Nirup B. Mondal

Regio- and Stereoselective Synthesis of a Library of Bioactive Dispiro-Oxindolo/Acenaphthoquino Andrographolides via 1,3-Dipolar Cycloaddition Reaction Under Microwave Irradiation

Dispiro-pyrrolidino/pyrrolizidino fused oxindoles/acenaphthoquinones have been derived from andrographolide via azomethine ylide cycloaddition to the conjugated double-bond under microwave (MW) irradiation. The reactions are chemo-, stereo-, and regioselective in nature. Change in amino acid from sarcosine/N-benzyl glycine to l-proline changes the regiochemistry. A representative library of 40 compounds along with in vitro anticancer evaluation is reported.

Determination of drug-like properties of a novel antileishmanial compound: In vitro absorption, distribution, metabolism, and excretion studies

In drug discovery research, the compounds should not only to be potent and selective but also must possess acceptable pharmacokinetic properties such as absorption, distribution, metabolism, and excretion (ADME) to increase success rate in clinical studies. Objective: Exploration of drug-like properties of 2-(2-methylquinolin-4-ylamino)-N-phenyl acetamide, a potent antileishmanial compound by performing some in vitro ADME experiments along with validation of such studies. Materials and Methods: Experimental protocols were established and validated for stability (in PBS pH7.4, simulated gastric and intestinal fluid), solubility, permeability, distribution coefficient (Log D), plasma protein binding and metabolism by rat liver microsomes by using spectrophotometer or HPLC. Methods were considered valid if the results of the standard compounds matched with reported results or within acceptable range or with proper ranking (high-medium-low). Results: The compound was found to be stable (>95% remaining) in all stability studies and aqueous solubility was 299.7 ± 6.42 μM. The parallel artificial membrane permeability assay (PAMPA) indicated its medium permeability (Log Pe = −5.53 ± 0.01). The distribution coefficients (Log D) in octanol/PBS and cyclohexane/PBS systems were found to be 0.54 and −1.33, respectively. The plasma protein binding study by the equilibrium dialysis method was observed to be 78.82 ± 0.13% while metabolism by Phase-I enzymes for 1 hour at 37°C revealed that 36.07 ± 4.15% of the compound remained after metabolism. Conclusion: The methods were found to be very useful for day-to-day ADME studies. All the studies with the antileishmanial compound ascertained that the compound bears optimum pharmacokinetic properties to be used orally as a potential drug for the treatment of leishmaniasis.

Overcoming multidrug resistance (MDR) in cancer in vitro and in vivo by a quinoline derivative.

Multidrug resistance (MDR) mediated by the over expression of drug efflux protein P-glycoprotein (P-gp) is one of the major impediments to successful treatment of cancer. P-gp acts as an energy-dependent drug efflux pump and reduces the intracellular concentration of structurally unrelated drugs inside the cells. Therefore, there is an urgent need for development of new compound that are less toxic and effective against drug resistance in cancer. Preclinical studies have shown that quinoline derivatives possess anticancer activities. Here, we report the antitumor potential of quinoline derivative, 2-(2-Methyl-quinolin-4ylamino)-N-phenyl acetamide (S4). To evaluate the cytotoxic potential of S4, we used four different cell lines (Hela, HCT-116, CCRF-CEM, and CEM/ADR 5000) in vitro, and showed that S4 kills doxorubicin resistant T lymphoblastic leukemia cell, CEM/ADR 5000 in a concentration dependent manner while others remains unaffected. Moreover, S4 induces apoptosis in CEM/ADR 5000xa0cells through generation reactive oxygen species (ROS). This is substantiated by the fact that the antioxidant N-acetyle-cysteine (NAC) completely blocks ROS generation and, subsequently, abrogates S4 induced apoptosis. Furthermore, in vivo treatment with S4 significantly increases the life span of swiss albino mice bearing sensitive and doxorubicin resistant subline of Ehrlich ascites carcinoma. In addition, intraperitoneal application of S4 in mice does not show any systemic toxicity at concentrations that in preliminary trials in a mice Ehrlich ascites carcinoma model. Therefore, present report provides evidence that S4, a quinoline derivative, may be a promising new therapeutic agent against drug resistant cancers.

