Free Base Research Articles

Synthesis and reactivity of 5-hydrazino-3-nitro-1,2,4-triazole (HNT): an amphoteric energetic platform

Here is described the first synthesis of 5-hydrazino-3-nitro-1,2,4-triazole (HNT), as a free base, from 5-bromo-3-nitro-1,2,4-triazole (BNT) in three steps.

Induced circular dichroism from helicoidal nano substrates to porphyrins: the role of chiral self-assembly.

Because the combination of chiral and magnetic properties is becoming more and more attractive for magneto-chiral phenomena, we here aim at exploring the induction of chirality to achiral magnetic molecules as a strategy for the preparation of magneto-chiral objects. To this end, we have associated free base- and metallo-porphyrins with silica nano helices, using a variety of elaboration methods, and have studied them mainly by electronic natural circular dichroism (NCD) and magnetic circular dichroism (MCD) spectroscopies. While electrostatic or covalent surface grafting uniformly yielded very low induced CD (ICD) for the four assayed porphyrins, a moderate response was observed when the porphyrins were incorporated into the interior of the double-walled helices, likely due to the association of the molecules with the chirally-organized gemini surfactant. A generally stronger, but more variable, ICD was observed when the molecules were drop casted onto the helices immobilised on a quartz plate, likely due to the different capacities of the porphyrins to aggregate into chiral assemblies. Electronic spectroscopy, electron microscopy and IR spectroscopy were used to interpret the patterns of aggregation and their influence on ICD and MCD. No enhancement of MCD was observed as a result of association with the nanohelices except in the case of the free base, 5,10,15,20-tetra-(4-sulfonatophenyl)porphyrin (TPPS). This nanocomposite demonstrated a large ICD in the Soret region and a large MCD in the Q-region due to J-aggregation. However, no induced MChD was observed, possibly due to the spectral mismatch between the ICD and MCD peaks.

Histamine-bound magnesium porphyrins: diverse coordination modes, inhibitory role in photodegradation of chlorophyll a and antioxidant activity.

The neurotransmitter histamine exists in two isomeric forms and could be an interesting ligand due to three nitrogen atoms with the possibility of binding to metals in different ways besides its crucial role in biological systems. However, no metal-histamine interaction is known in the literature. Therefore, two histamine-bound magnesium porphyrins [MgT(4-Cl)PP(hist)2] 1 and [MgT(4-Br)PP(hist)] 2 have been synthesized and structurally characterized. Interestingly, 1 is a hexa-coordinated magnesium porphyrin due to the axial coordination of two histamine molecules via the nitrogen of the aliphatic amino group with the Mg-Nhistamine distance of 2.300 Å, while 2 is penta-coordinated due to the axial coordination of one histamine molecule through the imidazole nitrogen atom with the Mg-Nhistamine distance of 2.145 Å. The diverse coordination modes of this unique ligand are explored for the first time. Theoretical studies at the level of DFT supported the binding of histamine via imidazole nitrogen atoms for complex 2. Histamine-bound magnesium porphyrins are found to be stable against the photodegradation of magnesium porphyrin in the presence of light and oxygen. Freshly isolated chlorophyll a from spinach showed similar resistivity against photodegradation. Moreover, the histamine-bound complexes showed higher antioxidant activity for 1 (92.45%) compared to the free base porphyrin (73.11%) and MgT(4-Cl)PP (75.89%).

Light-responsive organic polaritons from first principles.

Controlling the optical properties of light-responsive organic molecules is essential for their application in photonics. We demonstrate how light-responsive organic polaritons formed inside an optical cavity can be used to modify these properties based on first principles. Specifically, we study the excited state properties of the trans-azobenzene molecule and the free base tetraphenyl porphyrin (H2TPP) molecule under weak to strong light-matter coupling. Our results show that the cavity can modulate the dispersion and absorption properties of organic molecules. Compared to the case outside the cavity, the anomalous dispersion of the trans-azobenzene molecule inside the cavity is suppressed and this suppression decreases with increasing coupling strength, showing the potential of strong light-matter coupling in manipulating the optical dipole trap of organic molecules. Moreover, by adjusting the cavity parameters to tune the strength of the light-matter coupling, we achieve free switching between symmetric Lorentz and asymmetric Fano line shapes for H2TPP polaritonic excitations. During the switching between these spectral features, we also find that the cavity can be used to control the spontaneous radiation of organic molecules via the Purcell effect. These findings provide a new pathway to manipulate the optical properties of light-responsive organic molecules.

