Garima Kumari

Rhodium(II) acetate-catalyzed stereoselective synthesis, SAR and anti-HIV activity of novel oxindoles bearing cyclopropane ring

Novel oxindole derivatives bearing substituted cyclopropane ring have been designed on the basis of docking studies with HIV-1 RT using the software DS 2.5 and synthesized as probable NNRTIs against HIV-1 using rhodium(II) acetate-catalyzed stereoselective cyclopropanation reaction. The cyclopropane isomer, having trans relationship with respect to carbonyl of lactam moiety and functional group on the cyclopropane ring, was the major product in all cases along with a small amount of cis and methylene products. The trans isomers interacted well with HIV-1 RT through H-bonding with amino acids, like Lys101, Lys103, His235, Tyr318, constituting the non-nucleoside inhibitor binding pocket (NNIBP) during docking experiments. However, the compounds showed very little activity when subjected to in vitro anti-HIV-1 screening using β-galactosidase assay (TZM-bl cells) and GFP quantification (CEM-GFP cells). The very low level of in vitro HIV inhibition, in comparison to predicted EC(50) values on the basis of computational studies, during CEM-GFP screening using AZT as positive control indicated that probably the HIV RT is not the viral target and the molecules work through some different mechanism.

Anti-HIV Drug Development: Structural Features and Limitations of Present Day Drugs and Future Challenges in the Successful HIV/AIDS Treatment

Acquired Immune Deficiency Syndrome (AIDS), an immuno-compromized condition, a sequel to untreated human immunodeficiency virus (HIV) infection, inviting several life-threatening diseases, has become one of the most fatal disorders in the recent past because of HIV strain variance due to mutations, passive latency and reservoirs helping in replenishing and reviving the HIV-1 proviral DNA. Scientific efforts have led to the discovery of several effective drugs against HIV and lowered the morbidity and mortality all over the world. However, despite availability of a good number of anti-HIV drugs, the problem, for the foreseeable reasons, stands out as the most chronic disease due to the less tolerability and low accessibility of drugs, life-long expensive treatment, and above all, the emergence of drug resistant viral strains. This review dwells upon HIV infection and its proliferation inside the host system, drug targets, different types of drugs, their structural features and mode of interaction with viral targets and drug regimens. It further focuses on topics of latest interest regarding drug development, fixed dose combinations (FDCs), the limitations of present day drugs with their structural features along with their pharmacodynamics, pharmacokinetics and pharmacogenomics and the challenges in finding a permanent cure for HIV/AIDS.

Synthesis, structure-activity relationship and antiviral activity of 3'-N,N-dimethylamino-2',3'-dideoxythymidine and its prodrugs.

Abstract A probable NRTI molecule, viz. 3′-N,N-dimethylamino-2′,3′-dideoxythymidine (4) and its 5′-O-carboxyl ester prodrugs – 5′-(N-α-BOC-l-phenylalanyl)-3′-N,N-dimethylamino-2′,3′-dideoxythymidine (5), 5′-l-phenylalanyl-3′-N,N-dimethylamino-2′,3′-dideoxythymidine (6) and 5′-decanoyl-3′-N,N-dimethylamino-2′,3′-dideoxythymidine (7) have been synthesized and screened against HIV, HSV-1 and 2, parainfluenza-3, vesicular stomatitis and several other viruses. The compound 6 showed good antiviral activity with EC50 value 0.03μM (SI=8) against VSV in Hela and HEL cell lines. However, the lead compound 4 and its derivatives 5, 6 and 7 showed no remarkable activity against HIV-1 and other viruses. Molecular docking studies with HIV-1 RT using DS 2.5 and pymol softwares have shown marked differences in the interaction patterns between the lead compound 4 and AZT.

Design and synthesis of novel oxindoles as potential non-nucleosidic reverse transcriptase inhibitors against HIV

We describe here the synthesis of novel oxindoles by cycloproponation of its diazo derivatives. The synthesis involves the use of allyl methyl sulfide and allyl alcohol as olefins and rhodium acetate as catalyst. These oxindoles have been designed to act as non-nucleosidic reverse transcriptase inhibitors (NNRTIs) against HIV.

