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Tropomyosin receptor kinases (Trks) are transmembrane receptor tyrosine kinases named TrkA, TrkB, and TrkC and encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively. These kinases have attracted significant attention and represent a promising therapeutic target for solid tumor treatment due to their vital role in cellular signaling pathways. First-generation TRK inhibitors, i.e., Larotrectinib sulfate and Entrectinib, received clinical approval in 2018 and 2019, respectively. However, the use of these inhibitors was significantly limited because of the development of resistance due to mutations. Fortunately, the second-generation Trk inhibitor Repotrectinib (TPX-0005) was approved by the FDA in November 2023, while Selitrectinib (Loxo-195) has provided an effective solution to this issue. Another macrocycle-based analog, along with many other TRK inhibitors, is currently in clinical trials. Two of the three marketed drugs for NTRK fusion cancers feature a pyrazolo[1,5- a ] pyrimidine nucleus, prompting medicinal chemists to develop numerous novel pyrazolopyrimidine-based molecules to enhance clinical applications. This article focuses on a comprehensive review of chronological synthetic developments and the structure-activity relationships (SAR) of pyrazolo[1,5- a ]pyrimidine derivatives as Trk inhibitors. This article will also provide comprehensive knowledge and future directions to the researchers working in the field of medicinal chemistry by facilitating the structural modification of pyrazolo [1,5- a ]pyrimidine derivatives to synthesize more effective novel chemotherapeutics as TRK inhibitors.

Due to their extended p-orbital delocalization, conjugated polymers absorb light in the range of visible-NIR frequencies. We attempt to exploit this property to create materials that compete with inorganic semiconductors in photovoltaic and light-emitting materials. Beyond competing for applications in photonic devices, organic conjugated compounds, polymers, and small molecules have also been extended to biomedical applications like phototherapy and biodetection. Recent research on conjugated polymers has focused on bioapplications based on the absorbed light energy conversions in electric impulses, chemical energy, heat, and light emission. In this review, we describe the working principles of those photonic devices that have been applied and researched in the field of biomaterials.

N 2 dissociative adsorption is commonly the rate-determining step in thermal ammonia synthesis. Herein, we performed density functional theory (DFT) calculations to understand the N 2 dissociation mechanism on models of unsupported Ru(0001) terraces, Ru B5 sites, and polar MgO(111)-supported Ru 8 cluster mimicking a B5 site geometry, denoted (Ru 8 (B5-like)/MgO(111)). The activation energy of N 2 dissociative adsorption on the Ru 8 (B5-like)/MgO(111) model ( E a = 0.33 eV) is much lower than that on the unsupported Ru(0001) terrace ( E a = 1.74 eV) and Ru B5 ( E a = 0.62 eV) models. The lower N 2 dissociation barrier on Ru B5 sites is facilitated by the enhanced σ donation and π* back-donation between N 2 (σ, π*) and Ru(d) orbitals resulting in the stronger activation of the molecular side-on N 2 * dissociation precursor. The Ru 8 (B5-like)/MgO(111) also exhibits enhanced σ donation because of the B5-like cluster geometry. Furthermore, the Ru cluster of the bare Ru 8 (B5-like)/MgO(111) model is positively charged. This induced an unusual π donation from N 2 (π) to Ru(d) orbitals as revealed by analyses of the density of states and partial charge densities. The combined σ and π donation resulted in an increased synergistic π* back-donation. The total interactions between N 2 (σ, π, π*) and Ru(d) resulted in an overall electron transfer to the adsorbed N 2 from the Ru atoms in the B5-like site with no direct involvement of the MgO(111) substrate. Analyses of bond stretching vibrations and bond lengths show that the N 2 (σ, π, π*) and Ru(d) interactions lead to a weaker N-N bond and stronger Ru-N bonds. These correspond to a lower barrier of N 2 dissociation on the Ru 8 (B5-like)/MgO(111) model, where the highest red-shift of N-N vibration and the longest N-N bond length were observed after side-on N 2 * adsorption. These results demonstrate that an electron-deficient Ru catalyst are not always inhibited from donating electrons to adsorbed N 2 . Rather, this study shows that the electron deficiency of Ru can promote π* back-donation and N 2 activation. These new insights may therefore open new avenues to design supported Ru catalysts for nitrogen activation.

