T. Prashanth

Synthesis, angiopreventive activity, and in vivo tumor inhibition of novel benzophenone-benzimidazole analogs.

AIM The development of anticancer drugs with specific targets is of prime importance in modern biology. This study investigates the angiopreventive and in vivo tumor inhibition activities of novel synthetic benzophenone-benzimidazole analogs. MAIN METHODS The multistep synthesis of novel benzophenone-benzimidazole analogs (8a-n) allowing substitution with methoxy, methyl and halogen groups at different positions on the identical chemical backbone and the variations in the number of substituents were synthesized and characterized. The newly synthesized compounds were further evaluated for cytotoxic and antiproliferative effects against Ehrlich ascites carcinoma (EAC) cells. The potent lead compounds were further assessed for antiangiogenic effects in a CAM model and a tumor-induced vasculature in vivo model. The effect of angioprevention on tumor growth was verified in a mouse model. KEY FINDINGS The cytotoxicity studies revealed that compounds 8f and 8n are strongly cytotoxic. Analyzing the structure-activity relationship, we found that an increase in the number of methyl groups in addition to methoxy substitution at the para position of the benzoyl ring in compound 8n resulted in higher potency compared to 8f. Furthermore, neovessel formation in in vivo systems, such as the chorioallantoic membrane (CAM) and tumor-induced mice peritoneum models, was significantly suppressed and reflected the tumor inhibition observed in mice. SIGNIFICANCE These results suggest the potential clinical application of compound 8n as an antiangiogenic drug for cancer therapy.

BP-1T, an antiangiogenic benzophenone-thiazole pharmacophore, counteracts HIF-1 signalling through p53/MDM2-mediated HIF-1α proteasomal degradation

Hypoxia is a feature of all solid tumours, contributing to tumour progression. Activation of HIF-1α plays a critical role in promoting tumour angiogenesis and metastasis. Since its expression is positively correlated with poor prognosis for cancer patients, HIF-1α is one of the most convincing anticancer targets. BP-1T is a novel antiproliferative agent with promising antiangiogenic effects. In the present study, the molecular mechanism underlying cytotoxic/antiangiogenic effects of BP-1T on tumour/non-tumour angiogenesis was evaluated. Evidences show that BP-1T exhibits potent cytotoxicity with prolonged activity and effectively regressed neovessel formation both in reliable non-tumour and tumour angiogenic models. The expression of CoCl2-induced HIF-1α was inhibited by BP-1T in various p53 (WT)-expressing cancer cells, including A549, MCF-7 and DLA, but not in mutant p53-expressing SCC-9 cells. Mechanistically, BP-1T mediates the HIF-1α proteasomal degradation by activating p53/MDM2 pathway and thereby downregulated HIF-1α-dependent angiogenic genes such as VEGF-A, Flt-1, MMP-2 and MMP-9 under hypoxic condition of in vitro and in vivo solid tumour, eventually leading to abolition of migration and invasion. Based on these observations, we conclude that BP-1T acts on HIF-1α degradation through p53/MDM2 proteasome pathway.

Synthesis and evaluation of novel benzophenone-thiazole derivatives as potent VEGF-A inhibitors

A series of 2-(4-benzoyl-phenoxy)-N-(4-phenyl-thiazol-2-yl)-acetamides (10a-n) were synthesized by multistep reaction sequence and all the compounds were well characterized for structural elucidation. The in vitro cytotoxicity of compounds 10a-n was evaluated against EAC and DLA cell lines using trypan blue dye exclusion method. Further MTT assay and LDH release assay, followed by in vivo studies on murine model were also evaluated. The compound 10h with a methyl and fluoro groups at benzophenone moiety and methoxy group at phenyl ring was in a leading position to exhibit the promising antiproliferative effect through translational VEGF-A inhibition.

SYNTHESIS AND BIOLOGICAL EFFICACY OF NOVEL PIPERAZINE ANALOGUES BEARING QUINOLINE AND PYRIDINE MOIETIES.

A series of novel piperazine analogues bearing quinolin-8-yloxy-butan-1-ones/pyridin-2-yloxyethanones were synthesized by a simple and convenient approach based on various substituted piperazine incorporating quinoline and pyridine moieties. The analogues were evaluated for in vitro antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and ferrous ion radical scavenging activities and anti-inflammatory activity by inhibition of Vipera russelli venom (PLA2) and gastric K+/H+-ATPase activities. Most of the title compounds exhibited promising activity. Best antioxidant and PLA2-inhibiting activities were found for piperazine analogues with phenyl and nitro phenyl groups, whereas methoxy group on phenyl piperazine indicated selectivity for the H+/K+-ATPase.

Synthesis, Antioxidant, and Xanthine Oxidase Inhibitory Activities of 5-[4-[2-(5-Ethyl-2-pyridinyl)ethoxy]phenyl]methyl]-2,4-thiazolidinedione Derivatives

Xanthine oxidase (XO) is a complex metalloflavoprotein, the overproduction of which usually leads to a pathological condition called gout. The XO inhibitors may prove to be promising antigout agents. The XO generates superoxide anions and H2O2 for the self‐defense system of the organism. Abnormal production of this superoxide (reactive oxygen species) is responsible for a number of complications including inflammation, metabolic disorder, cellular aging, reperfusion damage, atherosclerosis, and carcinogenesis. In this paper, we report the synthesis of N‐substituted analogs of thiazolidinedione derivatives as effective and new class of XO inhibitors and also as antioxidant agents. Among all the compounds in the series, compound 2i produced relatively better activity against human milk XO (72% inhibition), which was also supported by docking studies.

