Molecular-level strategic goals and repressors in Leishmaniasis - Integrated data to accelerate target-based heterocyclic scaffolds.

Leishmaniasis is a complex of neglected tropical diseases caused by various species of leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, these drugs have many drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Among several identified potential molecular targets, enzymes involved in the purine salvage pathway include polyamine biosynthetic process, such as arginase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, trypanothione reductase as well as enzymes in the DNA cell cycle, such as DNA topoisomerases I and II plays vital role in the life cycle survival of leishmanial parasite. This review mainly focuses on various heterocyclic scaffolds, and their specific inhibitory targets against leishmaniasis, particularly those from the polyamine biosynthesis pathway and DNA topoisomerases with estimated activity studies of various heterocyclic analogs in terms of their IC50 or EC50 value, reported molecular docking analysis from available published literatures.

Discovery of potent antitubercular agents: Design, synthesis and biological evaluation of 4-(3-(4-substitutedpiperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues.

A series of twenty-five novel 4-(3-(4-substituted piperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues were synthesized, characterized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. These compounds exhibited minimum inhibitory concentration in the range of 1.56-50 µg/mL. Among these derivatives, compounds 5a, 5b, 5f, 5m, 5p, and 5r displayed moderate activity (MIC 6.25 µg/mL). Compounds 5c, 5d, 5g, 5l, and 5o showed significant antitubercular activity (MIC 3.125 µg/mL), while compounds 5h, 5n, and 5q exhibited potent antitubercular activity (MIC 1.56 µg/mL). In addition, MTT assay was performed on the active analogues of the series against mouse macrophage cells to assess the cytotoxic effect of the newly synthesized compounds, and a selectivity index of the compounds was established. Selectivity index values of the most active compounds (5h, 5n, and 5q) are >47, indicating the compounds' suitability for further potential drug development. A molecular docking study was performed to understand the putative binding mode and binding strength of the selected significantly active and weakly active compounds with the target enzyme mycobacterial topoisomerase II using moxifloxacin as standard. In-silico ADME prediction and bioavailability studies of the titled compounds obey Lipinski's rule of five and Jorgensen's rule of three. To further ascertain the structure of the compounds, a suitable single crystal for the compounds 5a, 6, and 7d was developed and studied.

1,2,3,4-Tetrahydroisoquinoline (THIQ) as privileged scaffold for anticancer de novo drug design.

Introduction: Cancer is a dreadful disorder that is emerging as one of the leading causes of mortality across the globe. The complex tumor environment, supplemented with drawbacks of the existing drugs, has made it a global health concern. The Tetrahydroisoquinoline (THIQ) ring holds an important position in medicinal chemistry due to its wide range of pharmacological properties. Several THIQ based natural products have been previously explored for their antitumor properties, making it a vital scaffold for anticancer drug design.Areas covered: This review article addresses the potential of THIQ as anticancer agents. Various medicinal chemistry strategies employed for the design and development of THIQ analogs as inhibitors or modulators of relevant anticancer targets have been discussed in detail. Moreover, the common strategies employed for the synthesis of the core scaffold are also highlighted.Expert opinion: Evidently, THIQs have tremendous potential in anticancer drug design. Some of these analogs exhibited potent activity against various cancer molecular targets. However, there are some drawbacks, such as selectivity that need addressing. The synthetic ease for constructing the core scaffold complimented with its reactivity makes it ideal for further structure-activity relationship studies. For these reasons, THIQ is a privileged scaffold for the design and development of novel anticancer agents.

Design, synthesis and biological evaluation of 7-(5-((substituted - amino)-methyl)-thiophen-2-yl)-spiro-[chroman-2,4'-piperidin]-4-one hydrochloride analogues as anticancer agents.

A series of thirty-one novel 7-(5-((amino)-methyl)-thiophen-2-yl)-spiro-[chroman-2,4'-piperidin]-4-one hydrochloride analogues (Cst 1 - 31) have been designed, synthesized and characterized by 1H NMR, 13C NMR and MS spectral analysis. Here, we evaluated the anticancer potential and biological results of low-molecular-weight bridgehead oxygen and nitrogen-containing spirochromanones on proliferation and apoptosis of the human breast cancer cell line (MCF-7) and Murine melanoma (B16F10). The anticancer activity ranged from 2.9 to 35.0 µM. The most potent compounds Cst-22, Cst-24 and Cst-31 were found to be less toxic against human embryonic kidney (HEK-293) cell lines. Cst-24 and Cst-31 were found to be causing significant cytotoxicity through apoptotic cell death and also G2 phase arrest of cell cycle in B16F10 cells. In-silico ADME prediction stidies of the titled compounds were found within the rules outlined, and these compounds may not face any pharmacokinetic associated issues in the mere future upon developmental stage. These conjugates may serve as a lead for the discovery of potential anticancer drug candidate with better therapeutic profile.

Capsaicin-loaded solid lipid nanoparticles: design, biodistribution, in silico modeling and in vitro cytotoxicity evaluation.

Lower doses of capsaicin (8-methyl-N-vanillyl-6-nonenamide) have the potential to serve as an anticancer drug, however, due to its pungency, irritant effect, poor water solubility and high distribution volume often linked to various off-target effects, its therapeutic use is limited. This study aimed to determine the biodistribution and anticancer efficacy of capsaicin loaded solid lipid nanoparticles (SLNs) in human hepatocellular carcinoma in vitro. In this study, SLNs of stearic acid loaded with capsaicin was formulated by the solvent evaporation-emulsification technique and were instantly characterized for their encapsulation efficiency, morphology, loading capacity, stability, particle size, charge and in vitro drug release profile. Synthesized SLNs were predominantly spherical, 80 nm diameter particles that proved to be biocompatible with good stability in aqueous conditions. In vivo biodistribution studies of the formulated SLNs showed that 48 h after injection in the lateral tail vein, up to 15% of the cells in the liver, 1.04% of the cells in the spleen, 3.05% of the cells in the kidneys, 3.76% of the cells in the heart, 1.31% of the cells in the lungs and 0% of the cells in the brain of rats were determined. Molecular docking studies against the identified targets in HepG2 cells showed that the capsaicin is able to bind Abelson tyrosine-protein kinase, c-Src kinase, p38 MAP kinase and VEGF-receptor. Molecular dynamic simulation showed that capsaicin-VEGF receptor complex is highly stable at 50 nano seconds. The IC50 of capsaicin loaded SLNs in HepG2 cells in vitro was 21.36 µg × ml-1. These findings suggest that capsaicin loaded SLNs are stable in circulation for a period up to 3 d, providing a controlled release of loaded capsaicin and enhanced anticancer activity.