Quinoline, which consists of benzene fused with N -heterocyclic pyridine, has received considerable attention as a core template in drug design because of its broad spectrum of bioactivity. This review aims to present the recent advances in chemistry, medicinal potential and pharmacological applications of quinoline motifs to unveil their substantial efficacies for future drug development. Essential information in all the current and available literature used was accessed and retrieved using different search engines and databases, including Scopus, ISI Web of Knowledge, Google and PUBMED. Numerous derivatives of the bioactive quinolines have been harnessed via expeditious synthetic approaches, as highlighted herein. This review reveals that quinoline is an indisputable pharmacophore due to its tremendous benefits in medicinal chemistry research and other valuable areas of human endeavour. The recent in vivo and in vitro screening reported by scientists is highlighted herein, which may pave the way for novel drug development. Owing to the array of information available and highlighted herein on the medicinal potential of quinoline and its functionalized derivatives, a new window of opportunity may be opened to medicinal chemists to access more biomolecular quinolines for future drug development.

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Cortex Dictamni is a commonly-used traditional Chinese herbal medicine for the treatment of skin inflammation, tinea, and eczema. Recently, some studies reported that Cortex Dictamni might induce liver injury, suggesting more attention to its safety. The current study was designed to investigate subchronic toxicity of Cortex Dictamni aqueous extract (CDAE) and ethanol extract (CDEE) in mice and the potential hepatotoxicity mechanisms in vitro. Firstly, CDAE or CDEE groups were administrated with varying dosages (2.3, 4.6, or 9.2 g/kg/day, p.o.) in mice for 28 days in subchronic toxicity studies. General clinical signs and biochemical parameters were examined, and morphological analyses were conducted. Secondly, we identified the different constituents of CDAE and CDEE using HPLC-MS/MS and chose major components for further study. In order to determine the toxic components, we investigated the cytotoxicity of extracts and chosen components using CCK-8 assay in HepG2 cells. Furthermore, we explored the possible hepatotoxicity mechanisms of Cortex Dictamni using a high content analysis (HCA). The results showed that no significant differences of general clinical signs were observed in mice. Aspartate alanine aminotransferase (ALT) and aminotransferase (AST) were significantly increased in the high-dose CDAE and CDEE groups compared to the control group. Meanwhile, the absolute and relative liver weights and liver/brain ratio were significantly elevated, and histological examination of liver demonstrated cellular enlargement or nuclear shrinkage. In UPLC analysis, we compared the chemical constituents between CDAE and CDEE, and chose dictamnine, obakunone, and fraxinellone for hepatotoxicity evaluation in the in vitro studies. In the CCK-8 assay, CDAE, CDEE, dictamnine, obakunone, and fraxinellone decreased the cell viability in a dose-dependent manner after treatment for 48 h. Furthermore, the cell number decreased, while the nuclear intensity, cell membrane permeability, and concentration of reactive oxygen species were shown to increase, meanwhile, mitochondrial membrane potential was also changed in HepG2 cells following 48 h of compounds treatment using HCA. Our studies suggested that CDAE and CDEE have potential hepatotoxicity, and that the alcohol extraction process could increase toxicity. Dictamnine, obakunone, and fraxinellone may be the possible toxic components in Cortex Dictamni with dictamnine as the most potentially hepatotoxic component, whose potential hepatotoxicity mechanism may be associated with cell apoptosis. Moreover, this study could provide valuable data for clinical drug safety research of Cortex Dictamni and a good example for safety study of other Chinese herbal medicines.

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To follow-up on our prior Part I review, this Part II review summarizes and provides updated literature on novel quinoline and quinazoline alkaloids isolated during the period of 2009-2016, together with the biological activity and the mechanisms of action of these classes of natural products. Over 200 molecules with a broad range of biological activities, including antitumor, antiparasitic and insecticidal, antibacterial and antifungal, cardioprotective, antiviral, anti-inflammatory, hepatoprotective, antioxidant, anti-asthma, antitussive, and other activities, are discussed. This survey should provide new clues or possibilities for the discovery of new and better drugs from the original naturally occurring quinoline and quinazoline alkaloids.

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Citrus limonoids (CLs) are a group of highly oxygenated terpenoid secondary metabolites found mostly in the seeds, fruits and peel tissues of citrus fruits such as lemons, limes, oranges, pumellos, grapefruits, bergamots, and mandarins. Represented by limonin, the aglycones and glycosides of CLs have shown to display numerous pharmacological activities including anticancer, antimicrobial, antioxidant, antidiabetic and insecticidal among others. In this review, the chemistry and pharmacology of CLs are systematically scrutinised through the use of medicinal chemistry tools and structure-activity relationship approach. Synthetic derivatives and other structurally-related limonoids from other sources are include in the analysis. With the focus on literature in the past decade, the chemical classification of CLs, their physico-chemical properties as drugs, their biosynthesis and enzymatic modifications, possible ways of enhancing their biological activities through structural modifications, their ligand efficiency metrics and systematic graphical radar plot analysis to assess their developability as drugs are among those discussed in detail.

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Ethnopharmacological relevance Seven species from the genus Dictamnus are distributed throughout Europe and North Asia and only two species grow in China. One is Dictamnus dasycarpus Turcz., which could be found in many areas of China and has been recorded in Chinese Pharmacopoeia. The other is Dictamnus angustifolius G. Don ex Sweet, which is only present in Xinjiang province and has been used as an alternative for Dictamnus dasycarpus in the local for the treatment of rheumatism, bleeding, itching, jaundice, chronic hepatitis and skin diseases. The present paper reviewed the traditional uses, phytochemistry, pharmacology and toxicology of the genus Dictamnus. Materials and methods Information on the Dictamnus species was collected from classic books about Chinese herbal medicine and globally accepted scientific databases including PubMed, Elsevier, ASC, Scopus, Google Scholar, Web of Science, CNKI and others. Results About 170 chemical compounds, which include quinoline alkaloids, limonoids, sesquiterpenes, coumarins, flavonoids and steroids, have been isolated from the genus Dictamnus. The characteristic and active constituents of Dictamnus species are considered to be quinoline alkaloids and limonoids, which exhibited a broad spectrum of biological activities such as anti-cancer, anti-inflammation, anti-microbe, anti-platelet-aggregation, vascular-relaxation, anti-insect, anti-HIV, anti-allergy and neuroprotection. Moreover, quinoline alkaloids and limonoids could be used as quality control markers to distinguish different species from the genus Dictamnus. However, there were also some reports on the toxic hepatitis and phototoxic effect of Dictamnus species, and the related research needs to be further studied. Conclusion In this review, we summarized the chemical constituents, pharmacology, quality control and toxicology of the species from genus Dictamnus. Phytochemical investigations indicated that quinoline alkaloids and limonoids were the major bioactive components with potential cytotoxic, neuroprotective, anti-inflammatory, antimicrobial, anti-platelet-aggregation and vascular relaxing activities. These two kinds of compounds have attracted great interests in the past few years and may have great potential to be new drug lead compounds.

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