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Bacterial communication, Quorum Sensing (QS), is a target against virulence and prevention of antibiotic-resistant infections. 16 derivatives of Piperlongumine (PL), an amide alkaloid from Piper longum L., were screened for QS inhibition. PL-18 had the best QSI activity. PL-18 inhibited the lasR-lasI, rhlR-rhlI, and pqs QS systems of Pseudomonas aeruginosa. PL-18 inhibited pyocyanin and rhamnolipids that are QS-controlled virulence elements. Iron is an essential element for pathogenicity, biofilm formation and resilience in harsh environments, its uptake was inhibited by PL-18. Pl-18 significantly reduced the biofilm biovolume including in established biofilms. PL-18-coated silicon tubes significantly inhibited biofilm formation. The transcriptome study of treated P. aeruginosa showed that PL-18 indeed reduced the expression of QS and iron homeostasis related genes, and up regulated sulfur metabolism related genes. Altogether, PL-18 inhibits QS, virulence, iron uptake, and biofilm formation. Thus, PL-18 should be further developed against bacterial infection, antibiotic resistance, and biofilm formation.

Bacterial communication, termed Quorum Sensing (QS), is a promising target for virulence attenuation and the treatment of bacterial infections. Infections cause inflammation, a process regulated by a number of cellular factors, including the transcription Nuclear Factor kappa B (NF-κB); this factor is found to be upregulated in many inflammatory diseases, including those induced by bacterial infection. In this study, we tested 32 synthetic derivatives of coumaperine (CP), a known natural compound found in pepper (Piper nigrum), for Quorum Sensing Inhibition (QSI) and NF-κB inhibitory activities. Of the compounds tested, seven were found to have high QSI activity, three inhibited bacterial growth and five inhibited NF-κB. In addition, some of the CP compounds were active in more than one test. For example, compounds CP-286, CP-215 and CP-158 were not cytotoxic, inhibited NF-κB activation and QS but did not show antibacterial activity. CP-154 inhibited QS, decreased NF-κB activation and inhibited bacterial growth. Our results indicate that these synthetic molecules may provide a basis for further development of novel therapeutic agents against bacterial infections.

The incorporation of natural products into a suitable delivery system has the potential to augment their therapeutic effectiveness significantly. In this study, we demonstrate how silicasomes, a lipid‐coated mesoporous silica nanorods, influence the anticancer potency and release behaviour of the natural product. Piperlongumine (Pip), a natural product isolated from long pepper, is loaded into mesoporous silica nanorods (MSNRs) followed by a bilayer coating made of 1,2‐Dimyristoyl‐sn‐glycero‐3‐phosphocholine (DMPC). The size and morphology of Pip‐loaded MSNRs (Pip@MSNRs) and phospholipid‐coated Pip@MSNRs (PL‐Pip@MSNRs) are characterized well using suitable analytical techniques. The release of Pip from Pip@MSNRs attained saturation at 48 h while PL‐Pip@MSNRs exhibited the same only after 100 h in both simulated physiological and endolysosomal acidic environments. Moreover, PL‐Pip@MSNRs displayed a higher percentage of Pip release in an acidic medium than in a physiological medium after 24 h. These results confirm that the DMPC coating could assist the pH‐responsive and sustained release of loaded drug from silica nanorods. Most importantly, PL‐Pip@MSNRs demonstrate a higher potency of cytotoxicity and apoptosis against MCF‐7 (Human Breast Carcinoma) cells than the Pip@MSNRs, emphasizing the significance of DMPC‐coated MSNRs as a suitable nanocarrier for natural product delivery. [ABSTRACT FROM AUTHOR]

