Molecular Conjugates Research Articles

Phosphorylcholine-Grafted Molecular Bottlebrush-Doxorubicin Conjugates: High Structural Stability, Long Circulation in Blood, and Efficient Anticancer Activity.

Controlling the particle structure of tumor-targeting nanomedicines in vivo remains challenging but must be achieved to control their in vivo fate and functions. Molecular bottlebrushes (MBs), where brush side chains are densely grafted from a main chain, have recently received attention as building blocks of polymer-based prodrugs because their rigid structure would be expected to demonstrate high structural stability in vivo. Here, we synthesized a poly(methacryloyloxyethyl phosphorylcholine) (pMPC)-grafted molecular bottlebrush (PCMB) conjugated with a cancer drug, doxorubicin (DOX), via an acid-cleavable hydrazone bond. A pMPC-based linear polymer (LP) conjugated with DOX was also prepared for comparison. We confirmed the lack of structural transition in the PCMB between before and after conjugation with DOX using small-angle light and X-ray scattering techniques, whereas the structure of LP was significantly influenced by DOX conjugation and transformed from a random-coil structure to a large agglomerate via hydrophobic interactions among DOXs. Although PCMB-DOX and LP-DOX showed comparable tissue permeability, pharmacokinetics, and ability to accumulate in tumor tissues, the antitumor efficacy of PCMB-DOX was better than that of LP-DOX. This was presumably due to the formation of LP-DOX agglomerates. The diffusion of cleaved DOX would be restricted in the hydrophobic core of the agglomerate, resulting in the DOX release at the tumor site being compromised. In contrast to LP-DOX, DOX release from PCMB-DOX was not compromised after accumulation in tumor tissues because it did not form such an agglomerate, resulting in the strong antitumor effect. We have demonstrated the potential of MBs as building blocks of drug carriers and believe that these findings can contribute to the design of polymer-based nanomedicines.

Site-Specific Conjugation of Cell Wall Polyrhamnose to Protein SpyAD Envisioning a Safe Universal Group A Streptococcal Vaccine.

Development of an effective vaccine against the leading human bacterial pathogen group A Streptococcus (GAS) is a public health priority. The species defining group A cell wall carbohydrate (GAC, Lancefield antigen) can be engineered to remove its immunodominant N-acetylglucosamine (GlcNAc) side chain, implicated in provoking autoimmune cross-reactivity in rheumatic heart disease, leaving its polyrhamnose core (GACPR). Here we generate a novel protein conjugate of the GACPR and test the utility of this conjugate antigen in active immunization. Instead of conjugation to a standard carrier protein, we selected SpyAD, a highly conserved GAS surface protein containing both B-cell and T-cell epitopes relevant to the bacterium that itself shows promise as a vaccine antigen. SpyAD was synthesized using the XpressTM cell-free protein expression system, incorporating a non-natural amino acid to which GACPR was conjugated by site-specific click chemistry to yield high molecular mass SpyAD-GACPR conjugates and avoid disruption of important T-cell and B-cell immunological epitopes. The conjugated SpyAD-GACPR elicited antibodies that bound the surface of multiple GAS strains of diverse M types and promoted opsonophagocytic killing by human neutrophils. Active immunization of mice with a multivalent vaccine consisting of SpyAD-GACPR, together with candidate vaccine antigens streptolysin O and C5a peptidase, protected against GAS challenge in a systemic infection model and localized skin infection model, without evidence of cross reactivity to human heart or brain tissue epitopes. This general approach may allow GAC to be safely and effectively included in future GAS subunit vaccine formulations with the goal of broad protection without autoreactivity.

Characterization of Plasmodium falciparum NEDD8 and identification of cullins as its substrates

A variety of post-translational modifications of Plasmodium falciparum proteins, including phosphorylation and ubiquitination, are shown to have key regulatory roles during parasite development. NEDD8 is a ubiquitin-like modifier of cullin-RING E3 ubiquitin ligases, which regulates diverse cellular processes. Although neddylation is conserved in eukaryotes, it is yet to be characterized in Plasmodium and related apicomplexan parasites. We characterized P. falciparum NEDD8 (PfNEDD8) and identified cullins as its physiological substrates. PfNEDD8 is a 76 amino acid residue protein without the C-terminal tail, indicating that it can be readily conjugated. The wild type and mutant (Gly75Ala/Gly76Ala) PfNEDD8 were expressed in P. falciparum. Western blot of wild type PfNEDD8-expressing parasites indicated multiple high molecular weight conjugates, which were absent in the parasites expressing the mutant, indicating conjugation of NEDD8 through Gly76. Immunoprecipitation followed by mass spectrometry of wild type PfNEDD8-expressing parasites identified two putative cullins. Furthermore, we expressed PfNEDD8 in mutant S. cerevisiae strains that lacked endogenous NEDD8 (rub1Δ) or NEDD8 conjugating E2 enzyme (ubc12Δ). The PfNEDD8 immunoprecipitate also contained S. cerevisiae cullin cdc53, further substantiating cullins as physiological substrates of PfNEDD8. Our findings lay ground for investigation of specific roles and drug target potential of neddylation in malaria parasites.

Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain

Protein aggregates disrupt cellular homeostasis, causing toxicity linked to neurodegeneration. Selective autophagic elimination of aggregates is critical to protein quality control, but how aggregates are selectively targeted for degradation is unclear. We compared the requirements for autophagy receptor proteins: OPTN, NBR1, p62, NDP52, and TAX1BP1 in clearance of proteotoxic aggregates. Endogenous TAX1BP1 is recruited to and required for the clearance of stress-induced aggregates, whereas ectopic expression of TAX1BP1 increases clearance through autophagy, promoting viability of human induced pluripotent stem cell-derived neurons. In contrast, TAX1BP1 depletion sensitizes cells to several forms of aggregate-induced proteotoxicity. Furthermore, TAX1BP1 is more specifically expressed in the brain compared to other autophagy receptor proteins. Invivo, loss of TAX1BP1 results in accumulation of high molecular weight ubiquitin conjugates and premature lipofuscin accumulation in brains of young TAX1BP1 knockout mice. TAX1BP1 mediates clearance of a broad range of cytotoxic proteins indicating therapeutic potential in neurodegenerative diseases.

Pea GH3 acyl acid amidosynthetase conjugates IAA to proteins in immature seeds of Pisum sativum L. – A new perspective on formation of high-molecular weight conjugates of auxin

Gretchen Hagen 3 (GH3) acyl acid amidosynthetases are encoded by early auxin-responsive genes and catalyze an ATP-dependent biosynthesis of IAA-amino acid conjugates. An amide conjugate of IAA, indole-3-acetyl-aspartate (IAA-aspartate, IAA-Asp), is a predominant form of bound auxin in immature seeds of pea. However, there is some evidence that IAA is also able to form high molecular weight amide conjugates with proteins in pea and other plant species. In this short study we report that recombinant PsGH3 IAA-amino acid synthetase, which exhibits a preference for the formation of IAA-Asp, can also conjugate IAA with the protein fraction from immature seeds of pea (S-10 fraction). We studied [14C]IAA incorporation to the S-10 protein fraction by two assays: TLC method and protein precipitation by trichloroacetic acid (TCA). In both cases, radioactivity of [14C]IAA in the protein fraction increases in comparison to the control (without PsGH3), about 9.3- and 3.17-fold, respectively. l-Asp, as a preferred substrate in the IAA conjugation catalyzed by PsGH3, down-regulates [14C]IAA conjugation to the proteins as shown by the TLC assay (∼2.8-fold decrease) and the TCA precipitation variant (∼2-fold decrease). Moreover, l-Trp that competes with Asp for the catalytic site of PsGH3 and inhibits activity of the enzyme, diminished radioactivity of [14C]IAA-proteins about 1.2- and 2.8-fold, respectively. Taking into account that amino group of an amino acid or a protein acts as an acceptor of the indole-3-acetyl moiety from IAA-AMP intermediate during GH3-dependent conjugation, we masked amine groups (α- and ε-NH2) of the S-10 protein fraction from pea seeds by reductive alkylation. The alkylated proteins revealed about 3- and 2.8-fold lower radioactivity of [14C]IAA than non-alkylated fraction for TLC and TCA precipitation variant, respectively. This is a first study demonstrating that formation of high molecular weight IAA conjugates with proteins is catalyzed by a GH3 acyl acid amidosynthetase.

An Updated Review on the Synthesis and Antibacterial Activity of Molecular Hybrids and Conjugates Bearing Imidazole Moiety.

