Interplay between proteasome function and inflammatory responses in e-cig vapor condensate-challenged lung epithelial cells.

Exposure to cigarettes and other nicotine-based products results in persistent inflammation in the lung. In recent years, electronic cigarettes (e-cigs) have become extremely popular among adults and youth alike. E-cigarette vapor-induced oxidative stress promotes protein breakdown, DNA damage and cell death, culminating in a variety of respiratory diseases. The proteasome, a multi-catalytic protease, superintends protein degradation within the cell. When cells are stimulated with inflammatory cytokines such as IFN-γ and TNF-α, the constitutive catalytic proteasome subunits are replaced by the inducible subunits-low-molecular mass polypeptide (LMP)2 (ß1i), multi-catalytic endopeptidase complex-like (MECL)1 (ß2i), and LMP7 (ß5i), which are required for the production of certain MHC class I-restricted T-cell epitopes. In this study, we used human alveolar epithelial cells (A549) and exposed them to filtered air or (1%) tobacco-flavored (TF) electronic cigarette vapor condensate (ECVC) ± nicotine (6 mg/ml) (TF-ECVC ± N) for 24 h. We observed an increase in the levels of IFN-γ, TNF-α, and inducible proteasome subunits (LMP7/PSMB8, LMP2/PSMB9, MECL1/PSMB10), and a reduced expression of constitutive proteasome subunits (ß1/PSMB6 and ß2/PSMB7) in challenged A549 cells. Interestingly, knockdown of the inducible proteasome subunit LMP7 reversed ECVC-induced expression of NADPH oxidase and immunoproteasome subunits in A549 cells. In addition, pre-exposure to an LMP7 inhibitor (ONX-0914) abrogated the mRNA expression of several NOX subunits and rescued the excessive production/release of inflammatory cytokines/chemokines (IL-6, IL-8, CCL2, and CCL5) in ECVC-challenged cells. Our findings suggest an important role of LMP7 in regulating the expression of inflammatory mediators during ECVC exposure. Overall, our results provide evidence for proteasome-dependent ROS-mediated inflammation in ECVC-challenged cells.

Demographics of tuberculosis of spine and factors affecting neurological improvement in patients suffering from tuberculosis of spine: a retrospective analysis of 312 cases.

OBJECTIVES: The purpose of the study was to study demographics of tuberculosis of spine and analyze factors that might affect neurological improvement in such patients. METHODS: Of the 638 suspected cases of spinal tuberculosis, 312 cases with confirmed diagnosis with at least 1-year follow-up were selected for retrospective analysis. Two hundred cases who presented with neurological deficit were further divided into three groups-completely improved, partially improved and no improvement according to American Spinal Injury Association impairment scale (AIS) grading. All continuous variables and categorical variables were compared across groups. RESULTS: A total of 209 (66.99%) patients had typical clinical presentation. A total of 264 (84.62%) had typical magnetic resonance imaging (MRI) presentation. Among 356 involved vertebrae, thoracic levels (T1-10) were most commonly affected in 163 (45.78%) followed by thoracolumbar (T11-L2) vertebrae in 98 (27.52%). In 250 patients (80.12%), disease was restricted to one or two adjoining vertebrae. At presentation, 112 (35.89%) patients were neurologically intact, whereas 97 (31%) were AIS D, 65 (20.83%) were AIS C, 8 (2.5%) were AIS B and 30 (9.61%) were AIS A. On statistical analysis, although three groups of patients with complete improvement, partial improvement and no improvement were similar in age, sex, radiological presentation, and co-morbidities and the presence of pulmonary tuberculosis, they were significantly different with regard to the levels of vertebral involvement, AIS grade at presentation, bladder and bowel involvement and its duration. CONCLUSIONS: In management of patients suffering from tuberculosis of spine, levels of vertebral involvement, AIS grade at presentation, bladder and bowel involvement and its duration significantly affect the final neurological improvement.

Novel role of pancreatic differentiation 2 in facilitating self-renewal and drug resistance of pancreatic cancer stem cells.