Molecular Modeling, Synthesis, and Anti‐HIV Activity of Novel Isoindolinedione Analogues as Potent Non‐nucleoside Reverse Transcriptase Inhibitors

Different isoindolinedione derivatives bearing imine, amide, thioamide, and sulfonamide linkages have been designed in silico using discovery studio software (BIOVIA, San Diego, CA, USA), synthesized, and evaluated for their anti‐HIV activity. SAR studies revealed that the linkages in these molecules did affect their anti‐HIV activity and the molecules having sulfonamide linkages were the most potent HIV‐RT inhibitors as the S=O bonds of the sulfonamide moiety interacted with Lys103 (NH or carbonyl or both) and Pro236; the NH part of the sulfonamide linkage formed bond with carbonyl of Lys101. blood–brain barrier (BBB) plots were also studied, and it was found that all the designed molecules have potential to cross BBB, a very vital criteria for anti‐HIV drugs. In vitro screening was performed using HIV‐1 strain IIIB in MT‐4 cells using the MTT assay, and it was seen that some of these molecules were effective inhibitors of HIV‐1 replication at nanomolar concentration with selectivity indices ranging from 33.75 to 73.33 under in vitro conditions. Some of these molecules have shown good anti‐HIV activity at 3–4 nm concentrations. These derivatives have potential to be developed as lead molecules effective against HIV‐1.

