A liquid chromatography-tandem mass spectrometry method development for the quantification of favipiravir drug and its related impurities in rat plasma and its application to pharmacokinetic studies.

Favipiravir is an antiviral drug used for the treatment of virus-based diseases such as influenza. In this context, the development of a reliable liquid chromatography-tandem mass spectrometry method for the quantification of the drug and its impurities is necessary, particularly following the COVID-19 pandemic. Chromatographic separation was achieved on an inertial ODS column using gradient elution with a buffer containing triethylamine in high-performance liquid chromatography water and adjusting its pH with formic acid. The mixture of buffer and acetonitrile was used as a mobile phase with a flow rate of 1 ml/min at ambient temperature. The separation of favipiravir and its related impurities from remdesivir as an internal standard was achieved. The results indicated that all the variables, like precision, accuracy, linearity, matrix effect and stability, were successfully achieved within the limits of US Food and Drug Administration guidelines. This study could provide a new protocol for the development of new analytical methods for the detection of favipiravir and its impurities.

Synthesis and identification of new sacubitril derivatives as lead compounds for antibacterial, antifungal and antitubercular (TB) activities against dormant tuberculosis.

We identified twenty-two new sacubitril derivatives (5a-v) as lead compounds for various biologically active targets. These compounds were synthesized by reacting an intermediate compound (2R,4S)-5-([1,1'-biphenyl]-4-yl)-4-(amino)-2-methylpentanoic acid ethyl ester hydrochloride with respective carboxylic acid (RCOOH). The molecular structures of all the newly synthesized compounds were determined by 1H and 13C NMR, ESI mass spectrometry, FTIR spectroscopy, and CHN analysis. Moreover, compound 5n was characterized by a single-crystal X-ray diffraction (SXRD) study to confirm the structure obtained from spectral data. All these compounds were screened for various biological functions such as antifungal, antibacterial, and anti-TB activities. Among these twenty-two compounds (5a-v), some exhibited good to moderate anti-bacterial properties. Similarly, some compounds showed moderate anti-TB and antifungal activities. In addition, the anti-TB activity of compound 5q was estimated against M. tuberculosis in a nutrient starvation model (NSM). Similarly, toxicity was examined against RAW 264.7 cells. These biological activity studies were also correlated with molecular docking studies.

Temperature-Dependent Superhydrophobic Functionalized Coordination Polymers (SFCPs) for Selective Adsorption of C2H4 over C2H6.

We prepared two new superhydrophobic functionalized coordination polymers (SFCPs) [Zn4(OH)2(BTMB)2(4,4'-Bipy)2]∞ ⊃ solvent, 1, and [Cd4(OH)2(BTMB)2(4,4'-Bipy)3]∞ ⊃ solvent, 2, by solvothermal methods. For 1, the single-crystal XRD structure revealed that it contains two crystallographically distinct Zn2+ ions with two different types of coordination geometries of 4 and 6, exhibiting a unique superhydrophobic behavior with microporosity. Compound 1 exhibits superhydrophobicity with a contact angle of 155.5° (at 30 °C), which is stable even at high temperatures, whereas for the SFCP 2, all of the Cd2+ ions have only 6-coordination and exhibit a superhydrophobic character at room temperature with a contact angle of 156.7°(at 30 °C). However, surprisingly, this superhydrophobic character is stable only up to 60 °C, above which it is converted to hydrophilic nature, in contrast to the SFCP 1. Moreover, in this study, we also report a selective gas adsorption study of two C2 gases with similar kinetic diameters (∼3.9 Å) of ethylene over ethane.

Development of an efficient stability-indicating LC-MS/MS method for the analysis of selexipag and characterization of its degradation products.

A new RP-HPLC method with a quick, sensitive and stable indication for the quantitative measurement of selexipag and its associated substances was developed and validated in the present study. In this new method, using the impurity-spiked solution, the chromatographic approach was optimized. Similarly, using the X-bridge phenyl column with isocratic elution of mobile phase containing acetonitrile and formic acid, selexipag and its impurities were separated. Recovery experiments obtained were satisfactory, and also the calibration graphs plotted for selexipag and its five impurities were found to be linear. The system validation parameters such as specificity, linearity, precision, accuracy and robustness were determined successfully. The obtained results indicated that the developed method was found to be useful for analyzing selexipag from its impurities. Further, using stress tests against acid, alkali, peroxide, reduction, thermal, hydrolysis and UV conditions, the present established method of HPLC was assessed and validated as per ICH Q2(R1) guidelines.

Design and Synthesis of "Chloropicolinate Amides and Urea Derivatives" as Novel Inhibitors for Mycobacterium tuberculosis.

