutic substances capable of inhibiting, retarding, or reversing the process of multistage carcinogenesis, we synthesised a series of novel 1-(4-methoxybenzyl)-3-cyclopropyl-1H-pyrazol-5-amine derivatives 9(a-h) by a nucleophilic substitution reaction and characterized by (1)H and (13)C nuclear magnetic resonance (NMR), liquid chromatography mass spectrometry (LC/MS), Fourier-transform infrared (FTIR), and elemental analysis. These novel compounds were evaluated for their efficacy in inhibiting VERO normal and MCF-7 breast cancer cells proliferation by trypan blue exclusion assay, MTT assay, [(3)H] thymidine incorporation assay and DNA fragmentation analysis. Among the series, some compounds exhibited interesting growth inhibitory effects against cell lines. From the Structure-Activity Relationship studies, it has been revealed that, both novel patented compounds and therapeutic protocols of N-terminal pyrazole ring structures play key role in the antiproliferative activity.

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).

Inhibition of gastric H+, K+-ATPase by novel thiazolidinone derivatives.

In a program to identify new anti-ulcer compounds, a series of novel substituted thiazolidinone derivatives 5(a–j) were synthesized and screened for their in vitro H+, K+-ATPase inhibitory activity. The synthesized compounds were characterized by nuclear magnetic resonance (1H-NMR), liquid chromatography-mass spectrometry (LCMS) and fourier transform infrared (FTIR) analysis. We have briefly investigated the structure–activity relation (SAR) studies and reveal that the nature of position of the fluorine atom influences the anti-ulcer activity. Among the synthesized compounds 5b, 5c and 5e showed 4 and 10-fold higher H+, K+-ATPase activity when compared with those of other derivatives 5a, 5f, 5g and 5j, respectively. H+, K+-ATPase activity of 5b, 5c and 5e were comparable with those of known H+, K+-ATPase blocker lansoprazole which is a potential anti-ulcer drug.

Synthesis and Characterization of Substituted Ethyl 2-(1-aminocyclobutyl)- 5-(benzoyloxy)-6-hydroxypyrimidine-4-carboxylate Derivatives as Antioxidant Agents

A series of novel ethyl 2-(1-aminocyclobutyl)-5-(benzoyloxy)-6-hydroxy-pyrimidine-4-carboxylate derivatives 8(a-i) were synthesized by nucleophilic substitution reaction of ethyl 2-(1-aminocyclobutyl)-5-(benzoyloxy)-6-hydroxypyrimidine-4-carboxylate (7) with different substituted aliphatic/aromatic sulfonyl chlorides (R-SO(2)-Cl). All the synthesized compounds were characterized by IR, (1)H NMR and LC/MS analysis. The synthesized compounds were evaluated for their antioxidant activity by diphenylpicrylhydrazyl (DPPH) assay and also by hydroxy radical induced DNA strand scission assay. Among the synthesized compounds 8c, 8f and 8i showed promising antioxidant activity.

Synthesis of 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2- a] pyrimidin-4-one derivatives as antibacterial agents

A series of novel 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one aliphatic/ aromatic/ heterocyclic amine derivatives were synthesized in good yield. The synthesized compounds were characterized by 1H-NMR, FTIR and elemental analysis. All the synthesized compounds were screened for their in vitro antibacterial activity by agar well diffusion and micro dilution method against standard strains of Gram-Positive (Bacillus Subtilis MTCC 121 and Staphylococcus epidermidis 435), and Gram-negative (Xanthomonas Campestris 7903 and Pseudomonas aeruginosa MTCC 7908) bacteria. Compounds with substituted heterocyclic piperazine moiety showed good activity. In particular, compound 6i showed two fold better activity compared to the standard drug Strepyomycin sulphate.