The rapid growth of serious infections caused by antibiotic resistant bacteria, especially the nosocomial ESKAPE pathogens, has been acknowledged by Governments and scientists and is one of the world’s major health problems. Various strategies have been and are currently investigated and developed to reduce and/or delay the bacterial resistance. One of these strategies regards the design and development of antimicrobial hybrids and conjugates. This unprecedented critical review, in which our continuing interest in the synthesis and evaluation of the bioactivity of imidazole derivatives is testified, aims to summarise and comment on the results obtained from the end of the 1900s until February 2020 in studies conducted by numerous international research groups on the synthesis and evaluation of the antibacterial properties of imidazole-based molecular hybrids and conjugates in which the pharmacophoric constituents of these compounds are directly covalently linked or connected through a linker or spacer. In this review, significant attention was paid to summarise the strategies used to overcome the antibiotic resistance of pathogens whose infections are difficult to treat with conventional antibiotics. However, it does not include literature data on the synthesis and evaluation of the bioactivity of hybrids and conjugates in which an imidazole moiety is fused with a carbo- or heterocyclic subunit.

A Track-Based Molecular Synthesizer that Builds a Single-Sequence Oligomer through Iterative Carbon-Carbon Bond Formation

Summary We report an artificial molecular machine that moves along a track, iteratively joining building blocks to form an oligomer of single sequence with a continuous backbone of carbon-carbon bonds. The rotaxane features a macrocycle bearing an aldehyde-terminated chain and an axle containing different phosphonium ylides separated by rigid spacers. Each ylide is large enough to block the passage of the macrocycle, trapping the ring between the stopper at the terminus of original threading and the next ylide along the track. Once a building block is reachable, it is removed from the track through a Wittig reaction that adds it to the terminus of the growing chain. Operation on a four-barrier tetra(phosphonium salt) track produces a tetra(diphenylpropane) of single sequence linked through alkene bonds. The prototype extends the principle for molecular machines that build polymers by moving along tracks to the synthesis of sequence-encoded chains with continuous carbon backbones.

Structure and physiochemical characteristics of whey protein isolate conjugated with xylose through Maillard reaction at different degrees

The purpose of this study is to prepare Maillard reaction products (MRPs) with both good emulsification and antioxidant activity, and the relationship between the Maillard reaction degree and structural changes of whey protein isolate (WPI) conjugated with xylose through wet-heating was explored. Browning intensity didn’t change while the free amino groups reduced significantly at the initial stage of Maillard reaction (MR). Amino acid analysis indicated that the lysine and arginine reduced significantly. The antioxidant property of the MRPs was significantly improved. The best emulsifying properties could be obtained in the middle degree of MR. The sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis illustrated that WPI and xylose formed high molecular weight conjugates. The circular dichroism spectra suggested that α-helix and random coil were increased while the β-sheet and β-turns were decreased after the MR. All of the MRPs exhibited a marked red shift in the maximum fluorescence intensity, indicating that the hydrophilicity of MRPs was enhanced.

Design, synthesis, DNA binding, modeling, anticancer studies and DFT calculations of Schiff bases tethering benzothiazole-1,2,3-triazole conjugates

In an attempt to design and prepare a new library of anticancer candidates, focused thiopropargylated benzothiazole was reacted with ethyl azidoacetate and/or ethyl azidobenzoate to yield newer 1,2,3-triazole-benzothiazole conjugates bearing ester functionality through click chemistry approach. The hydrazinolysis of the obtained ester-based triazoles was also carried out to give the corresponding 1,2,3-triazole acid hydrazide derivatives as precursors for the synthesis of the focused Schiff bases by their condensation with various benzaldehyde derivatives. Spectroscopic study was investigated on the establishment of the structures of all newly synthesized Schiff bases bearing benzothiazole-1,2,3-triazole molecular conjugate. The newly designed hydrazones showed two isomers (cis-E and trans-E) with different isomeric distribution as confirmed by NMR spectral data and supported by DFT carried out in gas phase at B3LYP 6‒311G (d,p) basis set. The DFT results showed that the cis-E isomer is the lower energy structure and this finding was illustrated in terms of the intermolecular H-bonding. These molecules were screened for anticancer activities with A549 and H1299 lung cancer cell lines. The anticancer activities ranged from 55 to 90%. DNA binding study was also carried out to see the mechanism of action and the DNA binding constants were of good value ranging from of 2.0 × 105 and 14.7 × 105 M−1; indicating good interactions of the reported molecules with DNA. Finally, the modeling was confirmed and it was found that the results of modeling were in good agreement with the results of anticancer and DNA binding studies. All these finding confirmed that the reported molecules work as anticancer agents by interacting with DNA.

