Synthesis of novel isothiazolopyridines and their in vitro evaluation against Mycobacterium and Propionibacterium acnes

AbstractIn this paper we describe synthesis, structures and some physicochemical properties of 20 isothiazolopyridines 8–13 substituted differently into an isothiazole ring as well as their in vitro antibacterial assays against Mycobacterium tuberculosis H37Rv, Mycobacterium fortuitum PCM 672 and Propionibacterium acnes PCM 2400. Compound 13a was found to be the most active derivative against M. tuberculosis H37Rv, demonstrating 100% growth inhibition of microorganisms in the primary screen (minimum inhibitory concentration [MIC] 6.25μg/mL). Nineteen of the prepared compounds were evaluated against M. fortuitum PCM 672 and P. acnes PCM 2400 and only compounds 9 and 12d exhibited excellent activity against individual strains of microorganisms with MIC90 <1μg/mL. The inhibitory action of the remaining isothiazolopyridines towards the tested strains of the microorganism was low, absent, or a non-linear correlation prohibited accurate determination of MIC values. Unexpectedly, seven of the remaining isothiazolopyridines tested against M. fortuitum and P. acnes stimulated growth of the microorganisms in the range 10–50% or even more (10b) under experimental conditions

1-(3-Chloro­phen­yl)-3-(1-p-tolyl­imidazolidin-2-yl­idene)urea

In the crystal structure of the title compound, C17H17ClN4O, the existence of only one 2-imino–oxo of the five possible N-amino–imino/O-keto–hydr­oxy tautomers is observed and the dihedral angle between the aromatic rings is 29.78 (11)°. The mol­ecular conformation is stabilized by intra­molecular C—H⋯N, N—H⋯O and C—H⋯O hydrogen bonds, in each case generating a six-membered ring. In the crystal structure, the glide-plane-related mol­ecules are linked into C(4) amide chains by inter­molecular N—H⋯O hydrogen bonds, and an inter­molecular C—H⋯O link also occurs

5,6,7,8-Tetra­hydro­quinolin-8-one

In the quinoline fused-ring system of the title compound, C9H9NO, the pyridine ring is planar to within 0.011 (3) Å, while the partially saturated cyclo­hexene ring adopts a sofa conformation with an asymmetry parameter ΔC s(C6) = 1.5 (4)°. There are no classical hydrogen bonds in the crystal structure. Mol­ecules form mol­ecular layers parallel to (100) with a distance between the layers of a/2 = 3.468 Å

A Proline-Based Tectons and Supramolecular Synthons for Drug Design 2.0: A Case Study of ACEI

Proline is a unique, endogenous amino acid, prevalent in proteins and essential for living organisms. It is appreciated as a tecton for the rational design of new bio-active substances. Herein, we present a short overview of the subject. We analyzed 2366 proline-derived structures deposited in the Cambridge Structure Database, with emphasis on the angiotensin-converting enzyme inhibitors. The latter are the first-line antihypertensive and cardiological drugs. Their side effects prompt a search for improved pharmaceuticals. Characterization of tectons (molecular building blocks) and the resulting supramolecular synthons (patterns of intermolecular interactions) involving proline derivatives, as presented in this study, may be useful for in silico molecular docking and macromolecular modeling studies. The DFT, Hirshfeld surface and energy framework methods gave considerable insight into the nature of close inter-contacts and supramolecular topology. Substituents of proline entity are important for the formation and cooperation of synthons. Tectonic subunits contain proline moieties characterized by diverse ionization states: -N and -COOH(-COO&minus;), -N+ and -COOH(-COO&minus;), -NH and -COOH(-COO&minus;), -NH+ and -COOH(-COO&minus;), and -NH2+ and -COOH(-COO&minus;). Furthermore, pharmacological profiles of ACE inhibitors and their impurities were determined via an in silico approach. The above data were used to develop comprehensive classification, which may be useful in further drug design studies

<i>N</i>′-Substituted 4-Phenylpicolinohydrazonamides with Thiosemicarbazone Moiety as New Potential Antitubercular Agents: Synthesis, Structure and Evaluation of Antimicrobial Activity

Three new 4-phenylpicolin derivatives with a thiosemicarbazone structure were synthesized and evaluated for tuberculostatic activity. The compounds were obtained by the condensation of methyl 4-phenylpicolonimidate with the corresponding cycloalkylamino-1-carbothiohydrazides. The 1H NMR temperature spectra obtained showed proton lability at the nitrogen atom N2, and X-ray crystallography confirmed the zwitterionic structure of all products. ADME calculations indicate that the compounds can be tested as future drugs. All compounds were absorbed in the gastrointestinal tract. All compounds also showed very good tuberculostatic activity (MIC 3.1–12.5 µg/mL). Derivative 1b showed the best selectivity for M. tuberculosis compared to the other pathogenic species tested. The study has allowed the emergence of imine derivative 1b as a good structure for further optimization in the search for antitubercular drugs

Influence of Incorporation of Different d<i>ⁿ</i>-Electron Metal Cations into Biologically Active System on Its Biological and Physicochemical Properties

Three new compounds, namely [HL]2+[CuCl4]2−, [HL]2+[ZnCl4]2−, and [HL]2+[CdCl4]2− (where L: imipramine) were synthesized and their physicochemical and biological properties were thoroughly investigated. All three compounds form isostructural, crystalline systems, which have been studied using Single-Crystal X-ray diffraction analysis (SC-XRD) and Fourier-transform infrared spectroscopy (FTIR). The thermal stability was investigated using thermogravimetric analysis (TGA) and melting points for all compounds have been determined. Magnetic measurements were performed in order to study the magnetic properties of the compounds. The above mentioned techniques allowed us to comprehensively examine the physicochemical properties of the newly obtained compounds. The biological activity was investigated using the number of Zebrafish tests, as it is one of the most common models for studying the impact of newly synthesized compounds on the central nervous system (CNS), since this model is very similar to the human CNS