Distinctive Nucleic Acid Recognition by Lysine-Embedded Phenanthridine Peptides.

Three new phenanthridine peptide derivatives (19, 22, and 23) were synthesized to explore their potential as spectrophotometric probes for DNA and RNA. UV/Vis and circular dichroism (CD) spectra, mass spectroscopy, and computational analysis confirmed the presence of intramolecular interactions in all three compounds. Computational analysis revealed that compounds alternate between bent and open conformations, highlighting the latter's crucial influence on successful polynucleotide recognition. Substituting one glycine with lysine in two regioisomers (22, 23) resulted in stronger binding interactions with DNA and RNA than for a compound containing two glycines (19), thus emphasizing the importance of lysine. The regioisomer with lysine closer to the phenanthridine ring (23) exhibited a dual and selective fluorimetric response with non-alternating AT and ATT polynucleotides and induction of triplex formation from the AT duplex. The best binding constant (K) with a value of 2.5 × 107 M-1 was obtained for the interaction with AT and ATT polynucleotides. Furthermore, apart from distinguishing between different types of ds-DNA and ds-RNA, the same compound could recognize GC-rich DNA through distinct induced CD signals.

Biological activity and computational analysis of novel acrylonitrile derived benzazoles as potent antiproliferative agents for pancreatic adenocarcinoma with antioxidative properties.

Continuing our research into the anticancer properties of acrylonitriles, we present a study involving the design, synthesis, computational analysis, and biological assessment of novel acrylonitriles derived from methoxy, hydroxy, and N-substituted benzazole. Our aim was to examine how varying the number of methoxy and hydroxy groups, as well as the N-substituents on the benzimidazole core, influences their biological activity. The newly synthesized acrylonitriles exhibited strong and selective antiproliferative effects against the Capan-1 pancreatic adenocarcinoma cell line, with IC50 values ranging from 1.2 to 5.3 µM. Consequently, these compounds were further evaluated in three other pancreatic adenocarcinoma cell lines, while their impact on normal PBMC cells was also investigated to determine selectivity. Among these compounds, the monohydroxy-substituted benzimidazole derivative 27 emerged with the most profound and broad-spectrum anticancer antiproliferative activity being emerged as a promising lead candidate. Moreover, a majority of the acrylonitriles in this series exhibited significant antioxidative activity, surpassing that of the reference molecule BHT, as demonstrated by the FRAP assay (ranging from 3200 to 5235 mmolFe2+/mmolC). Computational analysis highlighted the prevalence of electron ionization in conferring antioxidant properties, with computed ionization energies correlating well with observed activities.

Discovery of harmiprims, harmine-primaquine hybrids, as potent and selective anticancer and antimalarial compounds.

Although cancer and malaria are not etiologically nor pathophysiologically connected, due to their similarities successful repurposing of antimalarial drugs for cancer and vice-versa is known and used in clinical settings and drug research and discovery. With the growing resistance of cancer cells and Plasmodium to the known drugs, there is an urgent need to discover new chemotypes and enrich anticancer and antimalarial drug portfolios. In this paper, we present the design and synthesis of harmiprims, hybrids composed of harmine, an alkaloid of the ß-carboline type bearing anticancer and antiplasmodial activities, and primaquine, 8-aminoquinoline antimalarial drug with low antiproliferative activity, covalently bound via triazole or urea. Evaluation of their antiproliferative activities in vitro revealed that N-9 substituted triazole-type harmiprime was the most selective compound against MCF-7, whereas C1-substituted ureido-type hybrid was the most active compound against all cell lines tested. On the other hand, dimeric harmiprime was not toxic at all. Although spectrophotometric studies and thermal denaturation experiments indicated binding of harmiprims to the ds-DNA groove, cell localization showed that harmiprims do not enter cell nucleus nor mitochondria, thus no inhibition of DNA-related processes can be expected. Cell cycle analysis revealed that C1-substituted ureido-type hybrid induced a G1 arrest and reduced the number of cells in the S phase after 24 h, persisting at 48 h, albeit with a less significant increase in G1, possibly due to adaptive cellular responses. In contrast, N-9 substituted triazole-type harmiprime exhibited less pronounced effects on the cell cycle, particularly after 48 h, which is consistent with its moderate activity against the MCF-7 cell line. On the other hand, screening of their antiplasmodial activities against the erythrocytic, hepatic, and gametocytic stages of the Plasmodium life cycle showed that dimeric harmiprime exerts powerful triple-stage antiplasmodial activity, while computational analysis showed its binding within the ATP binding site of PfHsp90.