A suitable drug delivery strategy for metallodrugs is as significant as the strategies adopted for an efficient metallodrug design. In this study, piperlongumine, which is isolated from long pepper, is coordinated with a Ru(II)-p-cymene moiety to obtain an organoruthenated complex containing the natural product (Ru(pip)). The isolated complex shows higher cytotoxicity in MCF-7 breast cancer cells than in THP-1 leukemia and HepG2 liver cancer cells. The IC50 value of the complex in non-cancerous HEK-239 cells is also almost equal to that in MCF-7 cells. Next, with an aim to modulate the antiproliferative activity of Ru(pip) using a drug delivery strategy, the complex is loaded into mesoporous silica nanorods (MSNRs), which have a higher surface area than spherical silica nanoparticles. Furthermore, the outer surface of the loaded nanorods is covered with a polydiacetylene-lipid (PL) hybrid bilayer. Given the unique optical properties of polydiacetylene, the PL coating modifies non-fluorescent MSNRs into red-emissive particles (PL-Ru(pip)@MSNRs), which can be useful for diagnostic applications. The release profile studies reveal that the ene-yne conjugation in the PL coating ensures the sustained release of the complex from nanoparticles in both physiological and simulated cancer cell media. While Ru(pip) exhibits both necrotic and apoptotic modes of cell death, PL-Ru(pip)@MSNRs preferably induce the apoptotic mode of cell death in MCF-7 and THP-1 cells. Also, the nanoformulation exhibits a higher percentage of cell cycle arrest in the G0/G1 phase than Ru(pip), as measured by flow cytometry analysis. In contrast, the in vitro antioxidant potency of the complex is decreased after being loaded into PL-coated silica nanoparticles. [ABSTRACT FROM AUTHOR]

Transamidation of weakly nucleophilic aromatic amines is achieved under melt conditions and in absence of catalyst, activating agent, base, and solvent. Chemoselectivity of the protocol is demonstrated with transamidation of aniline‐bearing protic carboxylic acid group and wide range of anilines. Broad applicability of the process is demonstrated with the synthesis of bioactive natural product amide, Avenanthranamide‐A. By‐product was isolated for re‐use in synthesis of starting amide, manifests atom economy, and sustainability of the protocol. Thus, our findings imply that the developed protocol is environmentally benign, operationally simple yet versatile for protection‐deprotection free synthesis of amides, peptides and amide‐based drugs. [ABSTRACT FROM AUTHOR]

Piperlongumine, an anticancer natural product, was sequentially demethylated to obtain mono, di and trihydroxy piperlongumines. The hydroxy piperlongumines were evaluated for cytotoxic effect on five human cancer cell lines (kidney, skin, cervical, breast, and lung) in vitro. Results from cytotoxic and cell growth inhibition studies showed monohydroxy piperlongumine (MHPL) was the most active of the series, exhibited potent cytotoxic effect on all the tested cell lines. Flow cytometry analysis shows MHPL inhibited cell cycle progression of HeLa cells in the S phase, indicated that it inhibits the DNA replication process. Fluorescence staining indicated MHPL treated cells were apoptotic. MHPL upregulated the apoptotic genes (caspase‐3, −8, Bax, and p53) and downregulated anti‐apoptotic gene (Bcl‐2). The antioxidant study revealed that hydroxy piperlongumines are effective antioxidants. For MHPL, all the molecular descriptors were within the range of 95 % of approved drugs suggesting high druglikeliness. Our results suggest that MHPL could be developed as a potential lead molecule for cancer therapy. [ABSTRACT FROM AUTHOR]