BACKGROUND: Cancer stem cells (CSCs) contribute towards disease aggressiveness and drug resistance. Specific identification of CSC maintenance genes and targeting can improve the efficiency of currently available treatment modalities. Pancreatic differentiation 2 (PD2) has a major role in the self-renewal of mouse embryonic stem cells. In the present study, we investigated the role of PD2 in pancreatic CSCs. METHODS: Characterisation of CSCs and non-CSCs from mouse models, pancreatic cancer cells and human tissues by CSC and self-renewal marker analysis using confocal assay. Effect of PD2 knockdown in CSCs (after gemcitabine treatment) was studied by immunoblot and apoptosis assays. RESULTS: A subpopulation of cells displayed PD2 overexpression in mouse (Kras(G12D); Pdx1-Cre and Kras(G12D); Trp53(R172H/+); Pdx1-Cre) and human pancreatic tumours, which co-express CSC markers. Cancer stem cells exhibited elevated expression of PD2 and self-renewal markers, such as Oct3/4, Shh and ß-catenin. Gemcitabine treatment maintained the CSC population with simultaneous maintenance of PD2 and CSC marker expression. Knockdown of PD2 in CSCs resulted in reduced viability of cells and enhanced apoptosis along with abrogated expression of CD133 and MDR2. CONCLUSIONS: Our results suggest that PD2 is a novel CSC maintenance protein, loss of which renders the CSCs more susceptible to drug-induced cell death.

Unbiased analysis of pancreatic cancer radiation resistance reveals cholesterol biosynthesis as a novel target for radiosensitisation.

BACKGROUND: Despite its promise as a highly useful therapy for pancreatic cancer (PC), the addition of external beam radiation therapy to PC treatment has shown varying success in clinical trials. Understanding PC radioresistance and discovery of methods to sensitise PC to radiation will increase patient survival and improve quality of life. In this study, we identified PC radioresistance-associated pathways using global, unbiased techniques. METHODS: Radioresistant cells were generated by sequential irradiation and recovery, and global genome cDNA microarray analysis was performed to identify differentially expressed genes in radiosensitive and radioresistant cells. Ingenuity pathway analysis was performed to discover cellular pathways and functions associated with differential radioresponse and identify potential small-molecule inhibitors for radiosensitisation. The expression of FDPS, one of the most differentially expressed genes, was determined in human PC tissues by IHC and the impact of its pharmacological inhibition with zoledronic acid (ZOL, Zometa) on radiosensitivity was determined by colony-forming assays. The radiosensitising effect of Zol in vivo was determined using allograft transplantation mouse model. RESULTS: Microarray analysis indicated that 11 genes (FDPS, ACAT2, AG2, CLDN7, DHCR7, ELFN2, FASN, SC4MOL, SIX6, SLC12A2, and SQLE) were consistently associated with radioresistance in the cell lines, a majority of which are involved in cholesterol biosynthesis. We demonstrated that knockdown of farnesyl diphosphate synthase (FDPS), a branchpoint enzyme of the cholesterol synthesis pathway, radiosensitised PC cells. FDPS was significantly overexpressed in human PC tumour tissues compared with healthy pancreas samples. Also, pharmacologic inhibition of FDPS by ZOL radiosensitised PC cell lines, with a radiation enhancement ratio between 1.26 and 1.5. Further, ZOL treatment resulted in radiosensitisation of PC tumours in an allograft mouse model. CONCLUSIONS: Unbiased pathway analysis of radioresistance allowed for the discovery of novel pathways associated with resistance to ionising radiation in PC. Specifically, our analysis indicates the importance of the cholesterol synthesis pathway in PC radioresistance. Further, a novel radiosensitiser, ZOL, showed promising results and warrants further study into the universality of these findings in PC, as well as the true potential of this drug as a clinical radiosensitiser.

MELD exceptions for portopulmonary hypertension: current policy and future implementation.

Since 2006, waitlist candidates with portopulmonary hypertension (POPH) have been eligible for standardized Model for End-Stage Liver Disease (MELD) exception points. However, there are no data evaluating the current POPH exception policy and its implementation. We used Organ Procurement and Transplantation Network (OPTN) data to compare outcomes of patients with approved POPH MELD exceptions from 2006 to 2012 to all nonexception waitlist candidates during this period. Since 2006, 155 waitlist candidates had approved POPH MELD exceptions, with only 73 (47.1%) meeting the formal OPTN exception criteria. Furthermore, over one-third of those with approved POPH exceptions either did not fulfill hemodynamic criteria consistent with POPH or had missing data, with 80% of such patients receiving a transplant based on receiving exception points. In multivariable multistate survival models, waitlist candidates with POPH MELD exceptions had an increased risk of death compared to nonexception waitlist candidates, regardless of whether they did (hazard ratio [HR]: 2.46, 95% confidence interval [CI]: 1.73-3.52; n = 100) or did not (HR: 1.60, 95% CI: 1.04-2.47; n = 55) have hemodynamic criteria consistent with POPH. These data highlight the need for OPTN/UNOS to reconsider not only the policy for POPH MELD exceptions, but also the process by which such points are awarded.

