Santosh L. Gaonkar

Growth inhibition and induction of apoptosis in MCF-7 breast cancer cells by a new series of substituted-1,3,4-oxadiazole derivatives

SummaryThe multiple pharmacological actions of unique synthetic compounds are a prerequisite for classifying a drug as highly efficacious, because the multiple pharmacological actions offer the possibility of treating various diseases like cancer. 1,3,4-Oxadiazoles are an important class of heterocyclic compounds with broad spectrum of biological activities. In this study we focused on the ability of these derivatives to induce apoptosis in cultured MCF-7 breast cancer cells. Treatment of MCF-7 cells with varying concentrations of the different derivatives resulted in dose and time dependent sequence of events marked by apoptosis, as shown by loss of cell viability, chromatin condensation, internucleosomal DNA fragmentation and sub G0 phase accumulation. Furthermore, apoptosis in MCF-7 cell was induced by upregulation of proto-oncoprotein Bax and activation of Caspase-3 activated DNase. Although the derivatives induced apoptosis was associated with Bax protein levels, negligible Bcl-2 reduction was observed. Analysis of the data suggests that the substituted oxadiazole derivatives exert antiproliferative action and growth inhibition on MCF-7 cells through apoptosis induction and that it may have anticancer properties valuable for application in drug products.

Synthesis of novel 3-[5-ethyl-2-(2-phenoxy-ethyl)-pyridin]-5-substituted isoxazoline libraries via 1,3-dipolar cycloaddition and evaluation of antimicrobial activities

A series of novel 3-[5-ethyl-2-(2-phenoxy-ethyl)-pyridin]-5-substituted isoxazolines were synthesized via 1,3-dipolar cycloaddition of in situ generated nitrile oxide from 4-[2-(5-ethylpyridyl)-ethoxy]-benzaldoxime with alkenes to obtain new heterocyclic libraries containing a pyridine moiety in addition to the isoxazoline ring. The newly synthesized compounds were screened for their antimicrobial activity and were compared with standard drugs. The compounds demonstrated potent to weak antimicrobial activity. Of the compounds studied, compounds 3c and 3f showed significant antibacterial as well as antifungal activity. Compounds 3e and 3g showed moderate activity. The title compounds represent a novel class of potent antimicrobial agents.

Microwave-assisted synthesis and evaluation of anti-inflammatory activity of new series of N-substituted 2-butyl-5-chloro-3H- imidazole-4-carbaldehyde derivatives

A series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives bearing potentially bioactive substituents were synthesized by microwave irradiation method in good yield compared with conventional method. The synthesized compounds were screened for their anti-inflammatory activity and were compared with a standard drug. The compounds demonstrated potent to weak anti-inflammatory activity. Of the compounds studied, compounds 6i and 6d showed potent activity comparable to the standard drug ibuprofen at the same dose in carrageenan-induced paw edema in rat model.

N-Substituted-2-butyl-5-chloro-3H-imidazole-4-carbaldehyde Derivatives as Anti-tumor Agents Against Ehrlich Ascites tumor Cells In Vivo

A new series of N-substituted 2-butyl-5-chloro-3H-imidazole-4-carbaldehyde derivatives were synthesized by using the different bioactive heteroaralkyl halides with 2-butyl-4-chloro-1H-imidazole-5-carbaldehyde in presence of powdered potassium carbonate in DMF medium. These compounds were screened for their antitumor activity. Our results show that treatment of imidazole derivatives inhibit proliferation EAT cells, decreases the ascites volume and increases the survivability of the animals in vivo. These compounds also inhibited the cellular proliferation of HUVEC cells in vitro by MTT assay. Further, these compounds could induce apoptosis, which is evident by the nuclear condensation of imidazole derivatives treated EAT cells in vivo by the cytological analysis. We have identified that pyrrolidine substituted imidazole derivative as potent anti-tumor compound. These inhibitors could represent as promising candidates for anticancer therapies, where the formation of peritoneal malignant ascites is a major cause of morbidity and mortality.

Neutralization of Haemorrhagic Activity of Viper Venoms by 1-(3-Dimethylaminopropyl)-1-(4-Fluorophenyl)-3-Oxo-1,3-Dihydroisobenzofuran-5-Carbonitrile

