Menthol- and thymol-based ciprofloxacin derivatives against Mycobacterium tuberculosis: in vitro activity, lipophilicity, and computational studies.

In this work, we investigated the antitubercular properties of Ciprofloxacin derivatives conjugated with menthol and thymol moieties. For the sixteen derivatives, we established minimal inhibitory concentrations (MIC) using isolates of Mycobacterium tuberculosis that were resistant or susceptible to other antibiotics. For the most potent compound 1-cyclopropyl-6-fluoro-7-{4-[6-((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-6-oxohexyl]piperazin-1-yl}-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (6), we determined fractional inhibitory concentration index (FICI) values to confirm antibacterial susceptibility and synergistic effects with other reference drugs. In addition, chromatographic studies of all the derivatives demonstrated a significant three to four-fold increase in lipophilicity and affinity to phospholipids compared to Ciprofloxacin. Finally, we conducted structure-based studies of the investigated compounds using molecular docking and taking into account protein target mutations associated with fluoroquinolone resistance. In summary, our findings indicate that the investigated compounds possess tuberculostatic properties, with some showing similar or even better activity against resistant strains compared to reference drugs. Increased lipophilicity and affinity to phospholipids of the new derivatives can offer several advantages for new drug candidates, beyond just improved cell membrane penetration. However, further studies are needed to fully understand their safety, efficacy, and mechanism of action.

Revealing the structure and mechanisms of action of a synthetic opioid with model biological membranes at the air-water interface.

Synthetic opioids such as piperazine derivative called MT-45 interact with opioid receptors in a manner similar to morphine leading to euphoria, a sense of relaxation and pain relief and are commonly used as substituents of natural opioids. In this study we show the changes in the surface properties of nasal mucosa and intestinal epithelial model cell membranes formed at the air - water interface using Langmuir technique upon the exposure to MT-45. Both membranes constitute the first barrier to absorb this substance into the human body. The presence of the piperazine derivative affects the organization of both DPPC and ternary DMPC:DMPE:DMPS monolayers treated as simple models of nasal mucosa and intestinal cell membranes, respectively. This novel psychoactive substance (NPS) leads to the fluidization of the model layers, which may indicate their increased permeability. MT-45 has a greater influence on the ternary monolayers characteristic of the intestinal epithelial cells than nasal mucosa. It might be attributed to the increased attractive interactions between the components of the ternary layer, which in turn increase the interactions with a synthetic opioid. Additionally, the crystal structures of MT-45 determined by single-crystal and powder X-ray diffraction methods allowed us to both provide useful data for facilitating the identification of synthetic opioids as well as to attribute the effect of MT-45 to the ionic interactions between protonated nitrogen atoms and negatively charged parts of the polar heads of the lipids.

"Salt mummification" - atypical method of embalming a corpse.

It is extremely rare for table salt to be used to preserve a dead body in criminal cases. In the case presented here, after the death of his 85-year-old mother, a son kept her body preserved in table salt for about 2 years to extort social benefits (pension). Before her death, the woman had been hospitalised twice due to chronic diseases. The case has been examined by the multi-disciplinary team. The unusual conditions in which the corpse was stored influenced its good condition (close to mummification), with limited colonisation of the corpse by necrophagous insects and insects involved in soft tissue biolysis (i.e. selected Diptera or Coleoptera). The use of table salt inhibited the growth of most fungi which would normally be present on a corpse stored in ambient conditions, and the corpse's surface was colonised by halophilic fungus (Scopulariopsis brevicaulis).

Synthetic Transition from Thiourea-Based Compounds to Tetrazole Derivatives: Structure and Biological Evaluation of Synthesized New N-(Furan-2-ylmethyl)-1H-tetrazol-5-amine Derivatives.

Twelve novel derivatives of N-(furan-2-ylmethyl)-1H-tetrazol-5-amine were synthesized. For obtained compound 8, its corresponding substrate single crystals were isolated and X-ray diffraction experiments were completed. In the initial stage of research, in silico structure-based pharmacological prediction was conducted. All compounds were screened for their antibacterial and antimycobacterial activities using standard and clinical strains. The cytotoxic activity was evaluated against a panel of human cancer cell lines, in contrast to normal (HaCaT) cell lines, by using the MTT method. All examined derivatives were found to be noncytotoxic against normal cell lines. Within the studied group, compound 6 showed the most promising results in antimicrobial studies. It inhibited four hospital S. epidermidis rods' growth, when applied at the amount of 4 µg/mL. However, the most susceptible to the presence of compound 6 was S. epidermidis T 5501 851/19 clinical strain, for which the MIC value was only 2 µg/mL. Finally, a pharmacophore model was established based on lead compounds from this and our previous work.