In silico designing and development of novel anti-HIV molecules

T protein modeling and virtual drug screening were performed to identify new inhibitors of Herpes virus DNA polymerase, a key enzyme in the viral replication cycle. Twelve potential inhibitors were identified, purchased and evaluated by plaque assays. Two compounds (Nos 2 and 9) were particularly active against HSV-1, HSV-2 and varicella-zoster virus (VZV) and one compound (No 3) inhibited more specifically human Cytomegalovirus (HCMV). These compounds exhibited activity against wild-type viruses and strains resistant to current antiviral agents, i.e. nucleoside and pyrophosphate analogues, with IC50 values between 3 and 10 μM. Furthermore, compounds 2 and 3 had good cellular permeability and metabolic stability as determined by parallel artificial membrane permeability assay (PAMPA) and microsomal stability assay, respectively. Derivatives of these compounds were also synthesized to evaluate their activity against representative strains of HSV-1, HSV-2, VZV and HCMV as well as their toxicity on different cell lines. One fluoro derivative of compound 2 (No 20) retained excellent activity against HSV-1, HSV-2 and VZV with a therapeutic index near 10 in Vero cells. In conclusion, we discovered a new class of non-nucleosidic Herpes virus inhibitors with in vitro activity against drug-resistant clinical isolates that warrant further pre-clinical studies.Human immunodeficiency virus (HIV) and acquired immune deficiency syndrome (AIDS) are global health problems. Since AIDS is not only a vital medical problem, but also a socioeconomic complication, increasing peoples knowledge and replacing their fatalistic belief by a non-fatalistic belief is important to decrease prevalence of the problems. The objective of the study is to examine beliefs about HIV/AIDS of pregnant women and to study the relationship between their belief and HIV/AIDS prevention behaviors. A cross-sectional structured and semi-structured interview with mixed method approach based survey was used. Convenience sampling technique was used to select study participants. Data was analyzed using SPSS V.15. Our result demonstrated that, out of 422 respondents 336 (79.6%) and 86 (20.4%) had a non-fatalistic and a fatalistic belief, respectively. Majority of the respondents 407 (96.4%) believe that HIV can be transmitted from mother to child and small proportion 15 (3.6%) don’t believe the transmission of HIV from mother to child. The findings showed that 20% of the women were fatalistic and that their beliefs about AIDS may affect prevention behaviors. Fatalistic believe is one of the factors influencing HIV/AIDS prevention behaviors, but it is a vital factor for health professionals to consider when developing future HIV/AIDS prevention strategies among fatalistic people.Method: SPARSHA NEPAL a community-led NGO of people living with HIV in Nepal initiated a “Community-based ART” from February 2005 with just 12 patients. In the beginning SPARSHA only had 1 Health Assistant and a weekly visit by Doctor along with basic medication service. With an overall management and implementation by the community of PLHIV, SPARSHA has managed to increase the number of patients on ART along with developing and empowering itself on crucial factors such as medical and technical know-how with the support from various Governmental and non-governmental partners and funding agencies.Methodology: Survey data of indicators of the four Information-Motivation-Behavioral skills (IMB) model’s latent constructs prevention information or knowledge, prevention motivation and prevention behavioral skills, as well as past exposure to violent living conditions (PEVLC)prevention was collected from students attending an HBCU. Exploratory principal component factor analysis and Cronbach’s alpha test were performed to identify the factorial structure of the PEVLC questionnaire and reliability of the violent exposure subscales, respectively. Confirmatory factor analysis was performed to estimate the overall model fit indices and the magnitude of effects of prevention motivation, PEVLC prevention and prevention information or knowledge on the prevention behavior of the students.I early stages of HIV infection, even if the infection is controlled and asymptomatic, several macrophages are loosened from granuloma, carry the mycobacteria within them, and help disseminate the infection through haematogenous route. By this time mycobacteremia may or may not cause clinical symptoms. In the current communication, we report findings of a study carried out on a cohort of 60 HIV-1 infected patients attending antiretroviral clinic at All India Institute of Medical Sciences, New Delhi, India. After taking informed consent from the caes blood and sputum samples were collected and processed, inoculated for culture examination under aseptic conditions, incubated at 37°C. Mycobacteremia was detectable in 40.7% of subjects whereas sputum cultures were positive in 48%. The rate of mycobacteremia was slightly higher in asymptomatic patients (44.4%, 8 of 18) than symptomatic patients (39%, 16 of 41). However, sputum positivity was higher in symptomatic cases (50%, 16 of 32) as compared to asymptomatic (44.4%, 8 of 18). Six (33.3%) asymptomatic cases had mycobacterial growth in both blood and sputum samples. Our study shows that HIV-1 positive cases, (symptomatic/asymptomatic), must be investigated for tuberculosis and blood culture has equal TB detection rate, if not higher, than sputum culture. Blood culture examination is desirable, specially in those patients who are asymptomatic and can not expectorate.I Russia 780,000 HIV-infected people registered and 130,000 people died. In St. Petersburg, recorded 50,000 cases from 1987 to 2011 and 8,500 people died. The main causes of death are generalized tuberculosis, rarely other opportunistic diseases and chronic viral hepatitis (CVH) cirrhosis. Every year in Russia revealed 60-65,000 “new cases” of HIV-infection and in St. Petersburg 2500 3000 per year. In St. Petersburg based on cumulative data from 2006, CVH with cirrhosis diagnosed in 200,000 patients, including patients with HIV infection. CVH patients with HIV infection have a rapidly progressive course disease development with a greater risk of liver failure, cirrhosis and hepatocellular carcinoma (HCC).Results: Overall, 26.8% (95% Confidence Interval [CI]: 23.4-30.2) of pregnant women did not know their HIV status. 9.2% of these women had high risk behaviors, 15% no health coverage, 24.2% were more than 35 years old, 64.4% were non-Hispanic White and 37.8% were college graduates. After controlling for cofounders, pregnant women with more than 35 years old (Odd Ratio [OR] =2.5, 95%CI: 1.4-4.4), self-identify as non-Hispanic White (OR=2.1, 95%CI: 1.2-3.8), no health coverage (OR=2.6, 95%CI: 1.4-4.8), and college degree (OR=1.6, 95%CI: 1.1-2.6) were significantly more likely to be unaware of their HIV status.H stigma persists to be a major public health challenge in Ethiopia. This study examines knowledge about HIV/ AIDS and factors explaining stigmatizing attitude towards people living with the virus based on demographic and health survey data collected from 15,786 women in 2011. The result shows that considerable percentage of rural women had inadequate knowledge about HIV/AIDS. The likelihood of having adequate knowledge about HIV/AIDS was significantly higher for relatively better educated women and lower in Afar, Somali, and Gambella regions and Dire Dawa City. Women with higher level of education and better access to media had lower likelihood of stigmatizing people living with the virus. Besides, respondents with adequate knowledge about HIV/AIDS had lower likelihood of stigmatization. The results entail that HIV/AIDS stigma in Ethiopia is partly explained by the level of knowledge of the people about HIV/AIDS and socio-cultural factors that shape their perception of the epidemic and infected persons. Hence, awareness raising campaign that considers the socio-cultural context in which stigma occurs is required to eliminate stigmatization.