Intratumoral Distribution and pH-Dependent Drug Release of High Molecular Weight HPMA Copolymer Drug Conjugates Strongly Depend on Specific Tumor Substructure and Microenvironment.

Stimulus-sensitive polymer drug conjugates based on high molecular weight N-(2-hydroxypropyl) methacrylamide (HPMA) copolymers carrying doxorubicin via a pH-dependent cleavable bond (pHPMA-Dox) were previously shown to be able to overcome multi-drug resistance. Nevertheless, a tumor type dependent differential response was observed. Although an improved and more selective tumor accumulation of pHPMA-Dox is generally achieved due to the enhanced permeability and retention (EPR) effect, little is known about the fate of these conjugates upon entering the tumor tissue, which could explain the different responses. In this study, we compared in vitro and in vivo accumulation and Dox-activation of pHPMA-Dox in three cancer cell line models (1411HP, A2780cis, HT29) and derived xenograft tumors using a near-infrared fluorescence-labeled pHPMA-Dox conjugate. Firstly, cytotoxicity assays using different pH conditions proved a stepwise, pH-dependent increase in cytotoxic activity and revealed comparable sensitivity among the cell lines. Using multispectral fluorescence microscopy, we were able to track the distribution of drug and polymeric carrier simultaneously on cellular and histological levels. Microscopic analyses of cell monolayers confirmed the assumed mechanism of cell internalization of the whole conjugate followed by intracellular cleavage and nuclear accumulation of Dox in all three cell lines. In contrast, intratumoral distribution and drug release in xenograft tumors were completely different and were associated with different tissue substructures and microenvironments analyzed by Azan- and Hypoxisense®-staining. In 1411HP tumors, large vessels and less hypoxic/acidic microenvironments were associated with a pattern resulting from consistent tissue distribution and cellular uptake as whole conjugate followed by intracellular drug release. In A2780cis tumors, an inconsistent pattern of distribution partly resulting from premature drug release was associated with a more hypoxic/acidic microenvironment, compacted tumor tissue with compressed vessels and specific pre-damaged tissue structures. A completely different distribution pattern was observed in HT29 tumors, resulting from high accumulation of polymer in abundant fibrotic structures, with small embedded vessels featuring this tumor type together with pronounced premature drug release due to the strongly hypoxic/acidic microenvironment. In conclusion, the pattern of intratumoral distribution and drug release strongly depends on the tumor substructure and microenvironment and may result in different degrees of therapeutic efficacy. This reflects the pronounced heterogeneity observed in the clinical application of nanomedicines and can be exploited for the future design of such conjugates.

Aptamer-Pyropheophorbide a Conjugates with Tumor Spheroid Targeting and Penetration Abilities for Photodynamic Therapy.

Pyropheophorbide a (Pyro) is a widely used photosensitizer for photodynamic therapy (PDT). However, poor water solubility, aggregation-induced fluorescence quenching, and lack of selectivity to targeted cells seriously limit its application. In this work, we prepared aptamer-Pyro conjugates (APCs) by linking Pyro to hydrophilic nucleic acid aptamer to enhance its water solubility and endow it with protein tyrosine kinase 7 (PTK7) overexpressed tumor spheroid specific targeting and penetration abilities for photodynamic therapy. The molecular conjugate was successfully synthesized and dissolved well in an aqueous solution. The APCs showed strong near-infrared fluorescence in the aqueous solution and produced singlet oxygen both in the solution and cells under laser irradiation, indicating its generation of singlet oxygen during PDT was guaranteed. Owing to the cancer cell targeting ability of the aptamer, the APCs specifically bound with PTK7 overexpressed cancerous cells and showed fluorescence signal for tumor cell imaging and diagnosis. The APCs exhibited favorable enhanced phototoxicity to target tumor cells compared with control cells. More importantly, due to the small size of the molecular conjugate, the APCs efficiently penetrated into the interior of multicellular tumor spheroids (MCTS) and caused cell damage. All these results indicated that the robust aptamer-Pyro conjugate is a promising selective tumor-targeting and penetrable molecule for cancer photodynamic therapy.