Novel acrylonitrile derived imidazo[4,5-b]pyridines as antioxidants and potent antiproliferative agents for pancreatic adenocarcinoma.

We present the design, synthesis, computational analysis, and biological assessment of several acrylonitrile derived imidazo[4,5-b]pyridines, which were evaluated for their anticancer and antioxidant properties. Our aim was to explore how the number of hydroxy groups and the nature of nitrogen substituents influence their biological activity. The prepared derivatives exhibited robust and selective antiproliferative effects against several pancreatic adenocarcinoma cells, most markedly targeting Capan-1 cells (IC50 1.2-5.3 µM), while their selectivity was probed relative to normal PBMC cells. Notably, compound 55, featuring dihydroxy and bromo substituents, emerged as a promising lead molecule. It displayed the most prominent antiproliferative activity without any adverse impact on the viability of normal cells. Furthermore, the majority of studied derivatives also exhibited significant antioxidative activity within the FRAP assay, even surpassing the reference molecule BHT. Computational analysis rationalized the results by highlighting the dominance of the electron ionization for the antioxidant features with the trend in the computed ionization energies well matching the observed activities. Still, in trihydroxy derivatives, their ability to release hydrogen atoms and form a stable O-H⋯O•⋯H-O fragment upon the H• abstraction prevails, promoting them as excellent antioxidants in DPPH• assays as well.

Phenanthridine-pyrene conjugates as fluorescent probes for DNA/RNA and an inactive mutant of dipeptidyl peptidase enzyme.

Two novel conjugate molecules were designed: pyrene and phenanthridine-amino acid units with a different linker length between the aromatic fragments. Molecular modelling combined with spectrophotometric experiments revealed that in neutral and acidic buffered water solutions conjugates predominantly exist in intramolecularly stacked conformations because of the π-π stacking interaction between pyrene and phenanthridine moieties. The investigated systems exhibited a pH-dependent excimer formation that is significantly red-shifted relative to the pyrene and phenanthridine fluorescence. While the conjugate with a short linker showed negligible spectrophotometric changes due to the polynucleotide addition, the conjugate with a longer and more flexible linker exhibited a micromolar and submicromolar binding affinity for ds-polynucleotides and inactivated a mutant of dipeptidyl peptidase enzyme E451A. Confocal microscopy revealed that the conjugate with the longer linker entered the HeLa cell membranes and blue fluorescence was visualized as the dye accumulated in the cell membrane.

Selective Deuteration Improves the Affinity of Adenosine A2A Receptor Ligands: A Computational Case Study with Istradefylline and Caffeine.

We used a range of computational techniques to assess the effect of selective C-H deuteration on the antagonist istradefylline affinity for the adenosine A2A receptor, which was discussed relative to its structural analogue caffeine, a well-known and likely the most widely used stimulant. The obtained results revealed that smaller caffeine shows high receptor flexibility and exchanges between two distinct poses, which agrees with crystallographic data. In contrast, the additional C8-trans-styryl fragment in istradefylline locks the ligand within a uniform binding pose, while contributing to the affinity through the C-H···π and π···π contacts with surface residues, which, together with its much lower hydration prior to binding, enhances the affinity over caffeine. In addition, the aromatic C8-unit shows a higher deuteration sensitivity over the xanthine part, so when both of its methoxy groups are d6-deuterated, the affinity improvement is -0.4 kcal mol-1, which surpasses the overall affinity gain of -0.3 kcal mol-1 in the perdeuterated d9-caffeine. Yet, the latter predicts around 1.7-fold potency increase, being relevant for its pharmaceutical implementations, and also those within the coffee and energy drink production industries. Still, the full potential of our strategy is achieved in polydeuterated d19-istradefylline, whose A2A affinity improves by -0.6 kcal mol-1, signifying a 2.8-fold potency increase that strongly promotes it as a potential synthetic target. This knowledge supports deuterium application in drug design, and while the literature already reports about over 20 deuterated drugs currently in the clinical development, it is easily foreseen that more examples will hit the market in the years to come. With this in mind, we propose that the devised computational methodology, involving the ONIOM division of the QM region for the ligand and the MM region for its environment, with an implicit quantization of nuclear motions relevant for the H/D exchange, allows fast and efficient estimates of the binding isotope effects in any biological system.