Marked improvement of cytotoxic effects induced by docetaxel on highly metastatic and androgen-independent prostate cancer cells by downregulating macrophage inhibitory cytokine-1.

BACKGROUND: Overexpression of macrophage inhibitory cytokine-1 (MIC-1) frequently occurs during the progression of prostate cancer (PC) to androgen-independent (AI) and metastatic disease states and is associated with a poor outcome of patients. METHODS: The gain- and loss-of-function analyses of MIC-1 were performed to establish its implications for aggressive and chemoresistant phenotypes of metastatic and AI PC cells and the benefit of its downregulation for reversing docetaxel resistance. RESULTS: The results have indicated that an enhanced level of secreted MIC-1 protein in PC3 cells is associated with their acquisition of epithelial-mesenchymal transition features and higher invasive capacity and docetaxel resistance. Importantly, the downregulation of MIC-1 in LNCaP-LN3 and PC3M-LN4 cells significantly decreased their invasive capacity and promoted the antiproliferative, anti-invasive and mitochrondrial- and caspase-dependent apoptotic effects induced by docetaxel. The downregulation of MIC-1 in PC3M-LN4 cells was also effective in promoting the cytotoxic effects induced by docetaxel on the side population (SP) endowed with stem cell-like properties and the non-SP cell fraction from PC3M-LN4 cells. CONCLUSION: These data suggest that the downregulation of MIC-1 may constitute a potential therapeutic strategy for improving the efficacy of current docetaxel-based chemotherapies, eradicating the total mass of PC cells and thereby preventing disease relapse and the death of PC patients.

Impaired expression of protein phosphatase 2A subunits enhances metastatic potential of human prostate cancer cells through activation of AKT pathway.

BACKGROUND: Protein phosphatase 2A (PP2A) is a dephosphorylating enzyme, loss of which can contribute to prostate cancer (PCa) pathogenesis. The aim of this study was to analyse the transcriptional and translational expression patterns of individual subunits of the PP2A holoenzyme during PCa progression. METHODS: Immunohistochemistry (IHC), western blot, and real-time PCR was performed on androgen-dependent (AD) and androgen-independent (AI) PCa cells, and benign and malignant prostate tissues for all the three PP2A (scaffold, regulatory, and catalytic) subunits. Mechanistic and functional studies were performed using various biochemical and cellular techniques. RESULTS: Through immunohistochemical analysis we observed significantly reduced levels of PP2A-A and -B'γ subunits (P<0.001 and P=0.0002) in PCa specimens compared with benign prostate. Contemporarily, there was no significant difference in PP2A-C subunit expression between benign and malignant tissues. Similar to the expression pattern observed in tissues, the endogenous levels of PP2A-A and B'γ subunits were abrogated from the low metastatic to high metastatic and AD to AI cell line models, without any change in the catalytic subunit expression. Furthermore, using in vitro studies we demonstrated that PP2A-Aα scaffold subunit has a role in dampening AKT, ß-catenin, and FAK (focal adhesion kinase) signalling. CONCLUSION: We conclude that loss of expression of scaffold and regulatory subunits of PP2A is responsible for its altered function during PCa pathogenesis.

Secreted semaphorin 5A suppressed pancreatic tumour burden but increased metastasis and endothelial cell proliferation.