Interface chemistry and displacement of porphyrin macrocycles on semiconductor quantum dot surface

Here, we present comparative experimental data and results of quantum chemical calculations (method MM+) describing electrostatic interactions of positively charged 5,10,15,20-(tetra-N-methyl-4-pyridyl)porphyrin molecules with negatively charged glutathione stabilized core/shell semiconductor quantum dots (QD) AgInS/ZnS leading to the formation of stable QD-porphyrin nanoassemblies in water (pH 7.5) at ambient temperature. Based on steady-state absorption/ photoluminescence, time-resolved experiments (TCSPC), and Raman spectroscopy, interface phenomena and changes in spectral properties for interacting subunits in nanoassemblies are analyzed. Using an elaborated size-consistent quantum chemical atomistic 3D model for glutathione stabilized AgInS/ZnS QD, we propose a detailed physico-chemical mechanism for the interaction of the porphyrin molecule with the QD surface. It includes electrostatic interactions of the positively charged porphyrin free base molecule with negatively charged capping ligand (glutathione), followed by a very fast metalation of porphyrin free base (formation of ligated Zn-porphyrin complex) which is directly fixed on the QD surface. These results highlight the complexity of interface processes in “QDs – porphyrin” nanoassemblies and provide valuable strategies for the detailed analysis of the excitation energy relaxation in the systems under study.

Experimental and theoretical study of resonant core-hole spectroscopies of gas-phase free-base phthalocyanine.

We studied N 1s-1 inner-shell processes of the free base Phthalocyanine molecule, H2Pc, in the gas-phase. This complex organic molecule contains three different nitrogen sites defined by their covalent bonds. We identify the contribution of each site in ionized, core-shell excited or relaxed electronic states by the use of different theoretical methods. In particular, we present resonant Auger spectra along with a tentative new theoretical approach based on multiconfiguration self-consistent field calculations to simulate them. These calculations may pave the road towards resonant Auger spectroscopy in complex molecules.

Structurally Unique Salts of Cyamemazine and Their Pharmaceutical Implications

The aim of this study was to prepare new crystalline salts of cyamemazine, an antipsychotic drug, with dicarboxylic acids, and compare their thermal stabilities, dissolution properties, and structural features. Among the eight acids investigated, we report novel salts with four acids, namely, L-malic, malonic, succinic, and fumaric acids. The study was extended to include the already known maleate and marketed L-tartrate salts as well. To the best of our knowledge, this is the first-ever study of the solid-state landscape of cyamemazine and report of its crystal structure. A rare phenomenon of kryptoracemic behavior exhibited by the L-tartrate, L-malate, and maleate salts adds an interesting perspective to this study since one of these salts is currently marketed. A powder second harmonic generation setup was developed as a tool to identify the kryptoracemates of this drug, and how this would help potentially in the production of specific solid forms of drugs is discussed. The dissolution rate measurement of the prepared salts confirmed that the succinate, L-malate, and malonate salts dissolve better and all of the new salts display improved thermal stability than the free base of the API, suggesting great potential for some of the candidates to be used for marketing purposes.

Clarifying the Active Site Role of meso‐Carboxyphenyl Group for Free Base Porphyrins in Photocatalytic H2 Evolution Reaction

AbstractThree kinds of free base meso‐carboxyphenylporphyrins were compared about their photocatalytic activity to elucidate the role of −COOH group playing in H2 evolution from water splitting. Meso‐tetra(3,5‐dicarboxyphenyl)porphyrin (H2TDCPP) gives a much larger H2 evolution rate than other two porphyrins, attributable to more −COOH groups involved that may interact with H2O. This interaction, as revealed by DFT calculation, initiates H2 evolution from the splitting of associated H2O under ultraviolet light irradiation resulted by effective transfer of photogenerated electron from central porphine ring to meso‐substituents and then further to the interacted water. Improving the accessibility of −COOH groups to water molecule by optimizing H2TDCPP dosage induces an H2 evolution rate around 31.21 mmol ⋅ h−1 ⋅ g−1 (pH=7, full‐spectrum light), which is unprecedented for free based porphyrin photocatalysts without metal‐cocatalysts. This work clarifies the active site role of −COOH groups and paves a new way to design high‐performed organic photocatalysis by introducing polar groups‐based active sites.

