Zhi Xu's research while affiliated with Nanjing University of Traditional Chinese Medicine and other places

A series of ester tethered dihydroartemisinin-3-(oxime/thiosemicarbazide)isatin hybrids 7a-p were designed, synthesized, and assessed for their antiproliferative activity against MCF-7, MDA-MB-231, MCF-7/ADR, and MDA-MB-231/ADR breast cancer cell lines. Among them, hybrids 7a,f (IC50 : 1.33-3.84 µM) showed potent activity against triple-negative (MDA-MB-231 and MDA-MB-231/ADR) breast cancer cell lines, and hybrid 7f (IC50 : 3.90 and 10.18 µM) also demonstrated promising activity against estrogen receptor-positive breast cancer cells (MCF-7 and MCF-7/ADR), and the activity was superior to these of artemisinin, dihydroartemisinin, and ADR, revealing their potential to fight against both drug-sensitive and drug-resistant breast cancers. The enriched structure-activity relationships may facilitate further design of more active candidates.

A series of novel pentanoate tethered artemisinin‐isatin hybrids 6 a–d and 7 a–m were synthesized and evaluated their activity against CCRF‐CEM, K562 and K562/ADR leukemia cell lines as well as normal human peripheral blood mononuclear cells (PBMCs) by MTT assay. In particular, hybrid 7 b (IC50: 2.30 and 2.77 μM) exhibited highest activity against CCRF‐CEM and K562 cells, and the activity was not inferior to these of adriamycin (IC50: 4.89 μM) and vorinostat (IC50: 3.83 μM) against K562 cells, whereas hybrid 7 g (IC50: 0.62 μM) was more potent than adriamycin (IC50: 4.89 μM) and vorinostat (IC50: 3.83 μM) against K562/ADR cells. Moreover, the two hybrids (IC50: >100 μM) displayed non‐cytotoxicity towards normal PBMCs cells, and the selectivity index values were >11.02, indicating their excellent selectivity and safety profiles. Thus, hybrids 7 b and 7 g could act as potential anti‐leukemic candidates and were worthy of further preclinical evaluations.

1,2,3-Triazole moiety which is usually constructed by highly versatile, efficacious and selective copper-catalyzed azide-alkyne cycloaddition not only can act as a linker to connect different pharmacophores, but also is a useful pharmacophore with diverse biological properties. 1,2,3-Triazoles are readily interact with diverse enzymes and receptors in cancer cells through non-covalent interactions and can inhibit cancer cell proliferation, arrest cell cycle and induce apoptosis. In particular, 1,2,3-triazole-containing hybrids have the potential to exert dual or multiple anticancer mechanisms of action, representing useful scaffolds in expediting development of novel anticancer agents. The current review summarizes the in vivo anticancer efficacy and mechanisms of action of 1,2,3-triazole-containing hybrids reported in the last decade to continuously open up a map for the remarkable exploration of more effective candidates.

Fifteen novel butyric ester tethered dihydroartemisinin-isatin hybrids 4a-d and 5a-k were designed, synthesized, and evaluated for cytotoxicity against four human breast cancer cell lines, including MCF-7, MDA-MB-231, MCF-7/ADR and MDA-MB-231/ADR using the MTT method. A significant part of them were active against the four tested cancer cell lines, and the representative hybrid 5b (IC50: 1.27 µM) was 14.88 -> 78.74 times more active than adriamycin (IC50: 18.90 µM), DHA (IC50: 28.28 µM) and ART (IC50: > 100 µM) against MCF-7 breast cancer cells, whereas hybrid 5c (IC50: 2.39 and 3.95 µM) was superior to adriamycin (IC50: 3.38 and >100 µM), DHA (IC50: 48.80 and 82.78 µM) and ART (IC50: >100 and >100 µM) against MDA-MB-231 and MDA-MB-231/ADR breast cancer cell lines. Moreover, the selected hybrids (IC50: >100 µM) displayed non-cytotoxicity towards normal MCF-10A breast cells, and the SI values of hybrids 5b,c were >78.74 and >41.84 respectively, demonstrating their excellent selectivity and safety profiles. Accordingly, hybrids 5b,c could serve as promising anti-breast cancer candidates and deserved further preclinical evaluations.

A series of novel amyl ester tethered dihydroartemisinin‐isatin hybrids 4a‐d and 5a‐h were designed, synthesized, and evaluated as anti‐breast cancer agents. The synthesized hybrids were preliminarily screened against estrogen receptor‐positive (MCF‐7 and MCF‐7/ADR) and triple‐negative (MDA‐MB‐231 and) breast cancer cell lines. Three hybrids 4a,d and 5e not only were more potent than artemisinin and adriamycin against drug‐resistant MCF‐7/ADR and MDA‐MB‐231/ADR breast cancer cell lines, but also displayed non‐cytotoxicity towards normal MCF‐10A breast cells, and the SI values were >4.15, indicating their excellent selectivity and safety profiles. Thus, hybrids 4a,d and 5e could act as potential anti‐breast cancer candidates and were worthy of further preclinical evaluations. Moreover, the structure‐activity relationships which may facilitate further rational design of more effective candidates were also enriched.

