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Organic compounds with antibacterial and antiparasitic properties are gaining significance for biomedical applications. This study focuses on the solvent-free synthesis (green synthesis) of 1,4-naphthoquinone or 2,3-dichloro-1,4-naphthoquinone with different phenylamines using silica gel as an acid solid support. The study also includes in silico PASS predictions and the discovery of antibacterial and antiparasitic properties of phenylaminonaphthoquinone derivatives 1 - 12 , which can be further applied in drug discovery and development. These activities were discussed in terms of molecular descriptors such as hydrophobicity, molar refractivity, and half-wave potentials. The in vitro antimicrobial potential of the synthesized compounds 1 - 12 was evaluated against a panel of six bacterial strains (three Gram-positive: Staphylococcus aureus , Proteus mirabilis , and Enterococcus faecalis ; and three Gram-negative bacteria: Escherichia coli , Salmonella typhimurium , and Klebsiella pneumoniae ). Six compounds ( 1 , 3 , 5 , 7 , 10, and 11 ) showed better activity toward S. aureus with MIC values between 3.2 and 5.7 μg/mL compared to cefazolin (MIC = 4.2 μg/mL) and cefotaxime (MIC = 8.9 μg/mL), two cephalosporin antibiotics. Regarding in vitro antiplasmodial activity, compounds 1 and 3 were the most active against the Plasmodium falciparum strain 3D7 (chloroquine-sensitive), displaying IC 50 values of 0.16 and 0.0049 μg/mL, respectively, compared to chloroquine (0.33 μg/mL). In strain FCR-3 (chloroquine-resistant), most of the compounds showed good activity, with compounds 3 (0.12 μg/mL) and 11 (0.55 μg/mL) being particularly noteworthy. Additionally, docking studies were used to better rationalize the action and prediction of the binding modes of these compounds. Finally, absorption, distribution, metabolism, excretion, and toxicity (ADMET) predictions were performed.

High prevalence of parasitic or bacterial infectious diseases in some world areas is due to multiple reasons, including a lack of an appropriate health policy, challenging logistics and poverty. The support to research and development of new medicines to fight infectious diseases is one of the sustainable development goals promoted by World Health Organization (WHO). In this sense, the traditional medicinal knowledge substantiated by ethnopharmacology is a valuable starting point for drug discovery. This work aims at the scientific validation of the traditional use of Piper species (" Cordoncillos ") as firsthand anti-infectious medicines. For this purpose, we adapted a computational statistical model to correlate the LCMS chemical profiles of 54 extracts from 19 Piper species to their corresponding anti-infectious assay results based on 37 microbial or parasites strains. We mainly identified two groups of bioactive compounds (called features as they are considered at the analytical level and are not formally isolated). Group 1 is composed of 11 features being highly correlated to an inhibiting activity on 21 bacteria (principally Gram-positive strains), one fungus ( C. albicans ), and one parasite ( Trypanosoma brucei gambiense ). The group 2 is composed of 9 features having a clear selectivity on Leishmania (all strains, both axenic and intramacrophagic). Bioactive features in group 1 were identified principally in the extracts of Piper strigosum and P. xanthostachyum . In group 2, bioactive features were distributed in the extracts of 14 Piper species. This multiplexed approach provided a broad picture of the metabolome as well as a map of compounds putatively associated to bioactivity. To our knowledge, the implementation of this type of metabolomics tools aimed at identifying bioactive compounds has not been used so far., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Vásquez-Ocmín, Cojean, Roumy, Marti, Pomel, Gadea, Leblanc, Dennemont, Ruiz-Vásquez, Ricopa Cotrina, Ruiz Mesia, Bertani, Ruiz Mesia and Maciuk.)