Green synthesis and antibacterial activity of some novel cyclic and acyclic imides bearing naphthalimide and allylidene moieties

In this study, graphene was functionalized via acid oxidation in the presence of a mixture of concentrated sulfuric acid (H2SO4) and nitric acid (HNO 3 ). Thus oxidized graphene (o-graphene) were silanized using a coupling agent, 3-aminopropyltriethoxsilane (3-APTES) resulting in functionalized graphene (f-graphene). Chitosan/graphenenanocomposites films have been prepared by the mixing aqueous solution of chitosan and multi-performance graphene in the present of diluted acetic acid. The chemical structure, thermal stability and mechanical properties of the nanocomposite films have been investigated by the wide-angle X-ray diffraction (XRD), Fourier Transform Infrared Spectroscopy (FT-IR), Scanning Electron Microscopy (SEM), Thermogravimetric Analysis (TGA), Atomic Force Microscopy (AFM), and mechanical test via Universal Testing Machine (Instron 8841). The results revealed that chitosan and graphene could mix with each other homogeneously and the mechanical properties of the as-prepared films were improved significantly over that of the pure chitosan film. These composites films have potential applications as biomaterials or packing materials.I experiments were conducted to observe the effects of organic amendments, which were produced from sewage sludge and food waste through pyrolysis, composting and drying processes, on immobilization of cadmium (Cd) in contaminated soil. The results show that concentrations of acid extractable Cd were significantly decreased (5.9-7.6 percentages) with application of 50 g.kg-1 pyrolytic products and composting products during 60 d incubation period, while were increased (0.9-3.0 percentages) with drying products application under the same condition. Concentrations of Fe-Mn oxides bound Cd were decreased and concentrations of organic bound and residual Cd were increased by different levels with application of all amendments. The performances of Cd immobilization with various sludge derived products as amendment presented in following order: Pyrolytic product>composting product>drying product. The performances of Cd immobilization with various food waste derived products as amendment presented in following order: Composting product>pyrolytic product>drying product. Soil pH, cation exchange capacity (CEC) and organic matter were also changed by different levels with application of all amendments. According to the result of correlation analysis, there was significant correlation between soil pH and Cd fractions. Therefore, it could be speculated that soil pH change is one of the main factors in charge of Cd forms distributions in soil with application of organic amendments from sludge and food waste. Based on experiment results, it can be concluded that different processing techniques result in distinguishing properties of organic amendment from same matrix and thus impact its performance of Cd immobilization in soil. As far as environmental effects and risks to be concerned, biochar produced from sewage sludge and food waste through pyrolysis processing could be a promising organic amendment for Cd contaminated soil remediation.C (Cr) is one of the most and important trace metals which can be present in two oxidation states: Toxic Cr(VI) and non-toxic (Cr III). Cr(III) is an important microelement for plant and animal nutrition and essentials for the maintenance of glucose as well as for the lipid and protein metabolism. With regard to human health, Cr(III) is a required nutrient, with 50-200 μg per day recommended for adults. On the contrary, Cr(VI) is toxic and carcinogenic, leading to lung cancer, skin allergy and probably also to asthma and renal diseases. A toxic effect for the biological systems is attributed to the ability of Cr(VI) to migrate across the cell membrane, thus enhancing the intracellular chromium concentration. Hexavalent chromium is rarely found in nature and is generally man-made, especially in fumes generated during the ferrochrome production. The permissible exposure limit (PEL) of chromium in air is 5 μg m-3 measured as Cr(VI). The dust with Cr(VI) could be a source of contamination of medicinal plants. Therefore, it is essential to monitor the concentration of Cr(VI) in the environment, to determine the risk of Cr(VI) to human health, not only from air breathing, but from the dust which settles on agricultural products grown in vicinity of chromium smelters and when into medicinal plants. For these studies, the samples of industrial dust, soil, bark of trees and medicinal plants samples were collected in the vicinity of chromium smelters and from local market. All measurements were carried out using a Perkin Elmer atomic absorption spectrometer model AAnalyst 600 with Zeeman background correction.Aminomethylation of benzotriazole was carried out by treating benzotrialzole with formaldehyde and 4-aminosalicylic acid. The resultant compound was designed as 1-(4-carboxy-3-hydroxy-4-phenyl amino methyl) benzotriazole. The transition