Life Sciences

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Shiv Nadar University

Three series of novel and new fused heterocyclic systems, viz. triazolo[4,3-a]-quinazolin-7-ones (4), [1,2,4,5]-tetrazino[4,3-a]-quinazolin-8-ones (6) and indolo[2,3-c][1,2,4]-triazino[4,3-a]-quinazolin-8-ones (8) have been synthesized from the key intermediate 3-(substituted-phenyl)-2-hydrazino-quinazolin-4-ones (3). Thus, condensation of (3) with appropriate aromatic acids in the presence of DCC in dichloromethane afforded the fused system (4), while reaction of (3) with isatin in methanol gave the corresponding Schiff base (7) which on cyclodehydration furnished another fused heterocyclic system (8). The intermediate (3) on refluxing with substituted-phenylisothiocyanate gave the substituted-thiosemicarbazide (5), which on oxidative cyclization with bromine in CCl4 furnished the novel fused system (6). The structures of intermediate and final compounds have been determined by means of IR, 1H NMR, 13C NMR, UV and elemental analysis. All the synthesized compounds have been screened for their antibacterial activity against Gram-negative bacteria, Escherichia coli, Pseudomonas aeruginosa and Gram-positive bacteria, Streptococcus pneumoniae, Bacillus subtilis, as well as demonstrated significant antifungal activity against fungi viz. Candida albicans, Aspergillus fumigatus, Aspergillus flavus, and Aspergillus niger. © 2008 Elsevier Masson SAS. All rights reserved.

World University root node

(SoNS) School of Natural Sciences

European Journal of Medicinal Chemistry

Antimicrobial studies of some novel quinazolinones fused with [1,2,4]-triazole, [1,2,4]-triazine and [1,2,4,5]-tetrazine rings

The discrete VLF chorus emissions recorded at low latitude ground station Jammu (geomag. lat. = 22°26′N, L = 1.17) are reported and their characteristics based on spectral analysis have been carried out. These discrete chorus emissions are falling tone emissions which are rarely observed at low latitude ground stations. These discrete chorus emissions are generated during a strong geomagnetic storm period of 2-7 May, 1998. We have computed the frequency sweep rate, repetition period and source region of the individual chorus elements. It is observed that the sweep rate increases with time. Copyright © The Society of Geomagnetism and Earth.

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Earth, Planets and Space

Characteristics of discrete VLF falling-tone chorus emissions observed at low latitude ground station Jammu

Origin recognition complex subunit 1 (ORC1) is essential for DNA replication in eukaryotes. The deadly human malaria parasite Plasmodium falciparum contains an ORC1/CDC6 homolog with several interesting domains at the catalytic carboxyl-terminal region that include a putative nucleoside triphosphate-binding and hydrolysis domain, a putative PCNA-interacting-protein (PIP) motif, and an extreme C-terminal region that shows poor homology with other ORC1 homologs. Due to the unavailability of a dependable inducible gene expression system, it is difficult to study the structure and function of essential genes in Plasmodium. Using a genetic yeast complementation system and biochemical experiments, here we show that the putative PIP domain in ORC1 that facilitates in vitro physical interaction with PCNA is functional in both yeast (Saccharomyces cerevisiae) and Plasmodium in vivo, confirming its essential biological role in eukaryotes. Furthermore, despite having less sequence homology, the extreme C-terminal region can be swapped between S. cerevisiae and P. falciparum and it binds to DNA directly, suggesting a conserved role of this region in DNA replication. These results not only provide us a useful system to study the function of the essential genes in Plasmodium, they help us to identify the previously undiscovered unique features of replication proteins in general. Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Eukaryotic Cell

Functional dissection of the catalytic carboxyl-terminal domain of origin recognition complex subunit 1 (PfORC1) of the human malaria parasite plasmodium falciparum

The hepatitis E virus (HEV), a nonenveloped RNA virus, is the causative agent of hepatitis E. The mode by which HEV attaches to and enters into target cells for productive infection remains unidentified. Open reading frame 2 (ORF2) of HEV encodes its major capsid protein, pORF2, which is likely to have the determinants for virus attachment and entry. Using an ∼56-kDa recombinant pORF2 that can self-assemble as virus-like particles, we demonstrated that cell surface heparan sulfate proteoglycans (HSPGs), specifically syndecans, play a crucial role in the binding of pORF2 to Huh-7 liver cells. Removal of cell surface heparan sulfate by enzymatic (heparinase) or chemical (sodium chlorate) treatment of cells or competition with heparin, heparan sulfate, and their oversulfated derivatives caused a marked reduction in pORF2 binding to the cells. Syndecan-1 is the most abundant proteoglycan present on these cells and, hence, plays a key role in pORF2 binding. Specificity is likely to be dictated by well-defined sulfation patterns on syndecans. We show that pORF2 binds syndecans predominantly via 6-O sulfation, indicating that binding is not entirely due to random electrostatic interactions. Using an in vitro infection system, we also showed a marked reduction in HEV infection of heparinase-treated cells. Our results indicate that, analogous to some enveloped viruses, a nonenveloped virus like HEV may have also evolved to use HSPGs as cellular attachment receptors. Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Journal of Virology

