Advances in Pyrazole Based Scaffold as Cyclin-dependent Kinase 2 Inhibitors for the Treatment of Cancer.

The transformation of a normal cell into a tumor cell is one of the initial steps in cell cycle deregulation. The cell cycle is regulated by cyclin-dependent kinases (CDKs) that belong to the protein kinase family. CDK2 is an enchanting target for specific genotype tumors since cyclin E is selective for CDK2 and the deregulation of specific cancer types. Thus, CDKs inhibitor, specifically CDK2/cyclin A-E, has the potential to be a valid cancer target as per the currently undergoing clinical trials. Most of the pyrazole scaffolds have shown selectivity and potency for CDK2 inhibitors. This review aims at examining pyrazole and pyrazole fused with other heterocyclic rings for antiproliferative activity. Based on the in vitro and molecular docking studies, the most potent analogues for CDK2 inhibition are exhibited by IC50 value. Moreover, the review emphasizes the various lead analogs of pyrazole hybrids which can be very potent and selective for anti-cancer drugs.

Bone Health and Natural Products- An Insight.

Bone metabolism involves a complex balance between matrix deposition, mineralization, and resorption. Numerous evidences have revealed that dietary components and phytoconstituents can influence these processes, through inhibition of bone resorption, thus exhibiting beneficial effects on the skeleton. Various traditional herbal formulae in ayurvedic and Chinese medicine have shown demonstrable benefits in pharmacological models of osteoporosis. The present review discusses normal bone metabolism and disorders caused by bone disruption, with particular reference to osteoporosis and current therapeutic treatment. Furthermore the effects of constituents from natural products on bone tissue are explained, with relevant evidences of efficacy in various experimental models.

Mycobacterial siderophore: A review on chemistry and biology of siderophore and its potential as a target for tuberculosis.

Mycobacterium tuberculosis (MTB), the causative agent of tuberculosis is known to secrete low molecular mass compounds called siderophores especially under low iron conditions to chelate iron from host environment. Iron is essential for growth and other essential processes to sustain life of the bacterium in the host. Hence targeting siderophore is considered to be an alternative approach to prevent further virulence of bacterium into the host. This review article presents classification of siderophores, their role in transporting iron into the tubercular cell, biosynthesis of mycobactins, viability of siderophore as a therapeutic target and also focuses on overview on various approaches to target siderophore. The approaches encompass mutation effect on genes involved in siderophore recycling, synthetic as well as natural compounds that can inhibit further spread of bacterium by targeting siderophore.

DNA gyrase inhibitors: Progress and synthesis of potent compounds as antibacterial agents.

DNA gyrase is classified as topoisomerase II, an ATP-dependent enzyme that is vital in the transcription, replication of DNA and chromosome segregation processes. It plays a crucial role in all bacteria except higher eukaryotes and this makes it a desirable and viable therapeutic target for development of new antibacterial agents. Fluoroquinolones are commonly used effective antibacterial agents that target DNA gyrase, however the spectrum of side-effects and emerging bacterial resistance with no new drugs in the antibacterial pipeline has fuelled intensive research in this area. New chemical entities with varied scaffolds possessing DNA gyrase inhibiting properties have been determined by screening chemical libraries that could serve as good leads for antibacterial drug development. A wide range of natural products and protein-based compounds have been identified and studied as DNA gyrase inhibitors and this adds a huge amount of structural diversity that can be exploited and harnessed in the discovery of new antibacterial agents. The development of new chemical compounds with DNA gyrase inhibitory activity (from natural sources, random screens or rational design) will further validate/corroborate the potential of this enzyme as a useful target. This review presents an overview of the DNA gyrase inhibitors obtained from natural and synthetic sources, their syntheses schemes and spectrum of biological activity of a variety of scaffolds and their analogues. The authors hope to provide focused direction for development of new chemical entities, synthetic routes for analogue synthesis, structure activity relationships and biological activity. The most potent ones can be used as templates to design novel compounds targeting DNA gyrase and are effective against resistant bacterial strains and biofilms.

Design, synthesis and antitubercular evaluation of novel series of N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives.

The analogs of N-[4-(piperazin-1-yl)phenyl]cinnamamide were designed and synthesized by molecular hybridization approach in which part C of the designed molecule was linked through amide and carbamate functionality that improves the physicochemical properties and govern the pharmacokinetic and pharmacodynamic behavior. The systematic modification was done around the Part C to explore the structure activity relationship of antitubercular cinnamamide. All 52 compounds were evaluated for its antitubercular activity against Mycobacterium tuberculosis (M. tb) using Resazurin microtitre plate assay (REMA). Compound 11 g with trifluoromethyl substitution exhibited good antitubercular activity of 3.125 µg/ml. The synthesized N-[4-(piperazin-1-yl)phenyl]cinnamamide derivatives showed promising activity against M. tb.

Pharmacophore development and docking studies of the hiv-1 integrase inhibitors derived from N-methylpyrimidones, Dihydroxypyrimidines, and bicyclic pyrimidinones.

To elucidate the crucial structural features for the HIV-1 integrase inhibitors, a three-dimensional pharmacophore model was developed based on N-methyl pyrimidones, dihydroxypyrimidines, and bicyclic pyrimidinones derivatives using Phase. N-methyl pyrimidone derivative raltegravir, the first US-FDA approved drug by Merck, belongs to this series. The best-fitted common pharmacophore hypothesis was characterized by two acceptor, two hydrophobic, and two ring features having a correlation coefficient of 0.895, cross-validated Q(2) value of 0.631, and survival score of 8.862, suggesting that a highly predictive pharmacophore model was developed. The cross-validation studies using 23 test set molecules and fifteen structurally diverse HIV-integrase inhibitors give extra confidence about the correctness of the pharmacophore model. The cross-validation studies proved that our developed model can successfully differentiate between active and inactive HIV-integrase inhibitors. The docking studies were also carried out wherein the molecules were docked against the active site of HIV integrase to analyze the binding mode and the necessary structural requirement for their respective enzymatic inhibition. The results obtained from our studies provide a valuable tool for designing of new lead molecules with potent activity.