Comprehensive Protocol for the Identification and Characterization of New Psychoactive Substances in the Service of Law Enforcement Agencies.

A non-routine, comprehensive protocol for characterization of emerging new psychoactive substances (NPS) including chemical structures, impurities, as well as crystal structures, has been developed to facilitate the work of law enforcement agencies. A set of NPS has been synthesized, identified, and characterized by various analytical methods in order to be used as certified reference standards (CRMs). Seven selected compounds (5-IT, NM-2201, MT-45, AB-CHMINACA, UR-144, 5F-PB-22, and 4-CMC) were synthesized on the laboratory scale, then the process was upscaled to semi-technical. All products were analyzed by electrospray Q/TOF-MS/MS for molecular structure identification. The presence of by-products, as well as metal impurities, arising from the performed syntheses, were characterized by reversed phase liquid chromatography (RP-HPLC) with DAD and Q/TOF-MS detection and inductively-coupled plasma with quadrupole mass spectrometer (ICP-QMS), respectively. Additionally, the crystal structures of UR-144, NM-2201, 5F-PB-22, and 4-CMC have been determined by single-crystal and powder X-ray diffraction.

Cytotoxicity Evaluation of Novel bis(2-aminoethyl)amine Derivatives.

Seven novel derivatives of bis(2-aminoethyl)amine were synthesized. For compounds 1 and 7 single crystals were isolated and X-ray diffraction experiments were done. Lipophilicity and drug likeness were calculated in the initial stage of research. All compounds were screened for their in vitro cytotoxic activity against a panel of human cancer cell lines, which is contrary to normal (HaCaT) cell lines, by using the MTT method. Studies were followed by lactate dehydrogenase assay, apoptotic activity, and interleukin-6 assay. Within the studied group, compound 6 showed the most promising results in all biological studies. The strongest influence in A549 cells was denoted for derivative 4, which inhibited interleukin release almost tenfold, as compared to the control.

Design and synthesis of novel 1H-tetrazol-5-amine based potent antimicrobial agents: DNA topoisomerase IV and gyrase affinity evaluation supported by molecular docking studies.

A total of 14 of 1,5-disubstituted tetrazole derivatives were prepared by reacting appropriate thiourea and sodium azide in the presence of mercury (II) chloride and triethylamine. All compounds were evaluated in vitro for their antimicrobial activity. Derivatives 10 and 11 showed the highest inhibition against Gram-positive and Gram-negative strains (standard and hospital strains). The observed minimal inhibitory concentrations values were in the range of 1-208 µM (0.25-64 µg/ml). Inhibitory activity of 1,5-tetrazole derivatives 10 and 11 against gyrase and topoisomerase IV isolated from S. aureus was studied. Evaluation was supported by molecular docking studies for all synthesized derivatives and reference ciprofloxacin. Moreover, selected tetrazoles (2, 3, 5, 6, 8, 9, 10 and 11) were evaluated for their cytotoxicity. All tested compounds are non-cytotoxic against HaCaT and A549 cells (CC50 ≤ 60 µM).

Cyclic π-electron delocalization in non-planar linear acenes.

Based on the experimental data of newly determined structures of per-substituted naphthalenes by halogen atoms (F, Cl and Br) and perchloroanthracene, as well as on the molecular modeling we have shown that deviation from planarity leads to relatively small changes in the cyclic π-electron delocalization of acenes. Per-substituted naphthalenes are twisted, whereas perchloroanthracene adopts a boat conformation in the solid state. For the most distorted case - perbromonaphthalene twisted by 34.7°, the geometry-based HOMA index drops down by 0.128 of the unit only, which means ca. 15% reduction of the extent of π-electron delocalization as referred to naphthalene. To account for the changes in the aromatic stabilization energies (ASEs), exaltation of magnetic susceptibilities (Λ) and strain energies (SEs) upon bending we have proposed a set of homodesmotic reactions based on the peri-substituted systems, where the reference compounds have similar conformation to the distorted aromatics. The decrease of aromaticity is smooth, but regular in a rather large range of distortion. Notably, the most extreme case - 1,4,5,8-tetra-t-butylnaphthalene, twisted by 51.7° with an estimated strain energy of 26 kcal mol(-1) - is still aromatic. The ASE, Λ and HOMA decrease by 19.1 kcal mol(-1), 7 cgs-ppm and 0.34 of the unit, respectively, as referred to naphthalene.