Utilization of a kinetic isotope effect to decrease decomposition of ceftriaxone in a mixture of D2O/H2O.

The discovery of cephalosporin and demonstration of its improved stability in aqueous solution, as well as enhanced in vitro activity against penicillin-resistant organisms, were major breakthroughs in the development of ß-lactam antibiotics. Although cephalosporins are more stable with respect to hydrolytic degradation than penicillins, they still experience a variety of chemical transformations. The present study offers an insight into the rates and mechanisms of ceftriaxone degradation at the therapeutic concentration in water, a mixture of water and deuterium oxide, and deuterium oxide itself at the neutral pH. Specific ceftriaxone degradation products were observed in aged samples (including a previously unreported dimer-type species), and by comparing the degradation rates in H2O and D2O, the observation of a kinetic isotope effect provided some valuable insight as to the nature of the initial ceftriaxone degradation. The effect of protium to deuterium isotope change on the degradation kinetics of ceftriaxone was evaluated using the method of initial rates based on HPLC analysis as well as by quantitative 1H NMR spectroscopy. Moreover, computational analysis was utilized to get a molecular insight into chemical processes governing the ceftriaxone degradation and to rationalize the stabilizing effect of replacing H2O with D2O.

Biological evaluation of novel amidino substituted coumarin-benzazole hybrids as promising therapeutic agents.

Herein we present the design and the synthesis of novel substituted coumarin-benzimidazole/benzothiazole hybrids bearing a cyclic amidino group on the benzazole core as biologically active agents. All prepared compounds were evaluated for their in vitro antiviral and antioxidative activity as well as for their in vitro antiproliferative activity against a panel of several human cancer cell lines. Coumarin-benzimidazole hybrid 10 (EC50 9.0-43.8 µM) displayed the most promising broad spectrum antiviral activity, while two other coumarin-benzimidazole hybrids 13 and 14 showed the highest antioxidative capacity in the ABTS assay, superior to the reference standard BHT (IC50 0.17 and 0.11 mM, respectively). Computational analysis supported these results and demonstrated that these hybrids benefit from the high C-H hydrogen atom releasing tendency of the cationic amidine unit, and the pronounced ease with which they can liberate an electron, promoted by the electron-donating diethylamine group on the coumarin core. The coumarin ring substitution at position 7 with a N,N-diethylamino group also caused a significant enhancement of the antiproliferative activity, with the most active compounds being derivatives with a 2-imidazolinyl amidine group 13 (IC50 0.3-1.9 µM) and benzothiazole derivative with a hexacyclic amidine group 18 (IC50 1.3-2.0 µM).

An expedient metal-free cascade route to chromonyl diene scaffolds: thermodynamic vs. kinetic control.

A piperidine-catalyzed reaction between 3-formylchromone, 1,3-dimethyl barbituric acid, and ylidenemalononitriles is developed that offers chromonyl diene products in good yields. This cascade reaction proceeds via the insertion of ylidenemalononitriles between the Knoevenagel adduct obtained from 3-formylchromone and 1,3-dimethylbarbituric acid, where the pyrimidine-based enaminone is integrated with the chromone through the central diene linker. Similarly, introducing pyrimidine-based enaminone into the terminal part of the chromonyl diene scaffold gave an equilibrium mixture of rotational isomers in DMSO, which could be separated and isolated by crystallization. The computational analysis confirmed the role of barbiturate in directing the type of final chromonyl diene via kinetic or thermodynamic control. Moreover, computations revealed that one of these species, observed in the NMR spectra, is produced by the bond cleavage in the spirocyclic intermediate.