Leishmaniasis is a neglected tropical disease, and there is an emerging need for the development of effective drugs to treat it. To identify novel compounds with antileishmanial properties, a novel series of functionalized spiro[indoline-3,2'-pyrrolidin]-2-one/spiro[indoline-3,3'-pyrrolizin]-2-one 23a - f , 24a - f , and 25a - g were prepared from natural-product-inspired pharmaceutically privileged bioactive sub-structures, i.e., isatins 20a - h , various substituted chalcones 21a - f , and 22a - c amino acids, via 1,3-dipolar cycloaddition reactions in MeOH at 80 °C using a microwave-assisted approach. Compared to traditional methods, microwave-assisted synthesis produces higher yields and better quality, and it takes less time. We report here the in vitro antileishmanial activity against Leishmania donovani and SAR studies. The analogues 24a , 24e , 24f , and 25d were found to be the most active compounds of the series and showed IC 50 values of 2.43 µM, 0.96 µM, 1.62 µM, and 3.55 µM, respectively, compared to the standard reference drug Amphotericin B (IC 50 = 0.060 µM). All compounds were assessed for Leishmania DNA topoisomerase type IB inhibition activity using the standard drug Camptothecin, and 24a , 24e , 24f , and 25d showed potential results. In order to further validate the experimental results and gain a deeper understanding of the binding manner of such compounds, molecular docking studies were also performed. The stereochemistry of the novel functionalized spirooxindole derivatives was confirmed by single-crystal X-ray crystallography studies.

In this study, a full organic and water-soluble material was synthesized by coupling low molecular weight polyethylenimine (PEI-800) with cyclotriveratrilene (CTV). The water-soluble cross-linked polymer contains hydrophobic holes with a high coordination capability towards different organic drug molecules. The coordinating capability towards hydrophilic drugs (doxorubicin, gatifloxacin and sinomenine) and hydrophobic drugs (camptothecin and celastrol) was analyzed in an aqueous medium by using NMR, UV-Vis and emission spectroscopies. The coordination of drug molecules with the armed CTV unit through hydrophobic interactions was observed. In particular, celastrol exhibited more ionic interactions with the PEI moiety of the hosting system. In the case of doxorubicin, the host-guest detachment was induced by the addition of ammonium chloride, suggesting that the intracellular environment can facilitate the release of the drug molecules.

In this paper, a modified Cyclotriveratrylene was synthesized and linked to a branched Polyethylenimine, and this unique polymeric material was subsequently examined as a potential supramolecular carrier for Doxorubicin. Spectroscopic analysis in different solvents had shown that Doxorubicin was coordinated within the hollow-shaped unit of the armed Cyclotriveratrylene, and the nature of the host-guest complex revealed intrinsic Van der Waals interactions and hydrogen bonding between the host and guest. The strongest interaction was detected in water because of the hydrophobic effect shared between the aromatic groups of the Doxorubicin and Cyclotriveratrylene unit. Density functional theory calculations had also confirmed that in the most stable coordination of Doxorubicin with the cross-linked polymer, the aromatic rings of the Doxorubicin were localized toward the Cyclotriveratrylene core, while its aliphatic chains aligned closer with amino groups, thus forming a compact supramolecular assembly that may confer a shielding effect on Doxorubicin. These observations had emphasized the importance of supramolecular considerations when designing a novel drug delivery platform.

In this report, the substitution of the oxygen group (=O) of Tetraphenylcyclopentadienone with =CR 2 group (R = methyl ester or nitrile) was found to have tuned the electro-optical properties of the molecule. Although both groups are electrons withdrawing in nature, their absorption from UV-vis spectra analysis was observed to have been blue-shifted by methyl ester substitution and red-shifted by nitrile substitution. Interestingly, these substitutions helped to enhance the overall intensity of emission, especially in the context of methyl ester substitution whereby the emission was significantly boosted at higher concentrations due to hypothesized restrictions of intramolecular motions. These observations were explained through detailed descriptions of the electron withdrawing capability and steric properties of the substituents on the basis of density functional theory calculations.

This work reports the outcome of thermal grafting of 2-ethynylaniline, 3-ethynylaniline, and 4-ethynylaniline on a hydrogenated Si(100) surface. Using high-resolution XPS and AFM, it was found that the grafting of these compounds could be attributed to resonating structures that arise from the position of an electron-donating NH 2 group and an electron-withdrawing acetylene group. For the ortho- and para-positioned acetylene group, surface reactions were observed to proceed predominantly via the acetylene to form a Si-C bond, whereas the meta-positioned acetylene group was found to have undergone nucleophilic grafting through the NH 2 group onto the silicon surface to form a Si-N bond. Furthermore, a tert-butoxycarbonyl-protected derivative for a meta-positioned ethynylaniline was synthesized to exclusively force the reaction to react with the acetylene group and subsequent analysis confirmed that unprotected 3-ethynylaniline had indeed reacted through the nucleophilic NH 2 group as hypothesized. Thus, for the first time, the interplay between resonance structures and their effects on silicon surface modifications were systematically catalogued., (© 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)