Novel vancomycin free base – Sterosomes for combating diseases caused by Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus infections (S. Aureus and MRSA)

A clarion call to save antimicrobials is the need for the evolution of novel delivery systems to combat resistance posed by Staphylococcus aureus and Methicillin-resistant Staphylococcus aureus (S. aureus and MRSA) to conventional forms. Herein, we present a novel vancomycin free base – sterosomes (VCM-FB – Sterosomes) for vancomycin free base (VCM-FB) delivery against S. aureus and MRSA. VCM-FB – Sterosomes were prepared using the thin-film hydration method and were characterised physiochemically, in silico, in vitro and in vivo. In vitro cytotoxicity on MCF-7 and HEK-293 cell lines were evaluated, with results revealing cell viability above 70% after exposure to VCM-FB – Sterosomes, indicating biosafety. VCM-FB – Sterosomes had a hydrodynamic diameter, polydispersity index and surface-charge of 114.14 ± 0.59 nm, 0.210 ± 0.02 and +36.3 ± 5.42 mV, respectively, with entrapment efficiency, drug loading and VCM-FB release after 48 h of 79.61 ± 0.59%, 90.91% w/w and 54.95 ± 9.75% respectively. In silico studies showed a self-assembly in five nano seconds, which was stable thereafter. VCM-FB – Sterosomes were seen to be stable over 90 days and were also non-hemolytic. VCM-FB – Sterosomes showed a 2-fold superior minimum inhibition efficiency (MIC) against S. aureus and MRSA, relative to bare VCM-FB, with MICs of 1.95 μg/mL and 0.98 μg/mL for VCM-FB and VCM-FB – Sterosomes (S. aureus), and 7.81 μg/mL and 3.91 μg/mL for VCM-FB and VCM-FB – Sterosomes (MRSA), respectively. A faster bacterial killing time was also recorded for VCM-FB – Sterosomes compared to bare VCM-FB. Greater MRSA membrane damage was indicated by an increase and decrease in electrical conductivity, and protein/DNA concentration, respectively. VCM-FB – Sterosomes showed superior MRSA biofilm reduction (27.22%) compared to VCM-FB (2.53%). In vivo BALB/c mice-infected skin model showed that VCM-FB – Sterosomes had significant MRSA eradication (27-fold) compared to bare VCM-FB (4-fold). These results amplify the superiority of VCM-FB – Sterosomes for S. aureus and MRSA infection treatment compared to conventional forms.

Synthesis and Studies of Fused Benzo-Benzisapphyrins.

A series of rare examples of fused benzo-benzisapphyrins were synthesized readily by (3 + 2) condensation of benzodipyrrole-derived diol and para-benzitripyrrane in the presence of 0.5 equiv of TFA in CH2Cl2 under inert atmosphere conditions accompanied by DDQ oxidation in open air. The crude compounds were separated by basic alumina column chromatography and afforded pure fused benzo-benzisapphyrins in 20-22% yields. The fused sapphyrins were characterized in detail by high-resolution mass spectrometry (HRMS) and one-dimensional (1D) and two-dimensional (2D) NMR spectroscopy. The 1H NMR spectra recorded at both 298 and at 233 K clearly exhibited the presence of a strong diatropic ring current in benzo-benzisapphyrins, and the macrocycles are of aromatic nature. The DFT-optimized structure of benzo-benzisapphyrin revealed that the macrocycle was planar to a great extent due to the rigid structure of the dibenzopyrrole moiety, and the NICS(0) value of -11.2 ppm supports the aromatic nature of macrocycles. The absorption spectra of benzo-benzisapphyrins showed three weak Q bands approximately in the region of 650-900 nm and a strong Soret band at 480 nm, along with a shoulder band at ∼510 nm. The diprotonated derivative generated by the addition of excess TFA to the benzo-benzisapphyrin macrocycle exhibited bathochromically shifted absorption bands compared to the free base macrocycle.