In the present work, we reported the design, synthesis, and in vitro cytotoxicity evaluation of novel dihydroartemisinin-isatin hybrids tethered via different length of esters against MCF-7, MDA-MB-231, MCF-7/ADR and MDA-MB-231/ADR breast cancer cell lines. The preliminary results showed that the majority of the hybrids exhibited good anti-breast cancer cell activity. In particular, hybrids 7 g and 7n not only were more potent than ART, DHA and ADR against the four tested breast cancer cell lines, but also were non-toxic towards normal MCF-10A breast cells. The selectivity index values of hybrids 7 g and 7n were > 12.83 and > 25.97 respectively, revealing their excellent safety and selectivity profiles. The drug-resistant index values of hybrids 7 g and 7n were in a range of 0.33 to 1.12, implying that these hybrids had the potential to overcome drug resistance. Accordingly, hybrids 7 g and 7n could be considered as potential lead molecules for the development of novel anti-breast cancer agents with minimal untoward events to normal human cells. The structure-activity relationships indicated that the length of ester likner between DHA and isatin as well as substituents at C-3 and C-5 positions of isatin moiety had great impact on the activity.

Cancer is one of the leading causes of death across the world, and the prevalence and mortality rates of cancer will continue to grow. Chemotherapeutics play a critical role in cancer therapy, but drug resistance and side effects are major hurdles to effective treatment, evoking an immediate need for the discovery of new anticancer agents. Triazines including 1,2,3‐, 1,2,4‐, and 1,3,5‐triazine have occupied a propitious place in drug design and development due to their excellent pharmacological profiles. Mechanistically, triazine derivatives could interfere with various signaling pathways to induce cancer cell death. Hence, triazine derivatives possess potential in vitro and in vivo efficacy against diverse cancers. In particular, triazine hybrids are able to overcome drug resistance and reduce side effects. Moreover, several triazine hybrids such as brivanib (indole‐containing pyrrolo[2,1‐f][1,2,4]triazine), gedatolisib (1,3,5‐triazine‐urea hybrid), and enasidenib (1,3,5‐triazine‐pyridine hybrid) have already been available in the market. Accordingly, triazine hybrids are useful scaffolds for the discovery of novel anticancer chemotherapeutics. This review focuses on the anticancer activity of 1,2,3‐, 1,2,4‐, and 1,3,5‐triazine hybrids, together with the structure–activity relationships and mechanisms of action developed from 2017 to the present. The enriched structure–activity relationships may be useful for further rational drug development of triazine hybrids as potential clinical candidates. This review provides the recent developments (2017–present) in triazine hybrids with anticancer potential. The structure–activity relationships as well as mechanisms of action are also discussed to facilitate the further rational design of more effective candidates.

Gram-positive and Gram-negative pathogens are able to evade the host immune system, persist within the human host, and lead to severe disease and even death. At present, bacterial infections are one of the leading causes of morbidity and mortality across the world. Development of novel antibacterial agents still represents a challenging endeavor, which is mainly attributed to the continuous emergence of more virulent and drug-resistant pathogens. Benzofuran constitutes the core of diverse pharmacologically active compounds, and there are a variety of approved benzofuran-based drugs in the market or currently going through different clinical phases or registration statuses. Benzofurans could exert antibacterial activity through various mechanisms and possess pronounced activity, so benzofuran is a useful skeleton for the discovery of novel antibacterial agents. This review focuses on the recent advancement of naturally occurring benzofuran derivatives and hybrids of benzofurans with other pharmacophores as antibacterial agents, covering articles published between January 2015 and July 2021. The chemical structures and structure-activity relationships are also discussed.

Methicillin-resistant Staphylococcus aureus (MRSA) has developed numerous mechanisms of virulence and strategies to evade the human immune system, and it can be transmitted between humans, animals, and the environment. Thus, MRSA is an important cause of morbidity and mortality in both hospitals and in the community, creating an urgent demand for the development of novel anti-MRSA candidates. The 1,2,4-triazole nucleus is a bioisostere of amide, ester, and carboxylic acid, and the 1,2,4-triazole ring is found in many compounds with diverse biological effects. 1,2,4-Triazole derivatives could exert their antibacterial activity through inhibition of efflux pumps, filamentous temperature-sensitive protein Z, penicillin-binding protein, DNA gyrase, and topoisomerase IV, and they play an important role in the discovery of novel antibacterial agents. Among them, 1,2,4-triazole hybrids, which have the potential to exert dual/multiple mechanisms of action, possess a promising broad-spectrum antibacterial activity against a panel of clinically important drug-resistant pathogens including MRSA. This review outlines the recent developments of 1,2,4-triazole hybrids with a potential anti-MRSA activity, covering articles published between 2010 and 2020. The mechanisms of action, critical aspects of their design, and structure-activity relationships are also discussed.

Cancer which has been cursed for human beings for long time is considered as one of the leading causes of morbidity and mortality across the world. In spite of different types of treatments available, chemotherapy is still deemed as a favored treatment for the cancer. Unfortunately, many currently accessible anticancer agents have developed multidrug resistance along with fatal adverse effects. Therefore, intensive efforts have been made to seek for new active drugs with improved anticancer efficacy and reduced adverse effects. In recent years, the emergence of heterocyclic ring-containing anticancer agents has gained a great deal of attention among medicinal chemists. 1,3-Oxazole is a versatile heterocyclic compound, and its derivatives possess broad-spectrum pharmacological properties including anticancer activity against both drug-susceptible, drug-resistant and even multidrug-resistant cancer cell lines through multiple mechanisms. Thus, the 1,3- oxazole moiety is a useful template for the development of novel anticancer agents. This review will provide a comprehensive overview of the recent advances on 1,3-oxazole derivatives with potential therapeutic applications as anticancer agents, focus on the chemical structures, anticancer activity, and mechanisms of action.