Co-administration of zinc phthalocyanine and quercetin via hybrid nanoparticles for augmented photodynamic therapy.

The photodynamic anticancer activity of a photosensitizer can be further increased by co-administration of a flavonoid. However, this requires that both molecules must be effectively accumulated at the tumor site. Hence, in order to enhance the activity of zinc phthalocyanine (ZnPc, photosensitizer), it was co-encapsulated with quercetin (QC, flavonoid) in lipid polymer hybrid nanoparticles (LPNs) developed using biodegradable & biocompatible materials and prepared using a single-step nanoprecipitation technique. High stability and cellular uptake, sustained release, inherent fluorescence, of ZnPC were observed after encapsulation in the LPNs, which also showed a higher cytotoxic effect in breast carcinoma cells (MCF-7) compared to photodynamic therapy (PDT) alone. In vivo studies in tumor-bearing Sprague Dawley rats demonstrated that the LPNs were able to deliver ZnPc and QC to the tumor site with minimal systemic toxicity and increased antitumor effect. Overall, the photodynamic effect of ZnPc was synergized by QC. This strategy could be highly beneficial for cancer management in the future while nullifying the side effects of chemotherapy.

Synthesis of N-substituted indole derivatives as potential antimicrobial and antileishmanial agents.

Leishmaniasis and microbial infections are two of the major contributors to global mortality and morbidity rates. Hence, development of novel, effective and safer antileishmanial and antimicrobial agents having reduced side effects are major priority for researchers. Two series of N-substituted indole derivatives i.e. N-substituted indole based chalcones (12a-g) and N-substituted indole based hydrazide-hydrazones (18a-g, 19a-f, 21 a-g) were synthesized. The synthesized compounds were characterized by 1H NMR, 13C NMR, Mass and FT-IR spectral data. Further these derivatives were evaluated for their antimicrobial potential against Escherichia coli, Bacillus subtilis, Pseudomonas putida and Candida viswanathii, and antileishmanial potential against promastigotes of Leishmania donovani. Compounds 18b, 18d and 19d exhibited significant activity with an IC50 of 0.19 ± 0.03 µM, 0.14 ± 0.02 µM and 0.16 ± 0.06 µM against B. subtilis which was comparable to chloramphenicol (IC50 of 0.25 ± 0.03 µM). Compounds 12b and 12c exhibited an IC50 of 24.2 ± 3.5 µM and 21.5 ± 2.1 µM in the antileishmanial assay. Binding interactions of indole based hydrazide-hydrazones were studied with nitric oxide synthase in silico in order to understand the structural features responsible for activity.

Design, Sustainable Synthesis, and Programmed Reactions of Templated N-Heteroaryl-Fused Vinyl Sultams.

A de novo design and synthesis of N-heteroaryl-fused vinyl sultams as templates for programming chemical reactions on vinyl sultam periphery or (hetero)aryl ring is described. The key features include rational designing and sustainable synthesis of the template, customized reactions of vinyl sultams at C═C bond or involving N-S bond cleavage, and reactions on the periphery of the heteroaryl ring for late-stage diversification. The simple, easy access to the template coupled with opportunities for the synthesis of diversely functionalized heterocyles from a single template constitutes a rare study in contemporary organic synthesis.

Synthesis, biological evaluation and in silico studies of 2-aminoquinolines and 1-aminoisoquinolines as antimicrobial agents.

The current study reports synthesis of 2-aminoquinolines and 1-aminoisoquinolines derivatives and their characterization. Further, in vitro studies were conducted to determine antimicrobial activities. Compound 3 h showed maximum activity against B. subtilis (IC50: 0.10±0.02 µM) and E. coli (IC50: 0.13±0.01 µM) whereas compound 3i showed higher antimicrobial activity against E. coli (IC50: 0.11±0.01) and C. viswanathii (IC50: 0.10±0.05 µM). Safety profiles of the most potent derivatives were evaluated utilizing cell viability assay using RAW 264.7 and HeLa cell lines and in vitro hemolytic assay was carried out freshly isolated RBC from healthy rat. Furthermore, in silico studies, like molecular docking, binding free energy calculations and ADME predictions were done to get the best lead candidates. Additionally, molecular dynamic simulation for 100 ns was performed to know stability of protein and ligand complex. The active compounds were found to be non-toxic and non-hemolytic and hold great promise to become newer antimicrobial agents.

Light-assisted anticancer photodynamic therapy using porphyrin-doped nanoencapsulates.

