Syntheses of lipophilic chalcones and their conformationally restricted analogues as antitubercular agents

Lipophilic chalcones and their conformationally restricted analogues were synthesized and evaluated for their antitubercular efficacy against Mycobacterium tuberculosis H37Rv strain. Compounds 16, 24, 25a and 25c were found to be active MIC at 60, 30, 3.5 and 7.5 μg-mL^?1. In vitro cytotoxicity of compounds 16, 24, 25a, 25c and 26 in non-cancerous human epithelial kidney cell line (HEK-293) showed that most active compound 25a was approximately 2.85 times selective towards tubercular versus healthy cells whereas compound 24 was found to be 16 times selective.     

Hydroxyquinoline-derived compounds and analoguing of selective Mcl-1 inhibitors using a functional biomarker

Anti-apoptotic Bcl-2 family proteins are important oncology therapeutic targets. To date, BH3 mimetics that abrogate anti-apoptotic activity have largely been directed at Bcl-2 and/or Bcl-xL. One observed mechanism of resistance to these inhibitors is increased Mcl-1 levels in cells exposed to such therapeutics. For this reason, and because Mcl-1 is important in the onset of lymphoid, myeloid, and other cancers, it has become a target of great interest. However, small molecule inhibitors displaying potency and selectivity for Mcl-1 are lacking. Identifying such compounds has been challenging due to difficulties in translating the target selectivity observed at the biochemical level to the cellular level. Herein we report the results of an HTS strategy coupled with directed hit optimization. Compounds identified have selective Mcl-1 inhibitory activity with greater than 100-fold reduced affinity for Bcl-xL. The selectivity of these compounds at the cellular level was validated using BH3 profiling, a novel personalized diagnostic approach. This assay provides an important functional biomarker that allows for the characterization of cells based upon their dependencies on various anti-apoptotic Bcl-2 proteins. We demonstrate that cells dependent on Mcl-1 or Bcl-2/Bcl-xL for survival are commensurately responsive to compounds that genuinely target those proteins. The identification of compound 9 with uniquely validated and selective Mcl-1 inhibitory activity provides a valuable tool to those studying the intrinsic apoptosis pathway and highlights an important approach in the development of a first-in-class cancer therapeutic.     

Selenium induced anticonvulsant effect: A potential role of prostaglandin E1 receptor activation linked mechanism

ProjectSelenium deficiency has been associated with enhanced propensity of seizures in man and laboratory animals. Therefore, the present study has been designed to investigate the anti-convulsant effect of sodium selenite and seleno-dl-methionine on pentylenetetrazole induced seizures in mice and the role of prostaglandin receptor activation in the proposed anticonvulsant effect of sodium selenite.ProcedureSodium selenite (1, 3 and 10 mg kg^?1, i.p.) and seleno-dl-methionine (0.3, 1 and 3 mg kg^?1, i.p.) was used to evaluate the potential effect on pentylenetetrazole induced seizures in mice. Pentylenetetrazole induced seizures were assessed in terms of onset time of straub's tail phenomenon, jerky movements of the whole body and convulsions. Additionally, an isobolographic study design was used to examine the interaction between sodium selenite and celecoxib (a cyclooxygenase-2 inhibitor). Sodium selenite and seleno-dl-methionine significantly attenuated pentylenetetrazole induced seizures in mice.ResultsPrior administration of misoprostol (a selective agonist of prostaglandin E₁ receptors) markedly attenuated the anticonvulsant effect of sodium selenite as well as seleno-dl-methionine in mice. However, the administration of misoprostol per se did not produce any behavioral changes. Further, sodium selenite was observed to exert a synergistic interaction with celecoxib.ConclusionsSelenium induced reduction in seizure like behavior might be ascribed to the activation of a prostaglandin E₁ receptor activation linked mechanism. It is further proposed that sodium selenite exerts a synergistic anti-convulsant effect with celecoxib indicating the therapeutic usefulness of combining the two agents to treat epilepsy.     

Incidence and Prevalence of Tuberculosis among Household Contacts of Pulmonary Tuberculosis Patients in a Peri-Urban Population of South Delhi,India

Background

Tuberculosis (TB), caused by Mycobacterium tuberculosis, is one of the leading causes of mortality and morbidity across all age groups throughout the world, especially in developing countries.

Methodology/Principal Findings

In this study, we have included 432 open index cases with their 1608 household contacts in a prospective cohort study conducted from May 2007 to March 2009. The follow-up period was 2 years. All Index cases were diagnosed on the basis of suggestive signs and symptoms and sputum being AFB positive. Among the 432 index patients, 250 (57.9%) were males and 182 (42.1%) females; with mean age of 34±14.4 yr and 26±11.1 yr, respectively. Out of 1608 household contacts, 866 (53.9%) were males and 742 (46.1%) females; with mean age of 26.5±15.8 and 26.5±16.0 yr, respectively. Of the total 432 households, 304 (70.4%) had ≤4 members and 128 (29.6%) had ≥5 members. The median size of the family was four. Of the 1608 contacts, 1206 were able to provide sputum samples, of whom 83 (6.9%) were found MTB culture positive. Household contacts belonging to adult age group were predominantly (74, 89.2%) infected as compared to the children (9, 10.8%). On screening the contact relationship status with index patients, 52 (62.7%) were first-degree relatives, 18 (34.6%) second-degree relatives and 12 (14.5%) spouses who got infected from their respective index patients. Co-prevalent and incident tuberculosis was found in 52 (4.3%) and 31 (2.6%) contacts, respectively. In incident cases, the diagnosis could be made between 4 to 24 months of follow-up, after their baseline evaluation.