Natural ligand-receptor mediated loading of siRNA in milk derived exosomes

siRNA based therapeutics have become the next frontier in molecular medicine. Though exosomes emerge as a promising drug delivery vehicle for siRNAs, significant hurdle remains in finding safe and effective loading methods. Traditional methods of loading exogenous siRNAs in exosomes are marked by certain limitations like siRNA aggregation, toxicity to the cells and their high experimental cost. As an electroporation and lipofection free approach, we show that the molecular conjugate of bovine lactoferrin with polyl-l-ysine electrostatically interacts with negatively charged siRNA, wherein lactoferrin as a ligand is captured by the GAPDH present in exosomes, loading siRNA in an effortless manner. This method exhibited transfection efficiency, colocalization percentage and colocalization threshold similar to electroporation. Furthermore, efficient uptake of exosomes loaded with siRNA via conjugate in recipient cells was observed. Our current study univocally establishes chemical free and non-mechanical method for the encapsulation and intercellular delivery of siRNA for wider therapeutic applications.

Human Serum Albumin Labelled with Sterically-Hindered Nitroxides as Potential MRI Contrast Agents.

Four albumin-nitroxide conjugates were prepared and tested as metal-free organic radical contrast agents (ORCAs) for magnetic resonance imaging (MRI). Each human serum albumin (HSA) carrier bears multiple nitroxides conjugated via homocysteine thiolactones. These molecular conjugates retain important physical and biological properties of their HSA component, and the resistance of their nitroxide groups to bioreduction was retained or enhanced. The relaxivities are similar for these four conjugates and are much greater than those of their individual components: the HSA or the small nitroxide molecules. This new family of conjugates has excellent prospects for optimization as ORCAs.

Estradiol-Induced MMP-9 Expression via PELP1-Mediated Membrane-Initiated Signaling in ERα-Positive Breast Cancer Cells.

Proline-, glutamic acid-, leucine-rich protein 1 (PELP1) is a novel estrogen receptor (ER) coregulator, demonstrated distinctive characters from other ERα coregulators, and has been suggested to be involved in metastasis of several cancers. In ERα-positive breast cancer, PELP1 overexpression enhanced ruffles and filopodium-like structure stimulated by estradiol (E2) through extranuclear cell signaling transduction hereby increased cell motility. However, whether PELP1 is also involved in extracellular matrix remodeling of ERα-positive breast cancer cells is still unknown. In this study, we investigated the role of PELP1 in E2-induced MMP-9 expression and the underlined mechanism. The results demonstrated the following: E2-induced ERα-positive MCF-7 breast cancer cell MMP-9 mRNA and protein expression in a rapid response and concentration-dependent manner. Knocked down PELP1 significantly suppressed E2-induced MMP-9 expression. E2-bovine serum albumin (BSA), a large molecular membrane-impenetrable conjugate of E2, can also upregulate MMP-9 protein expression in MCF-7, and the action of E2-BSA can be abolished by PI3K inhibitor LY294002; treating MCF-7 simultaneously with PELP1-shRNA and LY294002 did not show synergetic inhibitory effect on E2-BSA-induced MMP-9 expression. Our results indicated that estrogen-induced MMP-9 expression in ER-positive breast cancer cells may be through PELP1-mediated PI3K/Akt signaling pathway.

Antioxidant shape amphiphiles for accelerated wound healing.

Shape amphiphiles refer to a class of molecular conjugates composed by distinct building blocks with incommensurate shapes and chemical interactions. Whilst extensive efforts have been devoted to the solid state self-assembly and nanolithography applications of shape amphiphiles, only very limited examples of their usage in the biomedical field have been explored. In this work, we reported a series of gallic acid functionalized polyhedral oligomeric silsesquioxane (POSS)-based shape amphiphiles with various macromolecular architectures for efficient and accelerated wound healing. These antioxidant giant amphiphiles demonstrated good biocompatibility and strong free radical scavenging activity to prevent cell oxidative damage and then promote wound recovery. We describe these POSS-based antioxidant shape amphiphiles in an initial proof-of-concept study and propose that this family of functional giant amphiphiles will be useful in regenerative biomedicine.

Selected Physicochemical and Pharmaceutical Properties of Poly-ε-caprolactone and Poly(d,l-lactide-co-ε-caprolactone) Conjugates of Lamivudine Synthesized via Ring-Opening Polymerization.