BACKGROUND: Our earlier reports demonstrated that membrane-bound semaphorin 5A (SEMA5A) is expressed in aggressive pancreatic cancer cells and tumours, and promotes tumour growth and metastasis. In this study, we examine whether (1) pancreatic cancer cells secrete SEMA5A and (2) that secreted SEMA5A modulates certain phenotypes associated with tumour progression, angiogenesis and metastasis through various other molecular factors and signalling proteins. METHODS AND RESULTS: In this study, we show that human pancreatic cancer cell lines secrete the extracellular domain (ECD) of SEMA5A (SEMA5A-ECD) and overexpression of mouse Sema5A-ECD in Panc1 cells (not expressing SEMA5A; Panc1-Sema5A-ECD; control cells - Panc1-control) significantly increases their invasion in vitro via enhanced ERK phosphorylation. Interestingly, orthotopic injection of Panc1-Sema5A-ECD cells into athymic nude mice results in a lower primary tumour burden, but enhances the micrometastases to the liver as compared with Panc1-control cells. Furthermore, there is a significant increase in proliferation of endothelial cells treated with conditioned media (CM) from Panc1-Sema5A-ECD cells and a significant increase in microvessel density in Panc1-Sema5A-ECD orthotopic tumours compared with those from Panc1-control cells, suggesting that the increase in liver micrometastases is probably due to increased tumour angiogenesis. In addition, our data demonstrate that this increase in endothelial cell proliferation by Sema5A-ECD is mediated through the angiogenic molecules - interleukin-8 and vascular endothelial growth factor. CONCLUSION: Taken together, these results suggest that a bioactive, secreted form of Sema5A-ECD has an intriguing and potentially important role in its ability to enhance pancreatic tumour invasiveness, angiogenesis and micrometastases.

Visual inspection of cervix with Lugol's iodine for early detection of premalignant & malignant lesions of cervix.

BACKGROUND & OBJECTIVES: Majority of cases of cervical cancer are diagnosed at an advanced stage as cytology based screening programmes are ineffective in developing countries. The present study was done to look for carcinoma cervix and its precursors by visual inspection with Lugol's iodine (VILI), visual inspection with acetic acid (VIA) and Papanicolaou smear, and to analyse their sensitivity, specificity and predictive values using colposcopic directed biopsy as reference. METHODS: In this cross-sectional study, 350 women were subjected to Pap smear, VIA, VILI and colposcopy. Cervical biopsy and endocervical curettage was taken from patients positive on any of these tests and in 10 per cent of negative cases. RESULTS: The Pap smear was abnormal in 3.71 per cent, including (2.85%), low grade (LSIL) and (0.85%) high grade squamous intraepithelial lesions (HSIL). Thirteen per cent of the patients were found to be positive by VIA and 11.71 per cent were positive on VILI. Sensitivity for VIA, VILI and Pap smear was 89.5, 100 and 52.6 per cent, respectively, while the specificity for VIA, VILI and Pap smear was 91.2, 93.3 and 99.1 per cent, respectively. INTERPRETATION & CONCLUSIONS: In low resource settings, cervical cancer screening by Pap smear can be replaced by visual methods like VILI, which has the highest sensitivity (100%) to detect any grade of dysplasia, and a good specificity (93.3%).

Discovering the route from inflammation to pancreatic cancer.

Pancreatic cancer (PC) remains a complex malignancy with the worst prognosis, lack of early diagnostic symptoms and resistance to conventional chemo- and radiotherapies. A better understanding of the etiology and early developmental events of PC requires profound attention. The evolution of fully blown PC from initial pancreatic injury is a multi-factorial phenomenon with a series of sequential events. The initial acute infection or tissue damage triggers inflammation that, in conjunction with innate immunity, establishes a state of homeostasis to limit harm to the body. Recurrent pancreatic injuries due to genetic susceptibility, smoking, unhealthy diet, and alcohol abuse induces a pro-inflammatory milieu, consisting of various types of immune cells, cytokines, chemokines, growth factors and restructured extracellular matrix, leading to prolonged inflammatory/chronic conditions. Cells having sustained DNA damage and/or mutagenic assault take advantage of this prolonged inflammatory response and aid in the initiation and development of neoplastic/fibrotic events. Eventually, many tumor-stromal interactions result in a chaotic environment accompanied by a loss of immune surveillance and repair response, thereby leading to PC. A better understanding of the inflammatory markers defining this "injury-inflammation-cancer" pathway would help to identify novel molecular targets for early screening and therapeutic intervention for this lethal malignancy.

Activated KrasG¹²D is associated with invasion and metastasis of pancreatic cancer cells through inhibition of E-cadherin.