Critical evaluation of the therapeutic potential of bassic acid incorporated in oil-in-water microemulsions and poly-d,l-lactide nanoparticles against experimental leishmaniasis

Bassic acid, an unsaturated triterpene acid isolated from Mimusops elangii, was tested for its antileishmanial properties both in vitro and in vivo. The in vitro antileishmanial activity of bassic acid being encouraging, its activity in vivo was evaluated in hamster models of visceral leishmaniasis, both in free form, as well as incorporated in two different delivery systems, viz microemulsions and polylactide nanoparticles. The delivery systems were prepared by published protocols. The percentage intercalation of bassic acid in nanoparticles and microemulsion was found to be about 50 and 100, respectively, when determined at its absorption maxima (λmax) 285 nm (εm = 2.3 × 102 M− 1 cm− 1). At an equivalent dose of 2 mg kg− 1 body weight, when injected subcutaneously for a total of six doses in 15 days, bassic acid was found to reduce spleen parasite loads by 45, 62 and 78% in free, microemulsion-incorporated and nanoparticle-incorporated forms, respectively. A comparison of specific biochemical tests related to normal liver and kidney functions revealed that the nanoparticulate form was successful in significantly reducing the hepatotoxicity and nephrotoxicity of the free drug, but the microemulsion delivery system was less effective and toxic to liver and kidney to some extent. Confocal microscopic images of Leishmania donovani promastigotes treated with bassic acid revealed that the drug induced necrotic cell death due to non-specific membrane damage. Because of its high efficacy as well as non-hepatotoxicity and non-nephrotoxicity, the nanoparticulate form of bassic acid may be considered for clinical application in humans rather than the microemulsion incorporated form.

Basic alumina-supported highly effective Suzuki-Miyaura cross-coupling reaction under microwave irradiation: application to fused tricyclic oxa-aza-quinolones†

Basic alumina used in lieu of traditional mineral bases efficiently promotes a solvent free, Pd(PPh3)4 catalyzed Suzuki–Miyaura cross-coupling reaction under microwave irradiation.

Evaluation of the wound healing activity of Shorea robusta, an Indian ethnomedicine, and its isolated constituent(s) in topical formulation.

ETHNOPHARMACOLOGICAL RELEVANCEnDifferent parts of Indian ethnomedicinal plant Shorea robusta is traditionally used for several ailments including wounds and burn by different tribal groups, since ages. Here we have validated, for the first time, the effectiveness and the possible mechanism of action of young leaf extracts of Shorea robusta, used by two distinct tribes of India, and its isolated compounds as a topical formulation in three wound models in rats.nnnMATERIALS AND METHODSnBioactivity-guided study of the active extract resulted in the isolation of two known compounds. The prepared ointment containing extracts (2.5 and 5%, w/w), fractions (5% w/w) and isolated compounds (0.25% w/w) were evaluated on excision, incision and dead space wound models in rats by the rate of wound closure, period of epithelialisation, tensile strength, granulation tissue weight, hydroxyproline content and histopathology.nnnRESULTSnThe animals treated with the extracts and fractions (5%) showed significant reduction in wound area 96.55 and 96.41% with faster epithelialisation (17.50 and 17.86), while the isolated compounds bergenin and ursolic acid heal the wound faster, but complete epithelialisation with 100% wound contraction was evident with 5% povidone-iodine group on 18th post-wounding day. Moreover, the tensile strength of incision wound, granuloma tissue weight, and hydroxyproline content was significantly increased in both the extract and compound(s) treated animals. Furthermore, the tissue histology of animals treated with the isolated compound(s) showed complete epithelialisation with increased collagenation, similar to povidone-iodine group.nnnCONCLUSIONnThus, our results validated the traditional use of Shorea robusta young leaves in wound management.

Chenopodium album seed extract-induced sperm cell death: exploration of a plausible pathway