The modification of drug fate after administration may be achieved by the covalent coupling of active pharmaceutical ingredients with macromolecules. To prolong or delay the release, slowly degrading polymers such as polyesters may be applied for conjugation. The detachment of a covalently conjugated drug from the polymeric matrix relies mostly on the material degradation profile and barely on the weak interaction between the drug and macromolecules. In the present study, lamivudine was conjugated via ring-opening polymerization with poly-ε-caprolactone and poly(d,l-lactide-co-ε-caprolactone). The influence of the reaction parameters on the course of the polymerization and physicochemical properties of obtained conjugates were investigated. Subsequently, selected reaction products were formulated into submicron particles, and drug release profiles in physiological-like conditions were investigated. The course of the reaction was monitored via gel permeation chromatography. The structure and physicochemical properties of products were evaluated via spectroscopic, calorimetric, and diffractometric methods. The profile of the drug release from particles prepared by the slow evaporation of conjugate solution from o/w emulsion was monitored with high-performance liquid chromatography. Both an elevated reaction temperature and higher catalyst concentration increased the polymerization rate and simultaneously promoted the side reactions, resulting in a broad molecular weight distribution of products in the range from 1.30 to 2.15. The physicochemical properties of conjugates obtained in different conditions varied and had a direct influence on the drug release. The release curve of lamivudine from particles based on low molecular weight conjugates achieved a plateau between 18.9 and 22.2 μg per mg of conjugate within a month. Drug detachment from particles composed of high molecular weight conjugates exhibited a distinct delay period preceded by a drug burst release at a maximal level of 13.3 μg per mg of conjugate. Conjugate chemical composition and the degree of crystallinity were also found to influence the release.

Recent Advances in the Design of Self‐Delivery Amphiphilic Drugs and Vaccines

AbstractAmphiphilic drugs are molecular drugs or drug conjugates possessing both hydrophilic and lipophilic properties. Representative amphiphilic drugs are composed of a pharmaceutical payload, a linker, and an appropriate amphiphilic modification. The physicochemical properties of amphiphilic drugs can be tailored by structure‐based engineering, which ultimately determine the drug molecules’ self‐assemble ability, bioavailability, protein binding, membrane anchoring, organ and intracellular distributions, side effects, and biological efficacy. Unlike the traditional carrier‐assistant drug delivery system, many of the amphiphilic drugs are carrier‐free and can self‐deliver to target sites/cells and access intracellular organelles without an external delivery carrier. This is achieved by molecular designs that control the delivery pathways of amphiphilic drugs at organ/tissue, cellular, and intracellular levels. In this review the recent advances in self‐delivery amphiphilic drugs and vaccines are highlighted, with emphasis on the underlying design principles and emerging applications.

Förster Resonant Energy Transfer Mediated by the Evanescent Fields of Nanophotonic Particles

Understanding the nonradiative Forster resonance energy transfer (FRET) in molecular conjugate systems mediated by nanophotonics is a new research direction in developing and optimizing photovoltai...

Light-Induced Therapies for Prostate Cancer Treatment.

Prostate cancer (PC) is one of the most widespread tumors affecting the urinary system and the fifth-leading cause from cancer death in men worldwide. Despite PC mortality rates have been decreasing during the last years, most likely due to an intensification of early diagnosis, still more than 300,000 men die each year because of this disease. In this view, researchers in all countries are engaged in finding new ways to tackle PC, including the design and synthesis of novel molecular and macromolecular entities able to challenge different PC biological targets, while limiting the extent of unwanted side effects that significantly limit men's life quality. Among this field of research, photo-induced therapies, such as photodynamic and photothermal therapies (PDT and PTT), might represent an important advancement in PC treatment due to their extremely localized and controlled cytotoxic effect, as well as their low incidence of side effects and tumor resistance occurrence. Based on these considerations, this review aims to gather and discuss the last 5-years literature reports dealing with the synthesis and biological activity of molecular conjugates and nano-platforms for photo-induced therapies as co-adjuvant or combined therapeutic modalities for the treatment of localized PC.

New library of pyrazole-imidazo[1,2-α]pyridine molecular conjugates: Synthesis, antibacterial activity and molecular docking studies.

A library of novel pyrazole-imidazo[1,2-α]pyridine scaffolds was designed and synthesized through a one-pot three-component tandem reaction. The structures of synthesized conjugates were confirmed by spectroscopic techniques (NMR, IR and HRMS). In vitro antibacterial evaluation of the twelve synthesized molecules (7a, 8a-k) against methicillin-resistant Staphylococcus aureus and normal strains of Escherichia coli, Salmonella typhimurium, Klebsiella pneumonia and Pseudomonas aeruginosa established 8b, 8d, 8e, 8h and 8i as potent antibacterial agents with superior minimum bactericidal concentration, compared with standard drug ciprofloxacin. Molecular docking studies of all active compounds into the binding site of glucosamine-6-phosphate synthase were further performed in order to have a comprehensive understanding of putative binding modes within the active sites of the receptor.