BACKGROUND: Pancreatic cancer (PC) harbours an activated point mutation (Kras(G12D)) in the Kras proto-oncogene that has been demonstrated to promote the development of PC. METHODS: This study was designed to investigate the effect of the oncogenic Kras(G12D) allele on aggressiveness and metastatic potential of PC cells. We silenced the oncogenic Kras(G12D) allele expression in CD18/HPAF and ASPC1 cell lines by stable expression of shRNA specific to the Kras(G12D)allele. RESULTS: The Kras(G12D) knockdown cells exhibited a significant decrease in motility (P<0.0001), invasion (P<0.0001), anchorage-dependent (P<0.0001) and anchorage-independent growth (P<0.0001), proliferation (P<0.005) and an increase in cell doubling time (P<0.005) in vitro and a decrease in the incidence of metastases upon orthotopic implantation into nude mice. The knockdown of the Kras(G12D) allele led to a significant increase in the expression of E-cadherin (mRNA and protein) both in vitro and in vivo. This was associated with a decrease in the expression of phoshpo-ERK-1/2, NF-κB and MMP-9, and transcription factors such as δEF1, Snail and ETV4. Furthermore, the expression of several proteins involved in cell survival, invasion and metastasis was decreased in the Kras(G12D) knockdown cells. CONCLUSIONS: The results of this study suggest that the Kras(G12D) allele promotes metastasis in PC cells partly through the downregulation of E-cadherin.

Activation of ATM/Chk1 by curcumin causes cell cycle arrest and apoptosis in human pancreatic cancer cells.

Curcumin has been shown to inhibit the growth of various types of cancer cells; however, at concentrations much above the clinically achievable levels in humans. The concentration of curcumin achieved in the plasma after oral administration in humans was estimated to be around 1.8 microM. Here, we report that treatment of BxPC-3 human pancreatic cancer cells with a low and single exposure of 2.5 microM curcumin for 24 h causes significant arrest of cells in the G2/M phase and induces significant apoptosis. Immunoblot studies revealed increased phosphorylation of H2A.X at Ser-139 and Chk1 at Ser-280 and a decrease in DNA polymerase-beta level in curcumin-treated cells. Phosphorylation of H2A.X and Chk1 proteins are an indicator of DNA damage whereas DNA polymerase-beta plays a role in the repair of DNA strand breaks. Normal immortalised human pancreatic ductal epithelial (HPDE-6) cells remained unaffected by curcumin treatment. In addition, we also observed a significant increase in the phosphorylation of Chk1 at Ser-345, Cdc25C at Ser-216 and a subtle increase in ATM phosphorylation at Ser-1981. Concomitant decrease in the expressions of cyclin B1 and Cdk1 were seen in curcumin-treated cells. Further, curcumin treatment caused significant cleavage of caspase-3 and PARP in BxPC-3 but not in HPDE-6 cells. Silencing ATM/Chk1 expression by transfecting BxPC-3 cells with ATM or Chk1-specific SiRNA blocked the phosphorylation of ATM, Chk1 and Cdc25C and protected the cells from curcumin-mediated G2/M arrest and apoptosis. This study reflects the critical role of ATM/Chk1 in curcumin-mediated G2/M cell cycle arrest and apoptosis in pancreatic cancer cells.

Pancreatic cancer cells resistance to gemcitabine: the role of MUC4 mucin.

BACKGROUND: A major obstacle to the successful management of pancreatic cancer is to acquire resistance to the existing chemotherapeutic agents. Resistance to gemcitabine, the standard first-line chemotherapeutic agent for advanced and metastatic pancreatic cancer, is mainly attributed to an altered apoptotic threshold in the pancreatic cancer. The MUC4 transmembrane glycoprotein is aberrantly overexpressed in the pancreatic cancer and recently, has been shown to increase pancreatic tumour cell growth by the inhibition of apoptosis. METHODS: Effect of MUC4 on pancreatic cancer cells resistance to gemcitabine was studied in MUC4-expressing and MUC4-knocked down pancreatic cancer cell lines after treatment with gemcitabine by Annexin-V staining, DNA fragmentation assay, assessment of mitochondrial cytochrome c release, immunoblotting and co-immunoprecipitation techniques. RESULTS: Annexin-V staining and DNA fragmentation experiment demonstrated that MUC4 protects CD18/HPAF pancreatic cancer cells from gemcitabine-induced apoptosis. In concert with these results, MUC4 also attenuated mitochondrial cytochrome c release and the activation of caspase-9. Further, our results showed that MUC4 exerts anti-apoptotic function through HER2/extracellular signal-regulated kinase-dependent phosphorylation and inactivation of the pro-apoptotic protein Bad. CONCLUSION: Our results elucidate the function of MUC4 in imparting resistance to pancreatic cancer cells against gemcitabine through the activation of anti-apoptotic pathways and, thereby, promoting cell survival.