Amides are indispensable building blocks of biological systems, pharmaceuticals, and materials. We report a highly selective method for the synthesis of amides via transamidation process. Transamidation of N‐acyl‐2‐piperidones with a broad range of amines is demonstrated under exceedingly mild and metal‐free reaction condition that relies on the amide bond twist to weaken the amidic resonance. Transamidation proceeds under the neat condition at room temperature, in short reaction times (30–90 min) with good yields. Considerable variation is tolerated with both amine and imide substrates. Of note, amines bearing carboxylic acids (glycine and serine) and hydroxyl groups (dopamine, tyramine, etc.) are well tolerated which are otherwise problematic under the metal‐catalyzed protocol. Our current method is applicable for transamidation of both alkyl and aryl‐N‐acyl‐2‐piperidones. The practical value of the method is highlighted by the synthesis of four natural product amide alkaloids in high yields under mild reaction conditions. In the absence of nucleophilic amines, N‐acyl‐2‐piperidones undergoes esterification with EtOH at elevated temperature. Single crystal X‐ray analysis of an N‐acyl‐2‐piperidone shows amide bond twist, τ = –20.39° and pyramidalization, χN = –11.73°. This weakens the amidic conjugation and might be the factor controlling the reactivity and selectivity of these imides. We envision that the N‐acyl‐2‐piperidone scaffold would be useful in the synthesis of pharmaceuticals and materials. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • Hexagonal mesoporous carbon nitride (HMCN) catalyst pore size was tuned for the synthesis of cinnamic acid derivatives. • HMCN (x) catalysts were used in the synthesis in metal/pyridine-free, eco-friendly conditions. • When the pore size HMCN catalysts increases, product yield increased with increase in the molecular size of substrates. • Use of HMCN (x) catalysts results a very high product yield, short reaction time, simple work-up, and no loss in catalytic activity even after six reaction cycles. • This manuscript gives the broad idea about how the pore size controls catalytic reaction for high product yield to various organic transformations. Abstract The pore size of hexagonal mesoporous carbon nitride (HMCN) materials were engineered with different pore sizes of 3.5, 4.7, 5.9, 7.1, 7.9 and 9.2 nm using SBA-15 hard template synthesised at 80, 100, 120, 150, 160 and 180 °C, respectively. HMCN (x) and SBA-15 (x) materials were characterized by XRD, N 2 sorption, FESEM, CHN, FTIR, Raman and DR UV–Vis spectroscopy. N 2 sorption isotherms of HMCN (x) and SBA-15 (x) samples showed a type IV isotherm with H1 hysteresis loop having a region of steep increase due to capillary condensation. The catalytic performance of HMCN (x) catalysts were studied on the synthesis of α, β -unsaturated carboxylic acid and its derivatives via Knoevenagel-Doebner reaction in metal/pyridine-free, azeotropic conditions (Dean-Stark apparatus) by an environmental friendly approach. Among the HMCN (x) catalysts studied, HMCN (5.9) showed an excellent performance of 94.5% p -hydroxybenzaldehyde conversion with 100% selectivity of p -hydroxycinnamic acid (91% isolated yield) within 60 min. The reaction parameters of temperature, time and catalyst amount were studied on p -hydroxycinnamic acid synthesis. The derivatives of α, β -unsaturated carboxylic acid were synthesised under optimized reaction parameters. The experimental results of our study proved that the pore size engineering of HMCN is important for the catalytic reaction to get maximum product yield for the reactants with different molecular dimensions. [ABSTRACT FROM AUTHOR]

A suitable drug delivery strategy for metallodrugs is as significant as the strategies adopted for an efficient metallodrug design. In this study, piperlongumine, which is isolated from long pepper, is coordinated with a Ru(II)- p -cymene moiety to obtain an organoruthenated complex containing the natural product ( Ru(pip) ). The isolated complex shows higher cytotoxicity in MCF-7 breast cancer cells than in THP-1 leukemia and HepG2 liver cancer cells. The IC 50 value of the complex in non-cancerous HEK-239 cells is also almost equal to that in MCF-7 cells. Next, with an aim to modulate the antiproliferative activity of Ru(pip) using a drug delivery strategy, the complex is loaded into mesoporous silica nanorods ( MSNRs ), which have a higher surface area than spherical silica nanoparticles. Furthermore, the outer surface of the loaded nanorods is covered with a polydiacetylene-lipid ( PL ) hybrid bilayer. Given the unique optical properties of polydiacetylene, the PL coating modifies non-fluorescent MSNRs into red-emissive particles ( PL-Ru(pip)@MSNRs ), which can be useful for diagnostic applications. The release profile studies reveal that the ene-yne conjugation in the PL coating ensures the sustained release of the complex from nanoparticles in both physiological and simulated cancer cell media. While Ru(pip) exhibits both necrotic and apoptotic modes of cell death, PL-Ru(pip)@MSNRs preferably induce the apoptotic mode of cell death in MCF-7 and THP-1 cells. Also, the nanoformulation exhibits a higher percentage of cell cycle arrest in the G0/G1 phase than Ru(pip), as measured by flow cytometry analysis. In contrast, the in vitro antioxidant potency of the complex is decreased after being loaded into PL-coated silica nanoparticles.