Tuning the coordination properties of chiral pseudopeptide bis(2-picolyl)amine and iminodiacetamide ligands in Zn(II) and Cu(II) complexes.

Seven bis(2-picolyl)amine (bpa) and five iminodiacetamide (imda) ligands were prepared with different modifications in their side chain structure. The coordination properties of the ligands (L) were influenced by changes in the aliphatic linker length (C1, C2, or C3), amide group isomers and type of chiral terminal group. Complexation with Cu(II) afforded two polymorphs of a ML complex which features tetradentate coordination of a ligand with C2 linkers, while crystal structures of three trans-fac ML2 complexes with Cu(II) and Ni(II) show tridentate coordination of ligands with a C3 linker. The stoichiometry and stereochemistry of Zn(II) and Cu(II) complexes was further studied in solution by NMR and UV-Vis spectroscopy. DFT calculations gave an insight into the relative stability of isomers, as well as potential hydrogen bonding between two ligands in a ML2 complex. Furthermore, ML complexes of Cu(II) exhibited DNA cleavage activity.

Imidazo[4,5-b]pyridine derived tubulin polymerization inhibitors: Design, synthesis, biological activity in vitro and computational analysis.

Imidazo[4,5-b]pyridine derived acrylonitriles were synthesized and explored for their in vitro antiproliferative effect on a diverse human cancer cell line panel. Three compounds, 20, 21 and 33, showed strong activity in the submicromolar range (IC50 0.2-0.6 µM), and were chosen for further biological experiments. Immunofluorescence staining and tubulin polymerization assays confirmed tubulin as the main target, but excluded its colchicine-binding site as a potential interacting unit. This was supported by the computational analysis, which revealed that the most potent ligands act on the extended colchicine site on the surface between interacting tubulin subunits, where they interfere with their polymerization and reveal pronounced antitumor properties. In addition, lead molecule 21 potently inhibited cancer cell migration, while it did not affect the viability of normal cells even at the highest concentration tested (100 µM).

Design and synthesis of harmiquins, harmine and chloroquine hybrids as potent antiplasmodial agents.

Malaria remains one of the major health problems worldwide. The lack of an effective vaccine and the increasing resistance of Plasmodium to the approved antimalarial drugs demands the development of novel antiplasmodial agents that can effectively prevent and/or treat this disease. Harmiquins represent hybrids that combine two moieties with different mechanisms of antiplasmodial activity in one molecule, i.e., a chloroquine (CQ) scaffold, known to inhibit heme polymerization and a ß-carboline ring capable of binding to P. falciparum heat shock protein 90 (PfHsp90). Here we present their synthesis, evaluation of biological activity and potential mechanism of action. The synthesized hybrids differed in the type of linker employed (triazole ring or amide bond) and in the position of the substitution on the ß-carboline core of harmine. The antiplasmodial activity of harmiquins was evaluated against the erythrocytic stage of the Plasmodium life cycle, and their cytotoxic effect was tested on HepG2 cells. The results showed that harmiquins exerted remarkable activity against both CQ-sensitive (Pf3D7) and CQ-resistant (PfDd2, PfK1, and Pf7G8). P. falciparum strains. The most active compound, harmiquine 32, displayed single-digit nanomolar IC50 value against Pf3D7 (IC50 = 2.0 ± 0.3 nM). Importantly, it also showed significantly higher activity than CQ against the resistant Plasmodium strains and had a very high selectivity index (4450). Harmiquins may act through the inhibition of heme polymerization and binding to the ATP binding site of the PfHsp90, which would explain their increased activity against the CQ-resistant Plasmodium strains. These results establish harmiquins as valuable antiplasmodial hits for future optimization.

COVID-19 infection and neurodegeneration: Computational evidence for interactions between the SARS-CoV-2 spike protein and monoamine oxidase enzymes.