A series of 30 novel diamino phenyl chloropicolinate fettered carboxamides, urea, and thiourea derivatives were synthesized by coupling of methyl 4-amino-6-(2-aminophenyl)-3-chloropyridine-2-carboxylate with different acid chlorides, urea, and thiourea moieties, respectively. All of these compounds were characterized by 1H and 13C nuclear magnetic resonance spectroscopy, CHN analysis, and high-resolution mass spectra for confirmation of the structures. Two compounds were also characterized by single-crystal X-ray diffraction analysis to confirm the structures obtained by spectral analysis. All these 30 compounds were tested for their in vitro antimycobacterial activity using the microplate alamar blue assay method against Mycobacterium tuberculosis. Five compounds have shown good minimum inhibitory concentration (MIC) values with low cytotoxicity when compared with the reference drugs. Moreover, some of the compounds have high MIC values compared with isoniazid, rifampicin, and so forth and also had shown good reign in the spread of bacteria by the nutrient starvation model. These antimycobacterial activity results have shown a good correlation with molecular docking model analysis with the inhibitors MurB by exhibiting strong interactions. Some of these compounds could be promising candidates against M. tuberculosis for future preclinical agent drug development.

Design and synthesis of purine connected piperazine derivatives as novel inhibitors of Mycobacterium tuberculosis.

A series of novel purine linked piperazine derivatives were synthesized to identify new, potent inhibitors of Mycobacterium tuberculosis. The compounds were designed to target MurB disrupting the biosynthesis of the peptidoglycan and exert antiproliferative effects. The first series of purine-2,6-dione linked piperazine derivatives were synthesized using an advanced intermediate 1-(3,4-difluorobenzyl)-7-(but-2-ynyl)-3-methyl-8-(piperazin-1-yl)-1H-purine-2,6(3H,7H)-dione hydrochloride (6) which was coupled with varied carboxylic acid chloride derivatives. Following this piperazine linked derivatives were also synthesized from 6 using diverse isocyanate partners. The anti-mycobacterial activity of the analogues was tested againstMycobacterium tuberculosis H37Rv which revealed a cluster of six analogues (11, 24,27, 32, 33 and34), possessed promising activity. In comparison, a set of these new compounds possessed greater potencies relative to current drugs used in the clinic such as Ethambutol. These results were also correlated with computational molecular docking analysis, providing models for strong interactions of the inhibitors with MurB providing a template for the future development of preclinical agents against Mycobacterium tuberculosis.

Temperature-Stable Compelled Composite Superhydrophobic Porous Coordination Polymers Achieved via an Unattainable de Novo Synthetic Method.

We demonstrate a new de novo synthetic methodology to achieve high-temperature-stable compelled composite superhydrophobic porous coordination polymers (PCPs). These new PCPs were achieved based on coordination capabilities of first-row transition metal ions such as Co2+, Ni2+, and Zn2+. The obtained composite PCPs containing a [Zn2M2O]6+ (M = Co or Ni) bimetallic cluster core with open metal sites (OMSs) exhibited distinct isosteric heats of adsorption and surface areas due to the difference in their open metal Lewis acidic sites of solvent-free state. Additionally, these composite PCPs exhibit remarkable superhydrophobic properties with contact angles of 159.3° and 160.8° respectively for Zn-Co and Zn-Ni analogues. This superhydrophobic surface survives even at high temperature for longer time periods. As projected, these new composite PCPs exhibit better surface area and heats of adsorption compared to the PESD-1 (Zn) analogue due to a larger number of OMSs. Moreover, they display selective adsorption toward aromatic solvents such as benzene and toluene over aliphatic solvents such as cyclohexane due to corrugated and terminated aromatic hydrocarbon moieties toward the interactive surface. They also exhibit oil spill cleanup from the water surface in the powder form as well as pellet form up to 385 wt %. This study certainly offers a roadmap for designing and engineering new composite superhydrophobic porous materials for better water and thermal stability along with OMSs. This type of PCP exhibits a wide range of applications especially in catalysis, separation technology, and securing environmental problems such as oil spill cleanup in seawater.

Ultrasound Assisted Synthesis of 3,4-Diyne Substituted Isocoumarin Derivatives: Identification of Potential Cytotoxic Agents.

BACKGROUND: The 3,4-diyne substituted isocoumarins have been designed, synthesized and explored as potential anti-proliferative agents. METHOD: Ultrasound assisted synthesis of these compounds was carried out by using a three-step method involving (i) Pd/C-Cu catalyzed cross-coupling between the methyl 2-iodobenzoate and buta- 1,3-diynylbenzene followed by (ii) I2-mediated electrophilic cyclization of the resultant 2-(alk-1- ynyl)benzoate ester and (iii) subsequent alkynylation of 4-iodo-3-(phenylethynyl)-isocoumarin under Pd/C-Cu catalysis. CONCLUSION: The synthesized compounds showed promising growth inhibition when tested against MDA-MB 231 and K562 cancer cell lines.

A Dense I1O3 Hybrid Superhydrophobic Network, Pb(H-BTMB), Exhibits Selectivity toward CO2 Gas Sorption.

We achieved a dense I1O3 hybrid superhydrophobic porous coordination polymer (PCP), [Pb(H-BTMB)(DMF)] (1), by solvothermal methods. The single-crystal XRD structure of 1 indicated that it has a three-dimensional M-L-M framework with one-dimensional M-O-M connectivity leading to an I1O3 network. The new PCP obtained exhibited open metal sites (OMSs) by losing a coordinated DMF molecule. The degassed phase displayed selective adsorption of CO2 gas over N2, C2H6, and C2H4 gases. Additionally, it has a superhydrophobic surface with a contact angle of 156.4° at room temperature and it is stable even at 90 °C, displaying a contact angle of 135.3°.