Conclusion

Active household contact investigation is a powerful tool to detect and treat tuberculosis at early stages and the only method to control TB in high-TB-burden countries.     

In silico and bio assay of juvenile hormone analogs as an insect growth regulator against Galleria mellonella (wax moth) – Part I

Juvenile hormone (JH) analogs are nowadays in use to control harmful pests. In order to develop new bioactive molecules as potential pesticides, we have incorporated different active structural features like sulfonamide, aromatic rings, amide group, and amino acid moiety to the base structure. We have screened a series of designed novel JH analogs against JH receptor protein (jhbpGm-2RCK) of Galleria mellonella in comparison to commercial insect growth regulators (IGRs) – Pyriproxyfen (T₁) and Fenoxycarb (T₂). All analogs exhibit the binding energy profile comparable to commercial IGRs. Based upon these results, a series of sulfonamide-based JHAs (T₃–T₈) as IGRs have been synthesized and characterized. Further, the efficacy of synthesized analogs (T₃–T₈) and commercial IGRs (Pyriproxyfen and Fenoxycarb) has been assessed against fourth instars larvae of G. mellonella under the laboratory conditions. LC₅₀ values of all the analogs (T₁–T₈) against the fourth instars larvae were 9.99, 10.12, 24.76, 30.73, 38.45, 34.15, 34.14, 19.48 ppm and the LC₉₀ 153.27, 131.69, 112.15, 191.46, 427.02, 167.13, 217.10, 172.00 ppm, respectively. Among these analogs, N-(1-isopropyl-2-oxo-3-aza-3-N-ethyl-pentanyl)-p-toluene sulfonamide (T₈) and N-(1-isopropyl-2-oxo-3-aza-3-N-ethyl-pentanyl) benzene sulfonamide (T₇) exhibited the good pest larval mortality at different exposure periods (in hours) and different concentrations (in ppm) in comparison to in use IGRs- T₁ and T₂. Bio assay results are supported by docking at higher concentration. The present investigation clearly exhibits that analog T₈ could serve as a potential IGR in comparison to in use IGRs (T₁ and T₂). The results are promising and provide new array of synthetic chemicals that may be utilized as IGRs.     

Interaction of cobalt(II) and copper(II) hydroxamates with polyriboadenylic acid: An insight into RNA based drug designing

The polyadenylic acid [poly(A)] tail of mRNA plays a noteworthy role in the initiation of the translation, maturation, and stability of mRNA. It also significantly contributes to the production of alternate proteins in eukaryotic cells. Hence, it has recently been recognized as a prospective drug target. Binding affinity of bis(N-p-tolylbenzohydroxamato)Cobalt(II), [N-p-TBHA-Co(II)] (1) and bis(N-p-naphthylbenzohydroxamato)Copper(II), [N-p-NBHA-Cu(II)] (2) complexes with poly(A) have been investigated by biophysical techniques namely, absorption spectroscopy, fluorescence spectroscopy, diffuse reflectance infrared Fourier transform spectroscopy, circular dichroism spectroscopy, viscometric measurements and through molecular docking studies. The intrinsic binding constants (K_b) of complexes were determined following the order of N-p-TBHA-Co(II)] > N-p-NBHA-Cu(II), along with hyperchromism and a bathochromic shift for both complexes. The fluorescence quenching method revealed an interaction between poly(A)-N-p-TBHA-Co(II)/poly(A)-N-p-NBHA-Cu(II). The mode of binding was also determined via the fluorescence ferrocyanide quenching method. The increase in the viscosity of poly(A) that occurred from increasing the concentration of the N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) complex was scrutinized. The characteristics of the interaction site of poly(A) with N-p-TBHA-Co(II)/N-p-NBHA-Cu(II) were adenine and phosphate groups, as revealed by DRS-FTIR spectroscopy. Based on these observations, a partial intercalative mode of the binding of poly(A) has been proposed for both complexes. Circular dichroism confirmed the interaction of both the complexes with poly(A). The molecular docking results illustrated that complexes strongly interact with poly(A) via the relative binding energies of the docked structure as ?259.39eV and ?226.30eV for N-p-TBHA-Co(II) and N-p-NBHA-Cu(II) respectively. Moreover, the binding affinity of N-p-TBHA-Co(II) is higher in all aspects than N-p-NBHA-Cu(II) for poly(A).