Biological control in agroecosystems.

Living organisms are used as biological pest control agents in (i) classical biological control, primarily for permanent control of introduced perennial weed pests or introduced pests of perennial crops; (ii) augmentative biological control, for temporary control of native or introduced pests of annual crops grown in monoculture; and (iii) conservative or natural control, in which the agroecosystem is managed to maximize the effect of native or introduced biological control agents. The effectiveness of biological control can be improved if it is based on adequate ecological information and theory, and if it is integrated with other pest management practices.

Natural Polyesters: Dufour's Gland Macrocyclic Lactones Form Brood Cell Laminesters in Colletes Bees.

Bees in the genus Colletes make their brood cells in the ground and coat them with a highly resistant, waterproof, transparent membrane. This membrane is a polyester constructed mainly from 18-hydroxyoctadecanoic acid and 20-hydroxy-eicosanoic acid, which are stored as their corresponding lactones in the Dufour's gland of the bee. When lining the cells, the bee secretes its glandular content, and the membrane is apparently a product of polycondensation reaction of its contents. This appears to be the first report of a naturally occurring linear polyester. The term laminester (lamina approximately layer + ester) for this class of compounds is proposed.

Alkali bees: response of adults to pathogenic fungi in brood cells.

Female alkali bees (Nomia melanderi) opened sealed cells containing brood infested with Aspergillus flavus, A. tamarii, Fusarium solani, Rhizopus sp., or Mucor sp. and filled them with compact soil, thus reducing fungus sporulation. Such awareness of the condition of sealed brood is hitherto unknown among solitary bees.

Floral Mimicry Induced by Mummy-Berry Fungus Exploits Host's Pollinators as Vectors.

Leaves and shoots of blueberries(Vaccinium spp.) and huckleberries (Gaylussacia sp.) when infected by ascospores of Monilinia spp. become ultraviolet-reflective and fragrant and secrete sugars at their lesions. Insects that normally pollinate these hosts are attracted to the discolored leaves, ingest the sugars, and transmit conidia to their flowers, resulting in sclerotia (mummy-berry) formation.

Anthophora Bees: Unusual Glycerides from Maternal Dufour's Glands Serve as Larval Food and Cell Lining.

The Dufour's gland of Anthophora abrupta, a solitary bee, secretes a complex mixture of liquid triglycerides containing one long-chain and two shortchain fatty acids. This is applied inside the earthen brood cells and added to the provision, where it is converted, perhaps by enzymes from the bee's saliva or gut, to solid diglycerides that are later eaten by the bee larvae. This use of Dufour's gland secretion as food and its nutritive function are reminiscent of the royal jelly secreted by honey bees.

Search for new pharmacophores for antimalarial activity. Part II: synthesis and antimalarial activity of new 6-ureido-4-anilinoquinazolines.

Synthesis of new 6-ureido-4-anilinoquinazolines have been accomplished and their in vitro antimalarial activity against chloroquine-sensitive P. falciparum have been examined. Out of 64 compounds evaluated, the IC(50) of 16 compounds which have displayed MIC of 0.25 microg/mL were also recorded. One of the compounds (24 g) had IC(50) value of 2.27 ng/mL which was equipotent to the standard drug chloroquine used in the bioassay. The in vivo evaluation of a few compounds among the series led to discovery of one analog (30 g) displaying 40% curative activity (28 days) against mdr P. yoeillinigeriensis at an oral dose of 100 mg/kg x 4 days.

Search for new pharmacophores for antimalarial activity. Part I: synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides.

A total of 80 new 2-methyl-6-ureido-4-quinolinamides were synthesized and evaluated for their antimalarial activity. Several analogs elicited the antimalarial effect at MIC of 0.25 mg/mL against the chlooquine-sensitive P. falciparum strain. The IC(50) values of the active compounds were observed to be in ng/mL range and two of the analogs have better IC(50) value than the standard chloroquine. In the in vivo assay against mdr CQ resistant P. yoelii N67/P. yoelii nigeriensis, however, none of the compound showed complete suppression of parasitemia on day 7. One of the compounds displayed significant antibacterial effect against several strains of bacteria and was many-fold better than the standard drug gentamicin.