metal complex of Cu2+, Co , Ni, Mnand Zn of 1-(4-carboxy-3-hydroxy-4-phenyl amino methyl) benzotriazole have been prepared. Elemental analysis, spectral studies, magnetic moment determination, molar conductivity measurement and microbial activity of 1-(4-carboxy-3-hydroxy4-phenyl amino methyl) benzotriazole and its metal complexes were carried out.N chiral N-phosphoramide and N-phosphonyl imines were found to be efficient asymmetric chiral auxiliaries. Various nucleophilic addition reactions such as aza-Henry reaction, aza-Darzens reaction, Strecker reaction were performed on these chiral amines and desired products were obtained in excellent chemical yields (94-99%) and diastereo selectivities (upto >99%). These reactions were confirmed to follow the GAP chemistry (group assisted purification chemistry) process, which can avoid traditional chromatography and re-crystallization purifications, i.e., the chiral product bearing a chiral N-‐ phosphonyl group can simply be purified by washing the solid crude products with hexane or hexane:ethylacetate mixture, hence provide a green process to purify organic compounds and motivates the synthetic community to search more of such reagents/processes. Moreover, the chiral auxiliary can be cleaved under acidic conditions and can be easily recovered without loss of chirality.T human population is suffering increased exposure to existing and new chemicals and environmental toxins. Among the various environmental toxins, PAHs are an important class of environmental contaminants, and many PAHs are known or suspected carcinogens. PAHs are produced in the environment through the incomplete burning of organic fuels and cover wide classes of compounds. Exposure to some of these compounds is well-known to cause cancer in mice and they are suspected to be carcinogenic compounds for humans. The photocatalytic degradation of anthracene in aqueous solutions in the presence of TiO2 suspension has been investigated with the use of UV-irradiation. This study includes comparison between two types of titanium dioxide (P25 and UV100), also includes effect of different parameters on photocatalytic oxidation of anthracene by titanium dioxide were studied, such as: anthracene concentration, pH of aqueous solution, light intensity, addition of H2O2 and temperature on photocatalytic oxidation. The results showed that titanium dioxide, P25 type is better than UV100 type. The results also showed the optimum conditions for degradation process by photocatalytic oxidation are; perfect concentration of anthracene is 25 ppm, 6.8 of pH is the best value for anthracne, 2.5 mW. Cm-2 of light intensity, degradation rate of anthracene without addition of hydrogen peroxide is fastest and 308.15K is the appropriate degree of temperature. The results indicated that the photocatalytic degradation of anthracene was well described by pseudo first order kinetics according to the LangmuirHinshelwood model. The effect of temperature on the efficiency of photodegradation of anthracene was also studied in the range 278.15-308.15 K. The activation energy was calculated according to Arrhenius plot, and was found equal to 12.76 kJ.mol-1 for TiO2 (Degussa P25). The main product of anthracene after degradation was 9, 10-anthraquinone which was identified by GC-MS.The intermediate compound that produced of degradation of anthracene was 9,10-anthraquinone. This product characterises by FTIR and GC-MS, the complete degradation for 9-10 anthraquinone was achieved.The activity of lipase‐catalysedhydrolysis of olive oil in SDS‐1‐butanol‐olive oil‐watermicroemulsionswas investigated. The kinetics of lipases in reverse microemulsions and water were also compared. The influences of the characteristic parameters of these systems, such as pH, temperature (T), molar ratio (vo) of water to SDS, the concentrations of enzyme and substrate, on the activity of an enzyme were examined. According to the optimum conditions the production and activity were measured at pH1⁄44, T1⁄440 8C, vo1⁄412. The activation energy of the reaction was calculated from the Arrhenius plot. It was found that the hydrolysis reaction obeyedMichaelis–Menten kinetics and the apparentMichaelis Km,a and the apparentmaximal reaction rate Vmax were determined. The effect of microemulsions surfactant (SDS) on enzymatic activity was also discussed.

Novel acyclic nucleoside analogues as inhibitors of HIV-1 RT

Background Nucleoside reverse transcriptase inhibitors (NRTIs) were the first drugs introduced for treatment of human immunodeficiency virus-1 (HIV-1) infection. These NRTIs may be cyclic or acyclic analogs of natural nucleosides. Both these analogs interact at active site on HIV-RT and compete with indigenous nucleosides/ nucleotides, and thus, divert enzyme activity in manmade direction. All NRTIs follow three phosphorylation steps that convert the parent compound successively to 5’-triphosphate. These 5’-triphosphates act as alternate substrate for HIV-RT, and lead to chain termination when incorporated into the DNA chain as they don’t provide the 3’-OH function.