In this work, we have studied the benzofurans of Pericallis echinata (aerial parts and transformed roots), P. steetzii (aerial parts and transformed roots), P. lanata (aerial parts), and P. murrayi (aerial parts and roots). This work has permitted the isolation of the new benzofurans 10-ethoxy-11-hydroxy-10,11-dihydroeuparin ( 10 ), (-)-eupachinin A ethyl ether ( 12 ), 11,15-didehydro-eupachinin A ( 13 ), 10,12-dihydroxy-11-angelyloxy-10,11-dihydroeuparin ( 14 ), 2,4-dihydroxy-5-formyl-acetophenone ( 15 ) isolated for the first time as a natural product, 11-angelyloxy-10,11-dihydroeuparin ( 16 ), and 12-angelyloxyeuparone ( 17 ), along with several known ones ( 1 - 9, 11 ). In addition, the incubation of the abundant component, 6-hydroxytremetone ( 1 ), with the fungus Mucor plumbeus has been studied. Benzofurans in the tremetone series ( 1 , 1a , 2 - 5 , 18 , 18a ), the euparin series ( 6 , 7 , 7a , 8 - 10 , 14 , 16 ), and the eupachinin-type ( 11 , 12 ) were tested for antifeedant effects against the insect Spodoptera littoralis . The antifeedant compounds ( 1 , 4 , 6 , 11 , 12 ) were further tested for postingestive effects on S. littoralis larvae. The most antifeedant compounds were among the tremetone series, with 3-ethoxy-hydroxy-tremetone ( 4 ) being the strongest antifeedant. Glucosylation of 1 by its biotransformation with Mucor plumbeus gave inactive products. Among the euparin series, the dihydroxyangelate 14 was the most active, followed by euparin ( 6 ). The eupachinin-type compounds ( 11 , 12 ) were both antifeedants. Compounds 4, 11, and 12 showed antifeedant effects without postingestive toxicity to orally dosed S. littoralis larvae. Euparin ( 6) had postingestive toxicity that was enhanced by the synergist piperonyl butoxide.

The chemical composition of essential oils (EOs) from ten Peruvian Piper species (Piper coruscans, Pc; P. tuberculatum, Pt; P. casapiense, Pcs; P. obliquum, Po; P. dumosum, Pd; P. anonifolium, Pa; P. reticulatum, Pr; P. soledadense, Ps; P. sancti-felicis, Psf and P. mituense, Pm) has been studied, along with their antifungal and phytotoxic activities. These EOs contained β-bisabolene/nerolidol (Pc), β-bisabolene/δ-cadinene/caryophyllene (Pt), caryophyllene oxide (Pcs), bicyclogermacrene/10-epi-Elemol (Po), bicyclogermacrene/germacrene-D/apiol (Pd), caryophyllene/germacrene-D (Pa), germacrene-D (Pr), limonene/apiol (Ps), apiol (Psf), and apiol/bicyclogermacrene (Pm) as major components, and some are described here for the first time (Ps, Pcs, Pm). A composition-based dendrogram of these Piper species showed four major groups (G1: Pc and Pt, G2: Pcs, Po, Pd, Pa, and Pr, G3: Ps, and G4: Psf and Pm). The spore germination effects (Aspergillus niger, Botrytis cinerea, and Alternaria alternate) and phytotoxicity (Lolium perenne and Lactuca sativa) of these EOs were studied. Most of these Piper essential oils showed important activity against phytopathogenic fungi (except G1), especially against B. cinerea. Similarly, most of the essential oils were phytotoxic against L. perenne (except G1), with P. sancti-felicis (G4), P. casapiense (G2), and P. reticulatum (G2) being the most effective. Caryophyllene oxide, β-caryophyllene, β-pinene, limonene, α-humulene, and apiol were evaluated against B. cinerea, with the most effective compounds being β-pinene, apiol, and limonene. This work demonstrates the species-dependent potential of essential oils from Peruvian Piper species as fungicidal and herbicidal agents.