Although COVID-19 has been primarily associated with pneumonia, recent data show that its causative agent, the SARS-CoV-2 coronavirus, can infect many vital organs beyond the lungs, including the heart, kidneys and the brain. The literature agrees that COVID-19 is likely to have long-term mental health effects on infected individuals, which signifies a need to understand the role of the virus in the pathophysiology of brain disorders that is currently unknown and widely debated. Our docking and molecular dynamics simulations show that the affinity of the spike protein from the wild type (WT) and the South African B.1.351 (SA) variant towards MAO enzymes is comparable to that for its ACE2 receptor. This allows for the WT/SA⋅⋅⋅MAO complex formation, which changes MAO affinities for their neurotransmitter substrates, thereby impacting their metabolic conversion and misbalancing their levels. Knowing that this fine regulation is strongly linked with the etiology of various brain pathologies, these results are the first to highlight the possibility that the interference with the brain MAO catalytic activity is responsible for the increased neurodegenerative illnesses following a COVID-19 infection, thus placing a neurobiological link between these two conditions in the spotlight. Since the obtained insight suggests that a more contagious SA variant causes even larger disturbances, and with new and more problematic strains likely emerging in the near future, we firmly advise that the presented prospect of the SARS-CoV-2 induced neurological complications should not be ignored, but rather requires further clinical investigations to achieve an early diagnosis and timely therapeutic interventions.

Why Monoamine Oxidase B Preferably Metabolizes N-Methylhistamine over Histamine: Evidence from the Multiscale Simulation of the Rate-Limiting Step.

Histamine levels in the human brain are controlled by rather peculiar metabolic pathways. In the first step, histamine is enzymatically methylated at its imidazole Nτ atom, and the produced N-methylhistamine undergoes an oxidative deamination catalyzed by monoamine oxidase B (MAO-B), as is common with other monoaminergic neurotransmitters and neuromodulators of the central nervous system. The fact that histamine requires such a conversion prior to oxidative deamination is intriguing since MAO-B is known to be relatively promiscuous towards monoaminergic substrates; its in-vitro oxidation of N-methylhistamine is about 10 times faster than that for histamine, yet this rather subtle difference appears to be governing the decomposition pathway. This work clarifies the MAO-B selectivity toward histamine and N-methylhistamine by multiscale simulations of the rate-limiting hydride abstraction step for both compounds in the gas phase, in aqueous solution, and in the enzyme, using the established empirical valence bond methodology, assisted by gas-phase density functional theory (DFT) calculations. The computed barriers are in very good agreement with experimental kinetic data, especially for relative trends among systems, thereby reproducing the observed MAO-B selectivity. Simulations clearly demonstrate that solvation effects govern the reactivity, both in aqueous solution as well as in the enzyme although with an opposing effect on the free energy barrier. In the aqueous solution, the transition-state structure involving histamine is better solvated than its methylated analog, leading to a lower barrier for histamine oxidation. In the enzyme, the higher hydrophobicity of N-methylhistamine results in a decreased number of water molecules at the active side, leading to decreased dielectric shielding of the preorganized catalytic electrostatic environment provided by the enzyme. This renders the catalytic environment more efficient for N-methylhistamine, giving rise to a lower barrier relative to histamine. In addition, the transition state involving N-methylhistamine appears to be stabilized by the surrounding nonpolar residues to a larger extent than with unsubstituted histamine, contributing to a lower barrier with the former.

Proton affinity and gas phase basicity of diamandoid molecules: diamantane to C131H116.

Calculated proton affinities (PAs) and gas phase basicities (GPBs) are reported for diamantane (C14H20), triamantane (C18H24), 'globular and planar' isomers of tetramantane (C22H28) and pentamantane (C26H32), and for one 'globular' isomer of each of the larger diamondoid molecules: C51H58, C78H72, C102H90, and C131H116. Assuming CxHy as the parent diamondoid molecule, we calculated PA and GPB values for a variety of CxHy+1+ isomers, as well as for the reaction CxHy + H+ yielding CxHy-1+ + H2(g); the latter is slightly favored based on GPB values for diamantane through pentamantane, but less favored compared to certain CxHy+1+ isomers of C51H58, C102H90, and C131H116. Indeed, the GPB values of C51H58, C102H90, and C131H116 classifiy them as 'superbases'. Calculations that had the initial location of the proton in an interstitial site inside the diamondoid molecule always showed the H having moved to the outside of the diamondoid molecule; for this reason, we focused on testing a variety of initial configurations with the proton placed in an initial position on the surface. Additional protons were added to determine the limiting number that could be, per these calculations, taken up by the diamondoid molecules and the maximum number of protons are shown in parentheses: C14H20(2), C18H24(3), C22H28(3), C26H32(3), C51H58(4). Bader charge distributions obtained for CxHy+1+ isomers (for diamantane through pentamantane) suggest that the positive charge is essentially completely delocalized over all the H atoms. NMR spectra were calculated for different isomers of C14H19+, and compared to the published NMR spectrum for when diamantane was mixed with magic acid and H2(g) was produced.