Switchable Nanozyme Activity of Porphyrins Intercalated in Layered Gadolinium Hydroxide

In this study, organo-inorganic nanohybrids LHGd-MTSPP with enzyme-like activity were prepared by in situ intercalation of anionic 5,10,15,20-tetrakis-(4-sulfonatophenyl)porphyrin and its complexes with Zn(II) and Pd(II) (MTSPP, M = 2H, Zn(II) and Pd(II)) into gadolinium layered hydroxide (LHGd). The combination of powder XRD, CHNS analysis, FT-IR, EDX, and TG confirmed the layered structure of the reaction products. The basal interplanar distances in LHGd-MTSPP samples were 22.3-22.6 Å, corresponding to the size of an intercalated tetrapyrrole molecule. According to SEM data, LHGd-MTSPP hybrids consisted of individual lamellar nanoparticles 20-50 nm in thickness. The enzyme-like activity of individual constituents, LHGd-Cl and sulfoporphyrins TSPP, ZnTSPP and PdTSPP, and hybrid LHGd-MTSPP materials, was studied by chemiluminescence analysis using the ABAP/luminol system in phosphate buffer solution. All the individual porphyrins exhibited dose-dependent antioxidant properties with respect to alkylperoxyl radicals at pH 7.4. The intercalation of free base TSPP porphyrin into the LHGd preserved the radical scavenging properties of the product. Conversely, in LHGd-MTSPP samples containing Zn(II) and Pd(II) complexes, the antioxidant properties of the porphyrins changed to dose-dependent prooxidant activity. Thus, an efficient approach to the design and synthesis of advanced LHGd-MTSPP materials with switchable enzyme-like activity was developed.

Solubility-driven optimization of benzothiopyranone salts leading to a preclinical candidate with improved pharmacokinetic properties and activity against Mycobacterium tuberculosis

Solubility-driven optimization of the salts of nitro benzothiopyranone 1, which targets DprE1, led to an antimycobacterial preclinical candidate 2. Five pharmaceutically acceptable salts, including the maleate (2), fumarate (3), citrate (4, 5), and l-malate (6) of compound 1, were prepared via the salt formation reaction and evaluated for their physicochemical and pharmacokinetic properties. Compared with 1, all the target salts exhibited greatly increased aqueous solubility and improved oral bioavailability in mice. Maleate salt 2, which displayed higher chemical stability and lower log P, showed substantially improved bioavailability in rats and a much better in vivo effect compared with free base 1 at the same dose. The X-ray crystal structure of 2 revealed that the exposed hydrophilic piperazine-maleate moiety in the crystal structure cell may be critical in increasing the solubility of 2. Thus, this maleate salt 2 overcame the poor druggability of benzothiopyranone derivatives and was identified as a promising preclinical candidate for treating tuberculosis.

Usefulness of Applying Partial Least Squares Regression to T2 Relaxation Curves for Predicting the Solid form Content in Binary Physical Mixtures

This study applied partial least squares (PLS) regression to nuclear magnetic resonance (NMR) relaxation curves to quantify the free base of an active pharmaceutical ingredient powder. We measured the T2 relaxation of intact and moisture-absorbed physical mixtures of tetracaine free base (TC) and its hydrochloride salt (TC·HCl). The obtained T2 relaxation curves were analyzed by two methods, one using a previously reported T2 relaxation time (T2), and the other using PLS regression. The accuracy of estimating TC was inadequate when using previous T2 values because the moisture-absorbed physical mixtures showed biphasic T2 relaxation curves. By contrast, the entire measured whole of the T2 relaxation curves was used as input variables and analyzed by PLS regression to quantify the content of TC in the moisture-absorbed TC/TC·HCl. Based on scatterplots of theoretical versus predicted TC, the obtained PLS model exhibited acceptable coefficients of determination and relatively low root mean squared error values for calibration and validation data. The statistical values confirmed that an accurate and reliable PLS model was created to quantify TC in even moisture-absorbed TC/TC·HCl. The bench-top low-field NMR instrument used to apply PLS regression to the T2 relaxation curve may be a promising tool in process analytical technology.

Combining drug salt formation with amorphous solid dispersions - a double edged sword.

