No abstract

The approval of bedaquiline to treat tuberculosis has validated adenosine triphosphate (ATP) synthase as an attractive target to kill Mycobacterium tuberculosis (Mtb). Herein, we report the discovery of two diverse lead series imidazo[1,2-a]pyridine ethers (IPE) and squaramides (SQA) as inhibitors of mycobacterial ATP synthesis. Through medicinal chemistry exploration, we established a robust structure-activity relationship of these two scaffolds, resulting in nanomolar potencies in an ATP synthesis inhibition assay. A biochemical deconvolution cascade suggested cytochrome c oxidase as the potential target of IPE class of molecules, whereas characterization of spontaneous resistant mutants of SQAs unambiguously identified ATP synthase as its molecular target. Absence of cross resistance against bedaquiline resistant mutants suggested a different binding site for SQAs on ATP synthase. Furthermore, SQAs were found to be noncytotoxic and demonstrated efficacy in a mouse model of tuberculosis infection.

Approximately 15% of all human tumors harbor mutant KRAS, a membrane-associated small GTPase and notorious oncogene. Mutations that render KRAS constitutively active will lead to uncontrolled cell growth and cancer. However, despite aggressive efforts in recent years, there are no drugs on the market that directly target KRAS and inhibit its aberrant functions. In the current work, we combined structure-based design with a battery of cell and biophysical assays to discover a novel pyrazolopyrimidine-based allosteric KRAS inhibitor that binds to activated KRAS with sub-micromolar affinity and disrupts effector binding, thereby inhibiting KRAS signaling and cancer cell growth. These results show that pyrazolopyrimidine-based compounds may represent a first-in-class allosteric noncovalent inhibitors of KRAS. Moreover, by studying two of its analogues, we identified key chemical features of the compound that interact with a set of specific residues at the switch regions of KRAS and play critical roles for its high-affinity binding and unique mode of action, thus providing a blueprint for future optimization efforts.

The implications of metal contamination of agricultural soils due to long term irrigation with treated industrial wastewater and their subsequent accumulation in the vegetables/crops growing on such soils has been assessed in an area of industrial complex, Jajmau, Kanpur (India). Physico-chemical properties of the soil were also studied. The soil and vegetables/crops were sampled from an area of 2100 acre agricultural land and analyzed for physico-chemical properties and metal accumulation in different parts of the plants. The comparison of the data of physico-chemical properties of control and contaminated soil showed that salinity, electrical conductivity, available phosphorous, sodium and potassium content (both water soluble and exchangeable) were found high in contaminated soil. The analysis of plant available metal content in the soil showed the highest level of Fe, which ranged from 529.02 to 2615 microg g(-1) dw and lowest level of Ni (3.12 to 10.51 microg g(-1) dw). The analysis of the results revealed that accumulation of toxic metal Cr in leafy vegetables was found more than fruit bearing vegetables/crops. Thus, it is recommended that the leafy vegetables are unsuitable to grow in such contaminated sites. It is important to note that toxic metal, Ni was not detected in all the plants. The edible part of the vegetables (under ground) such as, garlic (19.27 microg g(-1) dw), potato (11.81 microg g(-1) dw) and turmeric (20.86 microg g(-1) dw) has accumulated lowest level of toxic metal, Cr than leafy and fruit bearing vegetables. In some fruit part of vegetables such as, bitter gourd, egg plant, jack tree, maize and okra, the accumulation of Cr was not detected and may be grown in this area.