Synthesis and structure evaluation of new complex butylarylpiperazin-1-yl derivatives.

A series of arylpiperazine derivatives of 1,16-diphenyl-19-azahexacyclo-[14.5.1.02,15.03,8.09,14.017,21]docosa-2,3,5,7,8,9,11,13,14-nonaene-18,20,22-trione and 4,10-diphenyl-1H,2H,3H,5H-indeno[1,2-f]isoindole-1,3,5-trione was synthesized. The pharmacological profile of compound 4 at the 5-HT1A receptor was measured by binding assay. The title compounds were tested in cell-based assay against the human immunodeficiency virus type-1. The X-ray crystallographic studies of derivatives 2, 6, 7, 11, 19, and 20 were presented.

Synthesis and biological activity of novel series of 1,3-benzoxazol-2(3H)-one derivatives.

In the search for novel biological agents, a series of new derivatives N-substituted 1,3-benzoxazol-2(3H)-one, 5-chloro-1,3-benzoxazol-2(3H)-one, 6-bromo-1,3-benzoxazol-2(3H)-one were prepared. All of the compounds were characterized by 1H NMR, 13C NMR and ESI MS spectra. Moreover, for compound 1 an Xray structure was determined. All derivatives were tested for antimicrobial activity against a selection of Gram-positive, Gram-negative bacteria and yeasts. The selected compounds (2-8, 10) were tested for their cytotoxic properties in K562, HeLa and normal cells.

On the aromatic stabilization of benzenoid hydrocarbons.

A general scheme for estimation of aromatic stabilization energies of benzenoid hydrocarbons based on selected topological features has been presented. The reactions have been applied to benzene, naphthalene, anthracene, phenanthrene, pyrene, tetracene, benz[a]anthracene, chrysene, [4]-helicene, anthanthrene and coronene.

6-Bromo-2-methyl-sulfanyl-1,3-benzo-thia-zole.

The title mol-ecule, C(8)H(6)BrNS(2), is almost planar with a dihedral angle of 0.9 (1)° between the benzene and thia-zole rings. The values of the geometry-based index of aromaticity (HOMA) and the nucleus-independent chemical shift (NICS) for the two cyclic fragments of the title mol-ecule are 0.95 and -9.61, respectively, for the benzene ring, and 0.69 and -7.71, respectively, for the thia-zole ring. They show that the benzene ring exhibits substanti-ally higher cyclic π-electron delocalization than the thia-zole ring. Comparison with other similar benzothia-zole fragments reveals a similar trend.

On the aromatic stabilization of corannulene and coronene.

The application of set of homodesmotic reactions allowed us to estimate the aromatic stabilization energy (ASE) of corannulene and coronene. Appropriate reactions have been applied to balance syn/anti mismatches in di-, tetra- and hexamethylene substituted derivatives. Based on many different polycyclic reference structures that compensate the effect of strain in the corannulene moiety the value of ASE comes to 44.5 kcal mol(-1). Planar corannulene is more stabilized by cyclic π-electron delocalization by ca. 10.7 kcal mol(-1), as compared with a bowl-shaped system. A similar approach for coronene leads to an ASE equal to 58.4 kcal mol(-1).

Graph-topological approach to magnetic properties of benzenoid hydrocarbons.

Application of topological properties and graph theory to benzenoid hydrocarbons allowed us to construct an effective approach interpreting ring current formation in molecules when exposed to an external magnetic field. Transformation of unexcited canonical structures for molecules of 34 benzenoid hydrocarbons into circuit structures and then to directed circuit structures allowed us to define global magnetic characteristics (GMC). GMC/n(2) values correlate very well with exaltation of magnetic susceptibility DeltaLambda/n(2) (computed at the CSGT/B3LYP/6-311G** level of theory by using optimized geometries at the B3LYP/6-311G** DFT level) with cc = 0.993. If the approach is applied to individual rings, then the correlation between local magnetic characteristics (LMC) for 129 various rings of 34 benzenoid hydrocarbons and NICS(1) works with cc = -0.975.