Viper envenomation undeniably induces brutal local manifestations such as haemorrhage, oedema and necrosis involving massive degradation of extracellular matrix at the bitten region and many a times results in dangerous systemic haemorrhage including pulmonary shock. Snake venom metalloproteases (SVMPs) are being considered to be the primary culprits for the venom-induced haemorrhage. As a consequence, the venom researchers and medical practitioners are in deliberate quest of SVMP inhibitors. In this study, we evaluated the inhibitory effect of 1-(3-dimethylaminopropyl)-1-(4-fluorophenyl)-3-oxo-1,3-dihydroisobenzofuran-5-carbonitrile (DFD) on viper venom-induced haemorrhagic and PLA(2) activities. DFD effectively neutralized the haemorrhagic activity of the medically important viper venoms such as Echis carinatus, Echis ocelatus, Echis carinatus sochureki, Echis carinatus leakeyi and Crotalus atrox in a dose-dependent manner. The histological examinations revealed that the compound DFD effectively neutralizes the basement membrane degradation, and accumulation of inflammatory leucocytes at the site of Echis carinatus venom injection further confirms the inhibition of haemorrhagic activity. In addition, DFD dose dependently inhibited the PLA(2) activities of Crotalus atrox and E. c. leakeyi venoms. According to the docking studies, DFD binds to hydrophobic pocket of SVMP with the ki of 19.26 × 10(-9) (kcal/mol) without chelating Zn(2+) in the active site. It is concluded that the clinically approved inhibitors of haemorrhagins could be used as a potent first-aid agent in snakebite management. Furthermore, a high degree of structural and functional homology between SVMPs and their relatives, the MMPs, suggests that DFD analogues may find immense value in the regulation of multifactorial pathological conditions like inflammation, cancer and wound healing.

Synthesis of new series of 5,6-dihydro-4H-1,2-oxazines via hetero Diels-Alder reaction and evaluation of antimicrobial activity

A new series of 5,6-dihydro-4H-1,2-oxazines were synthesized via hetero Diels-Alder reaction of alpha-nitrosoolefins with alkenes. alpha-Nitrosoolefins were generated from ketoximes by the action of chloramine-T. The newly synthesized compounds were characterized with IR, NMR, elemental analysis and screened for their antimicrobial activity; they exhibited excellent antimicrobial activity. The minimal inhibitory concentration of the compounds was in the range of 10-35 microg ml(-1) for bacteria and 10-40 microg ml(-1) for fungi.

A facile synthesis of N-substituted 2,5-dimethylpyrroles with saccharin as a green catalyst

The paper describes a convenient method for the preparation of N-substituted 2,5-dimethylpyrroles using edible sweetener saccharin. Various heterocyclic and aromatic hydrazides have been converted to their corresponding Paal–Knorr pyrroles at room temperature in methanol with saccharin as a green catalyst. Saccharin can be recycled for the next two runs without apparent loss in its activity. Here we propose a method which is speedy, proficient, and ecologically safe.

Microwave-Assisted Solution Phase Synthesis of Novel 2-{4-[2-(N-Methyl-2-pyridylamino)ethoxy]phenyl}-5-Substituted 1,3,4-Oxadiazole Library

A new series of 2-{4-[2-(N-methyl-2-pyridylamino)ethoxy]phenyl}-5-substituted 1,3,4-oxadiazoles were synthesized by the oxidative cyclization of hydrazones derived from 4-[2-(methylpyridin-2-ylamino)ethoxy]benzaldehyde and aryl hydrazines using chloramine-T as an efficient catalyst. All steps were assisted by microwave irradiation. Microwave enables all these reactions to be simple, rapid, high yielding, and avoid chromatograph purification and led environmentally benign total synthesis of focused oxadiazole library. All the synthesized compounds were isolated in good yield and characterized by 1H NMR, 13C NMR, and elemental analyses. The title compounds represent a novel class of biologically active heterocycles.

Microwave-Assisted Solvent-Free Synthesis of N-alkyl Benzotriazole Derivatives: Antimicrobial Studies

To elucidate further our structural activity relation on the chemistry and antimicrobial activity, a series of novel N-alkylated benzotriazole derivatives bearing pharmaceutically important substituted biphenyl and benzyl halides were synthesized. The synthesized compounds were characterized and tested for in vitro antimicrobial activities by MIC determination against a panel of susceptible and resistant Gram-positive and Gram-negative microorganisms. The synthesis has been carried out using microwave irradiation method with solvent and without solvent. The obtained results showed high yields. Interestingly, compounds 2a and 2b showed a two fold increased antibacterial activity than the standard drug tested and the compounds 2d and 2e showed potent antifungal activity than the standard drug tested.

Synthesis and pharmacological properties of chalcones: a review

Chalcones and their analogs have been an area of great interest in recent years. Numerous research papers have been published, and chalcones continue to show promise for new drug investigations. Researchers have explored new approaches for the synthesis of chalcone derivatives, which have revealed an array of pharmacological and biological effects. These chalcone derivatives have shown important antimicrobial, antifungal, anti-mycobacterial, antimalarial, antiviral, anti-inflammatory, antioxidant, antileishmanial anti-tumor, and anticancer properties. This review highlights the synthesis and pharmacological properties of chalcone derivatives.