BACKGROUNDnThis study was conducted for to explore the plausible pathway of Chenopodium album seed extract (CAE)-mediated sperm cell death.nnnSTUDY DESIGNnThe role of CAE for its spermicidal action was assessed by (a) measuring lipid peroxidation, protein carbonyl content and intracellular glutathione content in CAE exposed sperm cells; (b) assaying antioxidant enzymes like catalase and superoxide dismutase (SOD); (c) analyzing protein expressions by using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analysis; (d) fluorimetric measurement of intracellular H(2)O(2) level and generation of reactive oxygen species (ROS) in CAE-treated sperm cells; and (e) DNA ladder formation study.nnnRESULTSnCAE-induced sperm death is due to (a) lipid peroxidation of the sperm cell membrane, oxidation of some critical cellular proteins and depletion of intracellular reduced gluthathione, indicating production of ROS; (b) activation of Mn-SOD and inactivation of catalase favoring endogenous accumulation of H(2)O(2); (c) generation of O(2)(*-) at an enhanced rate during oxidative stress as evidenced by increased Mn-SOD activity and protein expression; (d) accumulation of ROS in spermatozoa reflected in the fluorimetric experiments; and (e) increased production of O(2)(*-) and H(2)O(2) induced apoptosis-like death in sperm cells as observed by DNA ladder formation.nnnCONCLUSIONnThe sperm death mediated by CAE is due to oxidative damage of cellular macromolecules by in situ generation of ROS.

Discovery of Safe and Orally Effective 4-Aminoquinaldine Analogues as Apoptotic Inducers with Activity against Experimental Visceral Leishmaniasis

ABSTRACT Novel antileishmanials are urgently required to overcome emergence of drug resistance, cytotoxic effects, and difficulties in oral delivery. Toward this, we investigated a series of novel 4-aminoquinaldine derivatives, a new class of molecules, as potential antileishmanials. 4-Aminoquinaldine derivatives presented inhibitory effects on L. donovani promastigotes and amastigotes (50% inhibitory concentration range, 0.94 to 127 μM). Of these, PP-9 and PP-10 were the most effective in vitro and demonstrated strong efficacies in vivo through the intraperitoneal route. They were also found to be effective against both sodium antimony gluconate-sensitive and -resistant Leishmania donovani strains in BALB/c mice when treated orally, resulting in more than 95% protection. Investigation of their mode of action revealed that killing by PP-10 involved moderate inhibition of dihydrofolate reductase and elicitation of the apoptotic cascade. Our studies implicate that PP-10 augments reactive oxygen species generation, evidenced from decreased glutathione levels and increased lipid peroxidation. Subsequent disruption of Leishmania promastigote mitochondrial membrane potential and activation of cytosolic proteases initiated the apoptotic pathway, resulting in DNA fragmentation and parasite death. Our results demonstrate that PP-9 and PP-10 are promising lead compounds with the potential for treating visceral leishmaniasis (VL) through the oral route.

Therapeutic effect of a novel anilidoquinoline derivative, 2-(2-methyl-quinoline-4ylamino)-N-(2-chlorophenyl)-acetamide, in Japanese encephalitis: correlation with in vitro neuroprotection.

2-(2-Methyl-quinoline-4ylamino)-N-(2-chlorophenyl)-acetamide, a novel anilidoquinoline derivative, was synthesised and evaluated for its therapeutic efficacy in treating Japanese encephalitis. The compound showed significant antiviral and antiapoptotic effects in vitro. Significant decreases in viral load (P<0.01) combined with an increase in survival was observed in Japanese encephalitis virus-infected mice treated with 2-(2-methyl-quinoline-4ylamino)-N-(2-chlorophenyl)-acetamide.

Synthesis and assessment of fertility-regulating potential of 2-(2″-chloroacetamidobenzyl)-3-(3′-indolyl) quinoline in adult rats as a male contraceptive agent

BACKGROUNDnThe purpose of this study was to investigate the fertility-regulating potential of the compound 2-(2-chloroacetamidobenzyl)-3-(3-indolyl) quinoline in male rats.nnnSTUDY DESIGNnRats of proven fertility were treated with the compound by oral gavage for 1 to 8 consecutive weeks. Functional fertility, testicular, epididymal and seminal vesicular weight, epididymal sperm count and spermatogenesis were quantitated. Reproductive hormones and some biochemical parameters were measured.nnnRESULTSnFunctional fertility was reduced significantly as revealed by a fall in fertility and pregnancy rate. The weight of the reproductive organs was reduced significantly. A reduction of sperm count and number of different types of testicular cells was observed. The treatment with the compound resulted in decline of testosterone and an increase of FSH hormone levels. The compound effectively reduced testicular protein, glycogen and epididymal glyceryl phosphorylcholine. Increase in testicular alkaline phosphatase and cholesterol was also observed. Fertility and other effects were regained gradually after cessation of treatment.nnnCONCLUSIONnThe results revealed from the study indicate that the compound has reversible antifertility activity and can be explored as male contraceptive agent.