Are thermodynamic and kinetic stabilities correlated? A topological index of reactivity toward electrophiles used as a criterion of aromaticity of polycyclic benzenoid hydrocarbons.

A topological index of reactivity (TIR) of benzenoid hydrocarbons is defined basing on an approximate value of the bicentric localization energies. TIR values correlate with all known (24) Hammett-Streitwieser position constants, based on kinetic data for electrophilic substitution in benzenoid hydrocarbons. The maximum value of the index, denoted by TIR(max), defines the stability of a molecule toward electrophiles. For all 35 nonisoarithmic molecules of benzenoid hydrocarbons for which Hess and Schaad data are known, TIR(max) values correlate with classical numerical characteristics of aromaticity: resonance energy per pi-electron (REPE), HOMO-LUMO gap, and geometry based aromaticity index HOMA. Correlation between TIR(max) and exaltation of magnetic susceptibility is also found for cata-condensed benzenoid hydrocarbons, whereas if the peri-condensed ones are included, no correlation is observed. This can be ascribed to the presence of both paratropic and diatropic rings in perifusenes.

Interplay of pi-electron delocalization and strain in [n](2,7)pyrenophanes.

The geometries of a series of [n](2,7)pyrenophanes (n = 6-12) were optimized at the B3LYP/6-311G** DFT level. The X-ray crystal structures determined for the [9](2,7)- and [10](2,7)pyrenophanes agreed excellently with the computed structures. The degree of nonplanarity of the pyrene moiety depends on the number of CH2 groups in the aliphatic bridge and, as analyzed theoretically, influences the strain energy and the extent of pi-electron delocalization in the pyrene fragment. Various indices, e.g., the relative aromatic stabilization energies (DeltaASE), magnetic susceptibility exaltations (Lambda), nucleus-independent chemical shifts (NICS), and the harmonic oscillator model of aromaticity (HOMA) were used to quantify the change in aromatic character of the pyrene fragment. DeltaASE and relative Lambda values (with respect to planar pyrene) were evaluated by homodesmotic equations comparing the bent pyrene unit with its bent quinoid dimethylene-substituted analog. The bend angle, alpha, DeltaASE, and Lambda were linearly related. The aromaticity decreases smoothly and regularly over a wide range of bending, but the magnitude of the change is not large. The differences between planar pyrene (alpha = 0 degrees) and the most distorted pyrene unit (alpha = 39.7 degrees in [6](2,7)pyrenophane) are only 15.8 kcal/mol (DeltaASE) and 18.8 cgs-ppm (Lambda). Also, the geometry-based HOMA descriptor changes by only 0.07 unit. The local NICS descriptors of aromatic character also correlate very well with the global indices of aromaticity. In line with the known reactivity of pyrenophanes, the variations of NICS(1), a measure of pi-electron delocalization, were largest for the outer, biphenyl-type rings. The strain energies of the pyrene fragments were much larger and varied more than those evaluated for the bridge. Both strain energies were interrelated (correlation coefficient R = 0.979) and depend on the bend angle, alpha.

Nonplanar aromatic compounds. 9. Synthesis, structure, and aromaticity of 1:2,13:14-dibenzo[2]paracyclo[2](2,7)- pyrenophane-1,13-diene.

Pyrenophane (6) and an octaphenyl derivative (16) were synthesized using two different routes. Both cyclophanes contain a severely bent pyrene unit (6: theta = 93.6 degrees and 16: theta = 95.8 degrees , according to DFT-calculations (B3LYP/6-311G**)), which was generated at room temperature by a valence isomerization/dehydrogenation (VID) reaction. HOMA and NICS indicate 92-98% retention of aromaticity of the highly distorted pyrene systems compared to planar pyrene.

The phenalenyl motif: a magnetic chameleon.

The 12pi cation (3) and 14pi anion (4) derived from the phenalenyl radical (2) support diatropic ("aromatic") perimeter ring currents, but isoelectronic replacement of the central atom by either boron (5) or nitrogen (6) leads to paratropic ("antiaromatic") current; the ipsocentric approach to molecular magnetic response accounts for all four patterns in terms of competition between translationally and rotationally allowed virtual pi-pi* excitations.