Heparan sulfate proteoglycans are required for cellular binding of the hepatitis E virus ORF2 capsid protein and for viral infection

The TIM23 complex is the major translocase of the mitochondrial inner membrane responsible for the import of essentially all matrix proteins and a number of inner membrane proteins. Tim23 and Tim50, two essential proteins of the complex, expose conserved domains into the intermembrane space that interact with each other. Here, we describe in vitro reconstitution of this interaction using recombinantly expressed and purified intermembrane space domains of Tim50 and Tim23. We established two independent methods, chemical cross-linking and surface plasmon resonance, to track their interaction. In addition, we identified mutations in Tim23 that abolish its interaction with Tim50 in vitro. These mutations also destabilized the interaction between the two proteins in vivo, leading to defective import of preproteins via the TIM23 complex and to cell death at higher temperatures. This is the first study to describe the reconstitution of the Tim50-Tim23 interaction in vitro and to identify specific residues of Tim23 that are vital for the interaction with Tim50. © 2009 by The American Society for Biochemistry and Molecular Biology, Inc.

Journal of Biological Chemistry

Interaction of Tim23 with Tim50 is essential for protein translocation by the mitochondrial TIM23 complex

In the present work the desired quinazolinone derivatives (DK-1, DK-2, DK-3, DK-4, DK-5, DK-6 &amp; DK-7) were synthesized by treating 2-Chloro-N-(4-oxo-2-phenylquinazolin-3(4H)-yl) acetamide (I-1) with the different substituted phenols in presence of anhydrous potassium carbonate &amp; catalytic amount of potassium iodide in dry acetone. The structures of the newly synthesized compounds have been established on the basis of their m.p., TLC, IR and 1HNMR data. All the newly synthesized quinazolinone derivatives were evaluated for their antibacterial activity by cup plate method by measuring inhibition zone. Ampicillin was used as standard drug. The compound DK-2 showed more potent antibacterial activity than the standard drug ampicillin.

International Journal of Pharmacy and Pharmaceutical Sciences

Synthesis and antibacterial activity of quinazolinone derivatives

We analysed the responses of Anabaena doliolum to elevated levels of copper and zinc in batch and semi-continuous cultures. Approximately 10, 4 and 8 and 5-times greater inhibition in final yield of A. doliolum occurred at 1, 2 μM Cu and 2.5 and 5 μM of Zn, respectively, in semi-continuous culture in comparison to batch culture. Protein, chlorophyl a and carotenoid contents of A. doliolum showed significantly (P<0.05) higher inhibition by test metals in semi-continuous culture than in batch culture. The greater sensitivity of different parameters of the test organism was related to the high metal content of the cells grown in semi-continuous system. Moreover, enhancement of pH of the culture suspension in batch culture showed a negative relationship with metal accumulation, and therefore with toxicity. This was due to decrease in free ionic concentrations of test metals. Carotenoids acted as a metal detoxifying agent by minimizing metal-induced inhibition in batch culture as was evident from its negative relationship with metal toxicity. © EDP Sciences, 2009.

Annales de Limnologie

Carotenoids and pH of the culture medium play an important role in displaying metal stress in batch and semi-continuous cultures of Anabaena doliolum