Chemistry of Spontaneous Alkylation of Methimazole with 1,2-Dichloroethane.

Spontaneous S-alkylation of methimazole (1) with 1,2-dichloroethane (DCE) into 1,2-bis[(1-methyl-1H-imidazole-2-yl)thio]ethane (2), that we have described recently, opened the question about its formation pathway(s). Results of the synthetic, NMR spectroscopic, crystallographic and computational studies suggest that, under given conditions, 2 is obtained by direct attack of 1 on the chloroethyl derivative 2-[(chloroethyl)thio]-1-methyl-1H-imidazole (3), rather than through the isolated stable thiiranium ion isomer, i.e., 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium chloride (4a, orthorhombic, space group Pnma), or in analogy with similar reactions, through postulated, but unproven intermediate thiiranium ion 5. Furthermore, in the reaction with 1, 4a prefers isomerization to the N-chloroethyl derivative, 1-chloroethyl-2,3-dihydro-3-methyl-1H-imidazole-2-thione (7), rather than alkylation to 2, while 7 further reacts with 1 to form 3-methyl-1-[(1-methyl-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8, monoclinic, space group P 21/c). Additionally, during the isomerization of 3, the postulated intermediate thiiranium ion 5 was not detected by chromatographic and spectroscopic methods, nor by trapping with AgBF4. However, trapping resulted in the formation of the silver complex of compound 3, i.e., bis-{2-[(chloroethyl)thio]-1-methyl-1H-imidazole}-silver(I)tetrafluoroborate (6, monoclinic, space group P 21/c), which cyclized upon heating at 80 °C to 7-methyl-2H, 3H, 7H-imidazo[2,1-b]thiazol-4-ium tetrafluoroborate (4b, monoclinic, space group P 21/c). Finally, we observed thermal isomerization of both 2 and 2,3-dihydro-3-methyl-1-[(1-methyl-1H-imidazole-2-yl)thioethyl]-1H-imidazole-2-thione (8), into 1,2-bis(2,3-dihydro-3-methyl-1H-imidazole-2-thione-1-yl)ethane (9), which confirmed their structures.

Synthesis, Computational Analysis, and Antiproliferative Activity of Novel Benzimidazole Acrylonitriles as Tubulin Polymerization Inhibitors: Part 2.

We used classical linear and microwave-assisted synthesis methods to prepare novel N-substituted, benzimidazole-derived acrylonitriles with antiproliferative activity against several cancer cells in vitro. The most potent systems showed pronounced activity against all tested hematological cancer cell lines, with favorable selectivity towards normal cells. The selection of lead compounds was also tested in vitro for tubulin polymerization inhibition as a possible mechanism of biological action. A combination of docking and molecular dynamics simulations confirmed the suitability of the employed organic skeleton for the design of antitumor drugs and demonstrated that their biological activity relies on binding to the colchicine binding site in tubulin. In addition, it also underlined that higher tubulin affinities are linked with (i) bulkier alkyl and aryl moieties on the benzimidazole nitrogen and (ii) electron-donating substituents on the phenyl group that allow deeper entrance into the hydrophobic pocket within the tubulin's ß-subunit, consisting of Leu255, Leu248, Met259, Ala354, and Ile378 residues.

Further investigation of harmicines as novel antiplasmodial agents: Synthesis, structure-activity relationship and insight into the mechanism of action.

