Many neurotherapeutics are unsuccessful in treating CNS disorders because they cannot be effectively drug delivered. Drug delivery to the brain is a challenge even though there is relatively high blood flow. There are two physiological barriers likes blood-brain barrier and blood-cerebrospinal fluid barrier which separates the brain from its blood supply controlling the transport of compounds. Many of the brain or CNS associated diseases remain untreated by effective therapies. This is not because there is a lack of candidate drugs but due to the inability of many therapeutic molecules to cross the BBB, the BCSFB or other specialized CNS barriers to reach the specific areas of brain. Hence there is a need in the modern approaches and present insights into using ligand conjugation and nanotechnology to target the BBB via different transport pathways and mechanisms. The field of novel drug delivery system has fully emerged and came into existence as an ideal approach of drug targeting and delivery to brain. The new approaches of drug delivery to brain help in successful transporting drugs across the BBB.

Kawade et al.: Therapeutic potential of PI3K/Akt/mTOR signalling pathway Cell signalling mechanism plays a vital role in cell functioning. Imbalance and disregulation between these signals, such as phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin signalling pathway may lead to uncontrolled cell proliferation. Generation of drug resistance is the hurdle in current cancer treatment. Designing an effective combination therapy for inhibition of two or more proteins of a given pathway might help to overcome the drug resistance and side effect related issues in cancer treatment. In this regard, application of computational tools firstly to predict newer combinations against phosphatidylinositol-3-kinase, protein kinase B and mammalian target of rapamycin involved in a single pathway have been proposed. The results obtained using the computational tools were shortlisted based on GlideScore and binding interactions of the drugs to the receptors of the pathway. One of the predicted combinations was further subjected to biological evaluation using the Western blot assay. The experimental results revealed synergistic effects that supported the predictions. The study also provided insights for the application and development of computational tools to predict newer combinations in a given network pharmacology.

Background: Dihydrofolate reductase is one of the important enzymes for thymidylate and purine synthesis in micro-organisms. A large number of drugs have been designed to inhibit microbial DHFR but over the period of time, some drugs have developed resistance and cross reactivity towards the enzyme. Over the past few decades, benzimidazoles, triazoles and their derivatives have been grabbing the attention of the synthetic chemists for their wide gamut of antibacterial and antifungal activities targeting microbial protein DHFR. Objective: Our goal behind present investigation is to explore benzimidazoles class of drugs as microbial DHFR inhibitors by studying ligand-receptor binding interactions, in vitro enzyme inhibition assay and confirmation of anti-microbial activity against selected pathogenic microorganisms. Methods: A library containing thirty novel 2,6-disubstituted 1H-benzimidazoles was synthesized by one pot condensation of o-nitro aniline or 2,4-dinitro aniline with series of aldehydes or acetophenones using Na2S2O4 or SnCl2 respectively and reflux for 5-6hr. Structures of compounds have been confirmed by spectroscopic methods as 1H and 13C NMR, FT-IR and MS. In vitro DHFR inhibition study was performed by using Epoch microplate reader and IC50 of the test compounds was compared with Trimethoprim. In vitro antimicrobial activity was performed against selected clinical pathogens by agar disk diffusion method and MIC (µg/mL) was reported. Results: Moderate to good level of DHFR inhibition was observed with IC50 values in the range of 7-23 µM. Compounds B1, B19, B22, B24 and B30 expressed 1.1 to 1.4 folds more prominent DHFR inhibitory activity as compared to standard Trimethoprim. Remarkable antimicrobial activity was exhibited by B1, B19, B22, B24 and B30. Molecular docking study revealed perfect binding of test ligands with key amino acids of DHFR as Phe31, Ile94, Ile5, Asp27, Gln32 and Phe36. Conclusion: Nature of 1H-benzimidazole substituents at position 2 and 6 had influence over magnitude and type of molecular binding and variation in the biological activity. The present series of 1H-benzimidazoles could be considered promising broad-spectrum antimicrobial candidates that deserve in future for preclinical antimicrobial evaluation and development of newer antimicrobial agents targeting microbial DHFR.

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: Purpose :Findings :Social Implications :Original : Key words :The Spiropyranopyrazole derivatives are used as cytotoxic agents and nitrogen containing heterocyclic analogs targeting CDK7 inhibition shows better cytotoxic activity. Methodology: A new series of compounds were synthesized using various substituted isatin derivatives and then characterized and analyzed for biological activity by in-silico and using MTT assay targeting CDK7. All the synthesized compounds were analyzed for their biological activity for this purpose breast cancer cell lines (MCF7) were used and analyzed by MTT assay. Docking studies into ATP binding site of CDK7 were performed to predict their binding affinity scores and possible interactions with receptor to evaluate bioactivity in-silico using VLife MDS 4.3.A novel series of Spiropyranopyrazole derivatives were successfully synthesized via Multicomponent reaction (MCR). From experimental data indicated that compounds 2c and 3c showed most promising results as their inhibitory activity with 23.20% and 26.50% respectively at 10µM and these were selected for further preclinical studies.If the present findings of spiropyranopyrazole derivatives passes preclinical studies and we develop drug like candidate then it is a massive achievement in anticancer therapy that could save many lives.Successfully develop a novel series of spiropyranopyrazole having CDK7 inhibitor activity. This could be helpful for development of a drug like candidate having significant cytotoxic activity.