Glass transition temperature (Tg) is important for amorphous compounds because it can have implications on their physical and chemical stability. With drugs that possess ionizable acidic or basic groups, salt formation is a potential strategy to reduce re-crystallization tendency through Tg elevation. While salt formation has been reported to impact re-crystallization tendency, it is not known if this holds true for all drugs and if it is useful in the context of amorphous solid dispersion (ASD) formulations. In addition, little information on the impact of salt formation on drug release performance of ASD is available. Herein, the influence of salt formation and Tg elevation on the release performance of lumefantrine (Tg=19.7°C) when formulated as an ASD with copovidone (PVPVA) was examined. Lumefantrine salts and lumefantrine salt-PVPVA ASDs with drug loadings (DLs) ranging from 5 to 30% were prepared. The acids used for salt formation were benzoic acid, benzenesulfonic acid, camphorsulfonic acid, hydrochloric acid, p-toluenesulfonic acid, poly(ethylene) glycol 250 diacid (PEG 250 diacid), and sulfuric acid. Salt formation resulted in an elevation of Tg compared to lumefantrine free base, with the largest increase in Tg observed with lumefantrine sulfate. With a lower Tg salt, ASDs could be formulated at higher DLs while ensuring drug release. In contrast, drug release ceased at a DL as low as 5% when Tg of the salt was high. However, ASDs with lower Tgs such as the benzoate and PEG 250 diacid salts showed poor stability against re-crystallization when stored under stress storage conditions. When using a salt in an ASD formulation, attention should be paid to the Tg of the salt, since it may show opposing effects on physical stability and drug release, at least for PVPVA-based ASDs.

Preclinical development of an EP2 antagonist for post-seizure cognitive deficits

Cognitive comorbidities can substantially reduce quality of life in people with epilepsy. Inflammation is a component of all chronic diseases including epilepsy, as well as acute events like status epilepticus (SE). Neuroinflammation is the consequence of several broad signaling cascades including cyclooxygenase-2 (COX-2)-associated pathways. Activation of the EP2 receptor for prostaglandin E2 appears responsible for blood-brain barrier leakage and much of the inflammatory reaction, neuronal injury and cognitive deficit that follows seizure-provoked COX-2 induction in brain. Here we show that brief exposure of mice to TG11-77, a potent, selective, orally available and brain permeant EP2 antagonist, eliminates the profound cognitive deficit in Y-maze performance after SE and reduces delayed mortality and microgliosis, with a minimum effective i.p. dose (as free base) of 8.8 mg/kg. All in vitro studies required to submit an investigational new drug (IND) application for TG11-77 have been completed, and non-GLP dose range-finding toxicology in the rat identified no overt, organ or histopathology signs of toxicity after 7 days of oral administration at 1000 mg/kg/day. Plasma exposure in the rat was dose-linear between 15 and 1000 mg/kg dosing. TG11-77 thus appears poised to continue development towards the initial clinical test of the hypothesis that EP2 receptor modulation after SE can provide the first preventive treatment for one of the chief comorbidities of epilepsy.

Development and Evaluation of Essential Oil-based Lozenges using Menthol and Eucalyptus and in vitro Evaluation of their Antimicrobial activity in S.aureus and E.coli

The throat lozenegs are most commonly used first line of treatment for relief of various throat infections. The most common ingredient used in the lozenegs are various herbal extracts and essential oil having local action of throat area. in the present studies a essential oil based lozenges were prepared using eucalyptus oil and menthol as active ingredient. Antibacterial activity was evaluated for menthol and eucalyptus oil against human pathogens E.coli and S.aureus. both the sugar based and sugar free base was used to develop two types of lozenges formulation. Quality parameters were evaluated for lozenges formulations such as hardness, friability, dissolving time, and moisture content. Compatibility study was carried out using thin layer chromatography and gas chromatography analysis. The eucalyptus oil and menthol displayed moderate antibacterial activity against E.coli and S.aureus. The lozenges were found to be having satisfactory quality parameters. GC and TLC analysis was found to be a suitable method for identification of menthol and eucalyptus oil in the lozenges. TLC was found to be a simple, quick and simple technique for rapid identification of the essential oil and to confirm the batch-to-batch consistency. 1H-NMR and 13C-NMR was found to be useful tool for rapid identification of essential oils on basis of diagonostic peaks. Overall this study can be used for standard methods for quality control of the essential lozeneges formulation for the new formulation and product available in the market as well.