The rise of the resistance of the malaria parasite to the currently approved therapy urges the discovery and development of new efficient agents. Previously we have demonstrated that harmicines, hybrid compounds composed from ß-carboline alkaloid harmine and cinnamic acid derivatives, linked via either triazole or amide bond, exert significant antiplasmodial activity. In this paper, we report synthesis, antiplasmodial activity and cytotoxicity of expanded series of novel triazole- and amide-type harmicines. Structure-activity relationship analysis revealed that amide-type harmicines 27, prepared at N-9 of the ß-carboline core, exhibit superior potency against both erythrocytic stage of P. falciparum and hepatic stages of P. berghei. Notably, harmicine 27a, m-(trifluoromethyl)cinnamic acid derivative, exhibited the most favourable selectivity index (SI = 1105). Molecular dynamics simulations revealed the ATP binding site of P. falciparum heat shock protein 90 as a druggable binding location, confirmed the usefulness of the harmine's N-9 substitution and identified favourable N-H … π interactions involving Lys45 and the aromatic phenyl unit in the attached cinnamic acid fragment as crucial for the enhanced biological activity. Thus, those compounds were identified as promising and valuable leads for further derivatization in the search of novel, more efficient antiplasmodial agents.

Potentiometric Surfactant Sensor Based on 1,3-Dihexadecyl-1H-benzo[d]imidazol-3-ium for Anionic Surfactants in Detergents and Household Care Products.

A 1,3-dihexadecyl-1H-benzo[d]imidazol-3-ium-tetraphenylborate (DHBI-TPB) ion-pair implemented in DHBI-TPB surfactant sensor was used for the potentiometric quantification of anionic surfactants in detergents and commercial household care products. The DHBI-TPB ion-pair was characterized by FTIR spectroscopy and computational analysis which revealed a crucial contribution of the C-H∙∙∙π contacts for the optimal complex formation. The DHBI-TPB sensor potentiometric response showed excellent analytical properties and Nernstian slope for SDS (60.1 mV/decade) with LOD 3.2 × 10-7 M; and DBS (58.4 mV/decade) with LOD 6.1 × 10-7 M was obtained. The sensor possesses exceptional resistance to different organic and inorganic interferences in broad pH (2-10) range. DMIC used as a titrant demonstrated superior analytical performances for potentiometric titrations of SDS, compared to other tested cationic surfactants (DMIC > CTAB > CPC > Hyamine 1622). The combination of DHBI-TPB sensor and DMIC was successfully employed to perform titrations of the highly soluble alkane sulfonate homologues. Nonionic surfactants (increased concentration and number of EO groups) had a negative impact on anionic surfactant titration curves and a signal change. The DHBI-TPB sensor was effectively employed for the determination of technical grade anionic surfactants presenting the recoveries from 99.5 to 101.3%. The sensor was applied on twelve powered samples as well as liquid-gel and handwashing home care detergents containing anionic surfactants. The obtained results showed good agreement compared to the outcomes measured by ISE surfactant sensor and a two-phase titration method. The developed DHBI-TPB surfactant sensor could be used for quality control in industry and has great potential in environmental monitoring.

Direct Metal-Free Transformation of Alkynes to Nitriles: Computational Evidence for the Precise Reaction Mechanism.

Density functional theory calculations elucidated the precise reaction mechanism for the conversion of diphenylacetylenes into benzonitriles involving the cleavage of the triple C≡C bond, with N-iodosuccinimide (NIS) as an oxidant and trimethylsilyl azide (TMSN3) as a nitrogen donor. The reaction requires six steps with the activation barrier ΔG‡ = 33.5 kcal mol-1 and a highly exergonic reaction free-energy ΔGR = -191.9 kcal mol-1 in MeCN. Reaction profiles agree with several experimental observations, offering evidence for the formation of molecular I2, interpreting the necessity to increase the temperature to finalize the reaction, and revealing thermodynamic aspects allowing higher yields for alkynes with para-electron-donating groups. In addition, the proposed mechanism indicates usefulness of this concept for both internal and terminal alkynes, eliminates the option to replace NIS by its Cl- or Br-analogues, and strongly promotes NaN3 as an alternative to TMSN3. Lastly, our results advise increasing the solvent polarity as another route to advance this metal-free strategy towards more efficient processes.