Design of superhydrophobic porous coordination polymers through the introduction of external surface corrugation by the use of an aromatic hydrocarbon building unit.

We demonstrate a new approach to superhydrophobic porous coordination polymers by incorporating an anisotropic crystal morphology featuring a predominant surface that is highly corrugated and terminated by aromatic hydrocarbon moieties. The resulting low-energy surface provides particularly promising hydrophobic properties without the need for postsynthetic modifications or surface processing that would block the porosity of the framework. Consequently, hydrophobic organic molecules and water vapor are able to penetrate the surface and be densely accommodated within the pores, whereas bulk water is repelled as a result of the exterior surface corrugation derived from the aromatic surface groups. This study provides a new strategy for the design and development of superhydrophobic porous materials.

A family of rare earth porous coordination polymers with different flexibility for CO2/C2H4 and CO2/C2H6 separation.

A family of new porous coordination polymers (PCPs) were prepared by the reaction of an acylamide modified ligand (H3L) and RE(NO)3·xH2O (RE = Y, La, Ce, Nd, Eu, Tb, Dy, Ho, and Tm). PXRD and single-crystal X-ray analyses of them revealed that, besides the La PCP, all other rare earth members gave isomorphous structures. The two types of structural toplogies obtained, although similar, differ in their alignment of acylamide functional groups and structural flexibility. Adsorption experiments and in situ DRIFT spectra showed that rigid frameworks have the typical microporous behavior and poor selective capture of CO2 over C2H4 and C2H6; however, the unique La-PCP with structural flexibility and close-packed acylamide groups has a high selective capture of CO2 with respect to C2H6 or C2H4 at 273 K, especially at the ambient pressure area (0.1-1 bar).

Benzo[e]pyrene skeleton dipyrylium dication with a strong donor-acceptor-donor interaction, and its two-electron reduced molecule.

The donor-acceptor-donor (D-A-D) conjugated molecules 1,4-bis(diarylaminophenylethynyl)anthraquinone (1,4-Am(2)Aq) and 1,4-bis(ferrocenylethynyl)anthraquinone (1,4-Fc(2)Aq), undergo a double proton cyclization reaction with bis(trifluoromethanesulfone)imide acid (TFSIH) to yield 1,4-bis(diarylaminophenyl or ferrocenyl) dipyrylium salts [1,4-R(2)Pyl(2)](TFSI)(2) (R=Am or Fc) with novel planar pentacyclic structures similar to the aromatic benzo[e]pyrene-type skeleton. [1,4-Am(2)Pyl(2)](TFSI)(2) could be reduced to give the neutral molecule [1,4-Am(2)Pyl(2)](0), which is stable and maintains the benzo[e]pyrene-type skeleton. To the best of our knowledge, this is the first oxygen-atom-containing polycyclic aromatic hydrocarbon with 22 (4n+2) π-electrons. The obtained condensed-ring benzo[e]pyrene-type skeleton compounds show physical and chemical properties that are significantly different from those of [1,5-Am(2)Pyl(2)](TFSI)(2), which has a perylene-type skeleton.

Platinadithiolene-conjugated pyrylium salt with strong intramolecular donor-acceptor interaction.

Protonation of a new platinum complex, Pt(1-pdtAq)((t)Bu(2)bpy), where 1-pdtAq is 1-(phenyldithiolenethynyl)anthraquinone, afforded a cyclized structure, [Pt(1-pdtPyl)((t)Bu(2)bpy)](+), with a unique electronic structure due to intense intramolecular charge transfer.

Double protonation of 1,5-bis(triarylaminoethynyl)anthraquinone to form a paramagnetic pentacyclic dipyrylium salt.

Protonation-induced intramolecular cyclization reactions of new donor (D)-acceptor (A) and D-A-D conjugated molecules 1-triarylaminoethynylanthraquinone (1-AmAq) and 1,5-bis(triarylaminoethynyl)anthraquinone (1,5-Am(2)Aq), respectively, were achieved. The former undergoes monoprotonation with bis(trifluoromethanesulfone)imide acid (TFSIH) to give pyrylium salt [1-AmPyl]TFSI, whereas the latter undergoes a novel double proton cyclization reaction to yield 1,5-bis(triarylamino)dipyrylium salt [1,5-Am(2)Pyl(2)](TFSI)(2) with a new pentacyclic backbone. This divalent cationic salt can be reduced to give the neutral species 2,8-bis(triarylamino)benzo[de]isochromeno[1,8-gh]chromene ([1,5-Am(2)Pyl(2)](0)), which maintains the planar pentacyclic backbone. The obtained condensed-ring compounds show unique optical, electrochemical, and magnetic properties due to the extremely narrow HOMO-LUMO gap. In particular, the dication [1,5-Am(2)Pyl(2)](2+) shows paramagnetic behavior with two spins centered on two triarylamine moieties through valence tautomerization with the pentacyclic backbone.