Synthesis of Subporphyrin Free Bases.

BIII subporphyrins are the legitimate ring-contracted porphyrins consisting of three pyrroles and three meso-carbons and their chemistry has been extensively developed since the first synthesis in 2006. However, subporphyrin free bases have never been synthesized, despite tremendous attempts to remove the BIII ion. Here we report that Suzuki-Miyaura coupling between α,α'-diborylated tripyrrane 1 and tetrabromide 5 gave subporphyrin free bases 6, 6 A, and free base dimer 7 in 6 %, 4 %, and 2 % yields as the first examples. Subporphyrin free bases exhibit curved bowl-like structures and distinct 14π-aromaticity. Steady-state and time-resolved spectroscopy revealed that the excited-state behaviors of the subporphyrin free bases are comparable with those of the corresponding BIII subporphyrins. Rotational relaxation processes in the excited states have been revealed, which enhance the electronic interactions with the meso-aryl substituents and between the two subporphyrins.

Synthesis of Subporphyrin Free Bases

AbstractBIII subporphyrins are the legitimate ring‐contracted porphyrins consisting of three pyrroles and three meso‐carbons and their chemistry has been extensively developed since the first synthesis in 2006. However, subporphyrin free bases have never been synthesized, despite tremendous attempts to remove the BIII ion. Here we report that Suzuki–Miyaura coupling between α,α′‐diborylated tripyrrane 1 and tetrabromide 5 gave subporphyrin free bases 6, 6 A, and free base dimer 7 in 6 %, 4 %, and 2 % yields as the first examples. Subporphyrin free bases exhibit curved bowl‐like structures and distinct 14π‐aromaticity. Steady‐state and time‐resolved spectroscopy revealed that the excited‐state behaviors of the subporphyrin free bases are comparable with those of the corresponding BIII subporphyrins. Rotational relaxation processes in the excited states have been revealed, which enhance the electronic interactions with the meso‐aryl substituents and between the two subporphyrins.

DMAP and HMTA manganese(III) meso-tetraphenylporphyrin-based coordination complexes: Syntheses, physicochemical properties, structural and biological activities

The reactions of the (triflato)(meso-tetra(para-methoxyphenyl)porphyrinato)manganese(III) ([MnIII(TMPP)(SO3CF3)] complex with an excess of 4-dimethylaminopyridine (DMAP) and hexamethylenetetramine (HMTA) have been examined. These reactions yield crystalline [MnIII(TMPP)(DMAP)2](0.1Cl)(0.9SO3CF3)•2CHCl3 (I) and [MnIII(TMPP)(HMTA)2](SO3CF3)•2CH2Cl2 (II) complexes, respectively. The hyper d-type electronic spectra of I-II are characteristic for high-spin (S = 2) Mn(III) metalloporphyrins with very redshifted Soret bands. A cyclic voltammetry investigation was carried out on these two Mn(III) coordination compounds. The crystal structures of the solid complexes I-II were determined by X-ray single-crystal diffraction and elucidated by Hirshfeld surface approach. Furthermore, bioactivity of the H2TMPP free base, the [MnIII(TMPP)(SO3CF3)] starting material and complexes I-II, was assessed by a set of in vitro tests checking for antioxidant, antibacterial and antifungal (against several strains) effects.

The Difficult Marriage of Triarylcorroles with Zinc and Nickel Ions.

The coordination chemistry of corrole has witnessed a great improvement in the past few years and its Periodic Table has been widened to be so large that it is compared with that of porphyrins. However, Ni and Zn ions, commonly used with porphyrins for both synthetic and theoretical purposes, are sparsely reported in the case of corroles. Here, we report synthetic protocols for preparing Ni and Zn triarylcorrole complexes. In the case of Zn, the preliminary oxidation of the free base corrole in DMSO to the neutral corrole radical is a necessary step to obtain the coordination of the metal ion, because the direct reaction led to the formation of an open-chain tetrapyrrole. The Ni complex could be directly obtained by heating the free base corrole and Ni(II) salt to 100 °C in a DMSO solution containing FeCl3. The non-innocent nature of the corrole ligand for both complexes has been elucidated by EPR, and in the case of the Zn derivative the first spectroelectrochemical characterization is presented.