Ethnopharmacological Relevance: In the Peruvian Amazon as in the tropical countries of South America, the use of medicinal Piper species (cordoncillos) is common practice, particularly against symptoms of infection by protozoal parasites. However, there is few documented information about the practical aspects of their use and few scientific validation. The starting point of this work was a set of interviews of people living in six rural communities from the Peruvian Amazon (Alto Amazonas Province) about their uses of plants from Piper genus: one community of Amerindian native people (Shawi community) and five communities of mestizos. Infections caused by parasitic protozoa take a huge toll on public health in the Amazonian communities, who partly fight it using traditional remedies. Validation of these traditional practices contributes to public health care efficiency and may help to identify new antiprotozoal compounds., Aims of Study: To record and validate the use of medicinal Piper species by rural people of Alto Amazonas Province (Peru) and annotate active compounds using a correlation study and a data mining approach., Materials and Methods: Rural communities were interviewed about traditional medication against parasite infections with medicinal Piper species. Ethnopharmacological surveys were undertaken in five mestizo villages, namely: Nueva Arica, Shucushuyacu, Parinari, Lagunas and Esperanza, and one Shawi community (Balsapuerto village). All communities belong to the Alto Amazonas Province (Loreto region, Peru). Seventeen Piper species were collected according to their traditional use for the treatment of parasitic diseases, 35 extracts (leaves or leaves and stems) were tested in vitro on P. falciparum (3D7 chloroquine-sensitive strain and W2 chloroquine-resistant strain), Leishmania donovani LV9 strain and Trypanosoma brucei gambiense. Assessments were performed on HUVEC cells and RAW 264.7 macrophages. The annotation of active compounds was realized by metabolomic analysis and molecular networking approach., Results: Nine extracts were active (IC 50  ≤ 10 μg/mL) on 3D7 P. falciparum and only one on W2 P. falciparum, six on L. donovani (axenic and intramacrophagic amastigotes) and seven on Trypanosoma brucei gambiense. Only one extract was active on all three parasites (P. lineatum). After metabolomic analyses and annotation of compounds active on Leishmania, P. strigosum and P. pseudoarboreum were considered as potential sources of leishmanicidal compounds., Conclusions: This ethnopharmacological study and the associated in vitro bioassays corroborated the relevance of use of Piper species in the Amazonian traditional medicine, especially in Peru. A series of Piper species with few previously available phytochemical data have good antiprotozoal activity and could be a starting point for subsequent promising work. Metabolomic approach appears to be a smart, quick but still limited methodology to identify compounds with high probability of biological activity., (Copyright © 2020 Elsevier B.V. All rights reserved.)

From a bioactive methanolic extract of Senecio fistulosus , the antifeedant effects of the alkaloidal and non-alkaloidal fractions were tested against the insects Spodoptera littoralis , Myzus persicae and Rhopalosiphum padi , with the non-alkaloidal fraction being antifeedant. The phytochemical study of the non-alkaloidal fraction of S. fistulosus , resulted in the isolation of four compounds, two 9-oxo-furanoeremophilanes ( 1 , 2 ), an eremophilanolide, 1β,10β-epoxy-6-acetoxy-8α-hydroxy-eremofil-7(11)-en-8β,12-olide ( 3 ) and a maaliol derivative ( 4 ). The alkaloidal fraction yielded two known pyrrolizidine alkaloids ( 5 , 6 ). Compounds 1 , 3 and 4 are new natural products. Furanoeremophilane 2 was a strong antifeedant against S. littoralis and maaliane 4 inhibited the settling of M. persicae .

Nine eremophilane sesquiterpenes 1 - 9, two flavonoids 11 and 12, and two known pirrolizidine alkaloids 13 and 14, were isolated from Senecio adenotrichius DC. Their structures were elucidated on the basis of spectroscopic data and by comparison with previously reported spectroscopic data of similar compounds. Compounds 5, 7, and 9 have not been previously reported as natural products. The antifeedant activity of these compounds was tested against Spodoptera litoralis and Myzus persicae. Eremophilanes 1, 3, and 8 were strong antifeedants to M. persicae, and 1 and 8 to Spodoptera littoralis. Their ixodicidal activity was tested against the tick Hyalomma lusitanicum, with eremophilanes 1, 3, and 8, being strong ixodicidal agents., (© 2017 Wiley-VHCA AG, Zurich, Switzerland.)

Twenty-four compounds including eleven eremophilanolides (1-11), one eremophilane (13), five shikimic acid derivatives (14-18), six flavonoids (19-24), and the macrocyclic unsaturated pyrrolizidine alkaloid integerrimine (25) were isolated from Senecio kingii, an endemic species from the Magallanes Region (Chile). Compounds 3, 5, 6, 8-11 and 13-18 have not been previously reported as natural products. Their molecular structures were determined by NMR spectroscopic analysis and comparison with published NMR data. An X-ray-analysis of compound 3 has been performed. Their insecticidal and antifungal activities were tested, being compound 3 the strongest insect antifeedant. Compounds 6, 9 and 18 were moderate antifungals., (Published by Elsevier Ltd.)