Evaluation of Benzophenone-N-ethyl Morpholine Ethers as Antibacterial and Antifungal Activities

Microorganisms are closely associated with the health and welfare of human beings. Whereas some microorganisms are beneficial, others are detrimental. Bacterial infections often produce inflammation and pains and in some instances, infections result in high mortality. Any subtle change in the drug molecule, which may not be detected by chemical methods, can be revealed by a change in the antimicrobial activity and hence microbiological assays are very useful. A series of substituted hydroxy benzophenones and benzophenone-N-ethyl morpholine ethers were screened for their antibacterial and antifungal activities. Antibacterial activity against S. aureus, E. aerogenes, M. luteus, K. pneumonia, and S. typhimurium, S. paratyphi-B and P. vulgaris bacterial strains and antifungal activity against C. albicans, B. cinerea, M. pachydermatis, C. krusei fungal strains were carried out. The bioassays indicated that most of the synthesized compounds showed potential antibacterial and antifungal agents.

(4-Hy-droxy-3,5-di-methyl-phen-yl)(phen-yl)methanone.

In the molecule of the title compound, C15H14O2, the dihedral angle between the benzene and phenyl rings is 61.27 (8)°. In the crystal, O—H⋯O and weak C—H⋯O hydrogen bonds link the molecules into chains extending along the c-axis direction.

SYNTHESIS AND CHARACTERIZATION OF COUMARIN ANALOGS: EVALUATION OF ANTIMICROBIAL AND ANTIOXIDANT ACTIVITIES

Coumarins and their analogs were found to be better antitumoral agents and still active against human retroviral invading system. This property could be ameliorated by coupling of few active groups to the parental molecule for enhancing its frequency of biofunctional diversity and multi spectrum characteristic, such an endeavor was done by 2-Oxo-2H-chromene-3-carboxylic acid phenylamide analogs. The structure were well characterized. Further the antimicrobial activity was examined by disc diffusion method and based on the minimum inhibitory concentration (MIC) values obtained the molecules were approximately 70% as active as the positive control especially halogenated compounds showed promising result. Even their free radical scavenging activity was considerably as good as 20% to that of ascorbic acid. Present research on coumarin analogs necessitate novel ideas in synthetic chemistry therein concerning the development of innovative synthetic strategies that could help in drug design.

Synthesis and Biological Applications of (E)-N-Benzylidene-5-bromo-2-chloropyrimidin-4-amine Derivatives

Schiff bases are aldehyde-like compounds in which an imine group replaces the carbonyl group. They are widely used for industrial purposes and also exhibit a broad range of biological activities. This study represents the synthesis of a new series of (E)-N-benzylidene-5-bromo-2-chloropyrimidin-4-amine derivatives (6a-l). The newly synthesized compounds were characterized by different spectral studies. All these compounds are screened for their anti-inflammatory, antimicrobial and in vitro antioxidant activities. The structure-activity relationship analysis demonstrates that hydroxyl groups on the aromatic ring contribute critically to the antioxidant activity. Compounds 6k, 6j, 6d and 6e showed significant radical scavenging and compounds 6d, 6e and 6f showed good antimicrobial and anti-inflammatory activities.

Azamacrocycle Complexes: Synthesis and Xanthine Oxidase and Antioxidant Activity

Aims: Gout is caused by high uric acid in the blood that leads to excess uric acid crystallizing in the joints causing swelling and pain. Uric acid is produced from the breakdown of the purine which is released when cells die or introduced from the food we eat. The enzyme that helps in breakdown of purine to uric acid is xanthine oxidase (XO). Since XO makes the conversion of purine into uric acid happen, preventing its activity results to slow down of uric acid production. Such is the role of xanthine oxidase inhibitors (XOI). In this context we aimed to synthesize new complex which can be potent towards XOI and antioxidant properties.Study Design: Based on the literature we have designed azamacrocyclic complexes for advanced biological applications.Place and Duration of Study: Department of Chemistry, Research Laboratory, Yuvaraj’s College, University of Mysore, Mysore for synthesis and for biological activities Mahajana Life Science Research Laboratory, Department of Biotechnology, Microbiology and Biochemistry. June 2012-may 2013.Methodology: The macrocyclic metal complexes were synthesized by the template condensation of diamine and formaldehyde in MeOH. After stirring for 10 min a solution of 1, 4-diaminobutane, metallic salt and 2, 4-pentanedione in MeOH was added and the resulting mixture was refluxed.Results: Macrocylic metal complexes containing phenylene bridges have been synthesized and subjected to biological activities. Among the four synthesized complexes (3a-3d), 3d exhibited 83.2% of XO inhibition and also showed potent antioxidant activity. The same was also evident from structure activity relationship with atomic contact energy values of -285.78 compared to allopurinol with -200.02.Conclusion: From the present study, we infer that, aza macrocyclic metal complexes could lead to the development of newer therapeutics for gout and other inflammatory diseases which are caused by oxidative stress.