Light activatable porphyrinic photosensitizers (PSs) are essential components of anticancer and antimicrobial therapy and diagnostic imaging. However, their biological applications are quite challenging due to the lack of hydrophilicity and biocompatibility. To overcome such drawbacks, photosensitizers can be doped into a biocompatible polymer such as gelatin and further can be used for biomedical applications. Herein, first, a novel A4 type porphyrin PS [5,10,15,20-tetrakis(4-pyridylamidephenyl)porphyrin; TPyAPP] was synthesized via a rational route with good yield. Further, this porphyrin was encapsulated into the gelatin nanoparticles (GNPs) to develop hydrophilic phototherapeutic nanoagents (PTNAs, A4por-GNPs). Notably, the synthesis of such porphyrin-doped GNPs avoids the use of any toxic chemicals or solvents. The nanoprobes have also shown good fluorescence quantum yield demonstrating their applicability in bioimaging. Further, the mechanistic aspects of the anticancer and antimicrobial efficacy of the developed A4por-GNPs were evaluated via singlet oxygen generation studies. Overall, our results indicated porphyrin-doped biodegradable polymeric nanoparticles act as effective phototherapeutic agents against a broad range of cancer cell lines and microbes upon activation by the low-cost LED light.

A mild and metal-free synthesis of 2- and 1-alkyl/aryl/dialkyl-aminoquinolines and isoquinolines.

A simple synthetic strategy has been developed for the synthesis of 2- and 1-alkyl/aryl/dialkylaminoquinolines and isoquinolines from the easily available quinoline and isoquinoline-N-oxides, different amines, triflic anhydride as activating agent and acetonitrile as solvent in a one-pot reaction under metal-free conditions at 0 °C to room temperature.

Porphyrin Functionalized Gelatin Nanoparticle-Based Biodegradable Phototheranostics: Potential Tools for Antimicrobial Photodynamic Therapy.

Photomedicine-based antimicrobial therapy has emerged as an alternative treatment for antibiotic-resistant microbial infections. Although various photosensitizers (PSs) have been reported as efficient antimicrobial agents, their efficient delivery to the specific target area requires further investigation. In the current study, development of a biodegradable phototheranostic nanoagent (PTNA) by incorporation of a PS (trans-AB-porphyrin) and gelatin nanomatrix is described. The antimicrobial efficacy of the PTNA against Gram-positive bacteria, Gram-negative bacteria, and yeast strains, along with other properties including hydrophilicity, biocompatibility, and targeting ability, is evaluated. Unlike the commonly used membrane permeabilizing chemicals that are toxic, the delivery vehicle gelatin used in this study is biocompatible and biodegradable. Here, the method offers a sustainable synthesis of gelatin-based stable formulation of nanotheranostic agents with high loading (>85%). The study revealed that the reactive oxygen species (ROS), generated in situ by the PTNAs, are primarily responsible for microbial cell death. The developed PTNAs described herein featured "nano size (<200 nm), have high fluorescence and singlet oxygen quantum yields, retain photophysical properties of PS after incorporation into the gelatin matrix, could be activated by a cost-effective light irradiation, and have efficient antimicrobial photodynamic activity." This antimicrobial photodynamic therapy using the newly synthesized phototheranostic nanoagent has manifested its competence, therapeutic modality of general acceptance, and wide-spectrum antimicrobial action.

Generation of novel family of reductases from PCR based library for the synthesis of chiral alcohols and amines.

Biocatalysis has shown tremendous potential in the synthesis of drugs and drug intermediates in the last decade. Screening of novel biocatalysts from the natural genome space is the growing trend to replenish the harsh chemical synthetic routes, commonly used in the pharmaceutical and chemical industry. Here, we report a novel ketoreductase (KERD) and a nitrile reductase isolated from the PCR based library generated from the genome of Rhodococcus ruber and Bacillus subtilis, respectively. Both the proteins are hypothetical in nature as there is no putative homology found in the database, although both the enzymes have significant activity towards the synthesis of chiral alcohols and amines. Enzyme activity over a wide range of substrates (aromatic and aliphatic) for both the novel catalysts was observed. From the unique gene sequence to activity over a broad range of substrate and >99% conversion at higher concentrations (100 mM and above) entitles both the hypothetical enzymes as novel. The novel KERD has shown >99% selectivity for the synthesis of (S)-phenylethanol which makes it a potential candidate for industrial catalysis. The novel nitrile reductase has also shown promising activity for the synthesis of (R)-2-phenylethanolamine, which is a difficult moiety to synthesize chemically. In this report, starting from a homology based library, two highly potent whole cell biocatalysts are obtained.

Development of Gelatin Nanoparticle-Based Biodegradable Phototheranostic Agents: Advanced System to Treat Infectious Diseases.

Rose bengal (RB)-conjugated and -entrapped gelatin nanoparticle (GNP)-based biodegradable nanophototheranostic (Bd-NPT) agents have been developed for the efficient antimicrobial photodynamic therapy. The study reveals that the use of gelatin nanoparticles could bypass the chemicals such as potassium iodide, EDTA, calcium chloride and polymyxin nonapeptide for the penetration of drug into the cell membrane to achieve antimicrobial activity. We demonstrated that the singlet oxygen generated by the biodegradable gelatin nanoparticles (BdGNPs) could damage the microbial cell membrane and the cell dies. The key features of the successive development of this work include the environmentally benign amidation of RB with GNPs, which was so far unexplored, and the entrapment of RB into the gelatin nanoparticles (GNP). The RB-GNP exhibited potent and broad-spectrum antimicrobial activity and could be useful in treating multi-drug-resistant microbial infections.