Design, synthesis and antimycobacterial activity of benzoxazinone derivatives and open-ring analogues: preliminary data and computational analysis

This study examines in depth benzoxazine nucleus for antimycobacterial property. We synthesized some benzoxazin-2-one and benzoxazin-3-one derivatives, which were tested for activity against a panel of Mycobacterium tuberculosis (Mtb) strains, including H37Ra, H37Rv and some resistant strains. Several compounds displayed a high antimycobacterial activity and the three isoniazid analogue derivatives 8a-c exhibited a MIC range of 0.125-0.250 \u3bcg/mL (0.37-0.75 \u3bcM) against strain H37Ra, therefore lower than the isoniazid reference drug. Two benzoxazin-2-one derivatives, 1c and 5j, together with isoniazid-analogue compound 8a, also revealed low MIC values against resistant strains and proved highly selective for mycobacterial cells, compared to mammalian Vero cells. To predict whether molecule 8a is able to interact with the active site of InhA, we docked it into the crystal structure; indeed, during the molecular dynamic simulation the compound never left the protein pocket. The more active compounds were predicted for ADME properties and all proved to be potentially orally active in humans

Improving selectivity preserving affinity: New piperidine-4-carboxamide derivatives as effective sigma-1-ligands

We report the design, synthesis and binding evaluation against \u3c31 and \u3c32 receptors of a series of new piperidine-4-carboxamide derivatives variously substituted on the amide nitrogen atom. Specifically, we assessed the effects exerted on \u3c3 receptor affinity by substituting the N-benzylcarboxamide group present on a series of compounds previously synthesized in our laboratory with different cyclic or linear moieties. The synthesized compounds 2a-o were tested to estimate their affinity and selectivity toward \u3c31 and \u3c32 receptors. Very high \u3c31 affinity (Ki\ua0=\ua03.7\ua0nM) and Ki\u3c32/Ki\u3c31 selectivity ratio (351) were found for the tetrahydroquinoline derivative 2k, featuring a 4-chlorobenzyl moiety linked to the piperidine nitrogen atom

Computer-assisted design, synthesis, binding and cytotoxicity assessments of new 1-(4-(aryl(methyl)amino)butyl)-heterocyclic sigma 1 ligands

In this work we applied a blend of computational and synthetic techniques with the aim to design, synthesize, and characterize new \u3c31 receptor (\u3c31R) ligands. Starting from the structure of previously reported, high-affinity benzoxazolone-based \u3c31 ligands, the threedimensional homology model of the \u3c31R was exploited for retrieving the molecular determinants to fulfill the optimal pharmacophore requirements. Accordingly, the benzoxazolone moiety was replaced by other heterocyclic scaffolds, the relevant conformational space in the \u3c31R binding cavity was explored, and the effect on \u3c31R binding affinity was ultimately assessed. Next, the compounds designed in silico were synthesized, and their affinity and selectivity toward \u3c31 and \u3c32 receptors were tested. Finally, a representative series of best \u3c31R binders were assayed for cytotoxic activity on the SH-SY5Y human neuroblastoma cell line. Specifically, the new 4-phenyloxazolidin-2-one derivatives 2b (i.e., (R)-2b and (S)-2b) emerged as potential leads for further development as \u3c31R agents, as they were found endowed with the highest \u3c31R affinity (Ki\u3c31 values in the range 0.95-9.3 nM), and showed minimal cytotoxic levels exhibited in the selected, cell-based test, in line with a \u3c31R agonist behavior

Antimycobacterial Activity of New 1,4-Benzoxazine-2-One Derivatives and Its 2-(Arylamino)-4-Oxobut-2-Enoate, Ring-Open Analogues

Menaquinone is one of the essential components of the electron transport chain in many pathogens and consequently enzymes in its biosynthesis pathway are potential drug targets for the development of novel antibacterial agents. [...

Synthesis and antimycobacterial activity of 1,3,4-oxadiazol-2-one derivatives.

Our search consists on the design, synthesis and in vitro evaluation of antimycobacterial activity of new isoniazid analogues. All compounds have been tested on strains of Candida Albicans 685 and Mycobacterium Tuberculosis H37R

Synthesis and receptor binding studies of some new arylcarboxamide derivatives as sigma-1 ligands

We describe here the synthesis and the binding interaction with simga1 and sigma2 receptors of a series of new arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaffold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution on sigma binding. The synthesized compounds have been tested to estimate their affinity and selectivity toward sigma1 and sigma2 receptors. Two out of 16 derivatives showed an interesting sigma1 affinity (21.2 and 13.6 nM - compounds 2m and 2p) and a good selectivity (Ki(sigma2) / Ki(sigma1) >140 and >40 respectively)