Background & objectives: Gametocyte sex-ratio in Plasmodium falciparum malaria is an important determinant of transmission success and basis of disease epidemiology. Information on ratio of male to female gametocytes after an exposure of antimalarial regimens under field conditions is very limited. In this retrospective study we observed high densities of gametocytes along with high sex-ratio in P. falciparum cases, which may be responsible for persistent malaria transmission in this area. Methods: Laksar PHC of Hardwar district, Uttarakhand State, India was selected because it contributed 90 per cent of the total malaria cases. A total of 568 uncomplicated P. falciparum malaria patients were assessed to investigate prevalence of gametocytes while 339 P. falciparum thick smears containing 5620 gametocytes were screened for measuring the gametocyte density for microgametocyte (male) and macrogametocyte (female). Homology of variance ('F' test) was checked on days 7 and 14 including the variables and risk factors namely fever, parasitaemia, gametocyte carriage in sensitive and resistant chloroquine treated P. falciparum cases. Results: Slide positivity rate (SPR) increased drastically from 0.23 to 11.4 per cent with the predominance in P. falciparum infection after 1998. All 568 cases showed gametocytes in their peripheral blood, of which 109 (19%) were infected with rings and gametocytes and 459 (81%) had gametocytes stages in their peripheral blood while 422 (74.3%) cases were infected with ring stages only. Of the 339 P. falciparum positive blood smears, 5620 gametocytes were screened for their sex-ratio. The mean sex-ratio was 0.31 (3.22 female per male). Prevalence of gametocytaemia was significantly higher (P<0.05) in chloroquine (CQ)- resistant than in CQ-sensitive patients with days 7 and 14 follow up. The homology of variance with risk factors for gametocytes on days 7 and 14 were highly significant (P<0.001) in the study period but during the post-exposure period of days 3 and 5, these were insignificantly correlated. Interpretation & conclusion: A high density of P. falciparum gametocytes was observed at the time of preparation of blood slide on day 0. Improper chloroquine treatment along with poor patient compliance for radical treatment and the presence of chloroquine resistant P. falciparum malaria may have enhanced the prevalence and density of P. falciparum gametocytes which was instrumental in signaling the persistent malaria in this area.

Indian Journal of Medical Research

Plasmodium falciparum gametocytaemia with chloroquine chemotherapy in persistent malaria in an endemic area of India

Background. Mosquitoes transmit serious human diseases, causing millions of deaths every year. Use of synthetic insecticides to control vector mosquitoes has caused physiological resistance and adverse environmental effects in addition to high operational cost. Insecticides of botanical origin have been reported as useful for control of mosquitoes. Azadirachta indica (Meliaceae) and its derived products have shown a variety of insecticidal properties. The present paper discusses the larvicidal activity of neem-based biopesticide for the control of mosquitoes. Methods. Larvicidal efficacy of an emulsified concentrate of neem oil formulation (neem oil with polyoxyethylene ether, sorbitan dioleate and epichlorohydrin) developed by BMR &amp; Company, Pune, India, was evaluated against late 3rdand early 4thinstar larvae of different genera of mosquitoes. The larvae were exposed to different concentrations (0.5-5.0 ppm) of the formulation along with untreated control. Larvicidal activity of the formulation was also evaluated in field against Anopheles, Culex, and Aedes mosquitoes. The formulation was diluted with equal volumes of water and applied @ 140 mg a.i./m2 to different mosquito breeding sites with the help of pre calibrated knapsack sprayer. Larval density was determined at pre and post application of the formulation using a standard dipper. Results: Median lethal concentration (LC50) of the formulation against Anopheles stephensi, Culex quinquefasciatus and Aedes aegypti was found to be 1.6, 1.8 and 1.7 ppm respectively. LC50 values of the formulation stored at 26°C, 40°C and 45°C for 48 hours against Ae. aegypti were 1.7, 1.7, 1.8 ppm while LC90 values were 3.7, 3.7 and 3.8 ppm respectively. Further no significant difference in LC50 and LC90 values of the formulation was observed against Ae. aegypti during 18 months storage period at room temperature. An application of the formulation at the rate of 140 mg a.i./m2 in different breeding sites under natural field conditions provided 98.1% reduction of Anopheles larvae on day 1; thereafter 100% reduction was recorded up to week 1 and more than 80% reduction up to week 3, while percent reduction against Culex larvae was 95.5% on day 1, and thereafter 80% reduction was achieved up to week 3. The formulation also showed 95.1% and, 99.7% reduction of Aedes larvae on day 1 and day 2 respectively; thereafter 100% larval control was observed up to day 7. Conclusion: The neem oil formulation was found effective in controlling mosquito larvae in different breeding sites under natural field conditions. As neem trees are widely distributed in India, their formulations may prove to be an effective and eco-friendly larvicide, which could be used as an alternative for malaria control. © 2009 Dua et al; licensee BioMed Central Ltd.

Malaria Journal

Larvicidal activity of neem oil (Azadirachta indica) formulation against mosquitoes

In this paper, we report observations of unusual whistlers recorded at Jammu (geomag. lat. = 22°26′N: L = 1.17), India on March 8, 1999 during the daytime. They are interpreted as one-hop ducted whistlers having propagated along higher L-values in closely spaced narrow ducts from the opposite hemispheres. After leakage from the duct, the waves might have propagated in the earth-ionosphere waveguide towards the equator in surface mode. Tentative explanation of the dynamic spectra of these events is briefly presented. © Printed in India.