Antioxidant, Anti-inflammatory, Antibacterial, and Analgesic Activities and Mechanisms of Quinolines, Indoles and Related Derivatives.

Quinoline, isoquinoline, and indoles are common heterocyclic compounds. They have many biological activities, such as antioxidant, anti-inflammatory, antibacterial, antitumor, anti-virus, anti-rheumatism, immunity regulation, expectorant, and analgesic. Over the past few centuries, traditional natural products have made great contributions to the discovery and development of new therapeutic agents. Many important drugs have been found from these three classes of compounds. In this mini-review, we mainly cover the research progress on antioxidant, anti-inflammatory, antibacterial, analgesic activities of quinoline, isoquinoline, and indole compounds over the past 20 years (2000- 2019). We aim to explore new characteristic groups or structures in the search for active lead compounds and provide a basis for rational drug design.

Biological evaluation of 2,3-dioxoindolin-N-phenylacetamide derivatives as potent CDC25B and PTP1B phosphatase inhibitors

A series of 2,3-dioxoindolin-N-phenylacetamide derivatives was evaluated for inhibitory activity against CDC25B and PTP1B enzymes. Most of the derivatives showed inhibitory activity against CDC25B (IC50 = 3.2-23.2 µg/mL) and PTP1B (IC50 = 2.9-21.4 µg/mL). Compound 2h showed the most inhibitory activity in vitro with IC50 values of 3.2 and 2.9 µg/mL against CDC25B and PTP1B, respectively, compared with the reference drugs Na3VO4 (IC50 = 2.7 µg/mL) and oleanolic acid (IC50 = 2.3 µg/mL). The results of selectivity experiments showed that the 2,3-dioxoindolin-N-phenylacetamide derivatives were selective inhibitors against CDC25B and PTP1B. Enzyme kinetic experiments demonstrated that compound 2h was a specific inhibitor with the typical characteristics of a mixed inhibitor. In cytotoxic activity assays compound 2h had potent activity against A549, HeLa, and HCT116 cell lines. In addition, compound 2h showed potent tumor inhibitory activity in a colo205 xenograft model in vivo.

Antidepressant-like effects and mechanisms of flavonoids and related analogues.

Flavonoids, possessing a basic phenylbenzopyrone core, are important components of the human diet, and are found in many medicinal plants. Flavonoids include chalcones, flavanones and their derivatives. Synthetic and natural isolated flavonoids display an enormous number of biological activities such as antitumor, antiplatelet, anti-malarial, anti-inflammatory, antidepressant and anticonvulsant properties. This review article focuses on the antidepressant-like effect, structure-activity relationship and mechanism of action of total flavonoid extracts isolation from natural sources, flavonoid compounds and their related analogues.

3,4-DHQLO and Triazole and Its Related Analogues with Anticonvulsant Effects.

The derivatives of quinolinone and triazole exhibit antitumor, antiplatelet, antidepressant, and anticonvulsant properties in diverse experimental systems. In the past decades, we have developed increasingly potent anticonvulsant agents by the structural modification of compounds derived from 3,4-DHQLO, triazole, and their analogs. Herein, we report the design and synthesis of a new series of 3,4-DHQLO and triazole and their derivatives; their anticonvulsant activity was evaluated. Moreover, we also reviewed the anticonvulsant activity of 3,4-DHQLO and triazole and their derivatives and new approaches.

New naphthopyrones from marine-derived fungus Aspergillus niger 2HL-M-8 and their in vitro antiproliferative activity.

A new cytotoxic dimeric naphthopyrone, aurasperone H (1), together with eight related known polyketides (2-9) was isolated from a marine-derived fungus Aspergillus niger 2HL-M-8. The structure of new compound 1 was elucidated on the basis of its spectroscopic data (1D, 2D NMR and CD). Compound 1 exhibited moderate inhibitory activity against the human lung adenocarcinoma A549 and the human leukaemia HL-60 cell lines. Compound 5 displayed significant in vitro antiproliferative activity against HL-60 cell line with an IC50 value of 0.8 µM.

Identification of Two Novel Compound Heterozygous PTPRQ Mutations Associated with Autosomal Recessive Hearing Loss in a Chinese Family.

Mutations in PTPRQ are associated with deafness in humans due to defects of stereocilia in hair cells. Using whole exome sequencing, we identified responsible gene of family 1572 with autosomal recessively non-syndromic hearing loss (ARNSHL). We also used DNA from 74 familial patients with ARNSHL and 656 ethnically matched control chromosomes to perform extended variant analysis. We identified two novel compound heterozygous missense mutations, c. 3125 A>G p.D1042G (maternal allele) and c.5981 A>G p.E1994G (paternal allele), in the PTPRQ gene, as the cause of recessively inherited sensorineural hearing loss in family 1572. Both variants co-segregated with hearing loss phenotype in family 1572, but were absent in 74 familial patients. Heterozygosity for c. 3125 A>G was identified in two samples from unaffected Chinese individuals (656 chromosomes). Therefore, the hearing loss in this family was caused by two novel compound heterozygous mutations in PTPRQ.

Turn-on phosphorescent chemodosimeter for Hg2+ based on a cyclometalated Ir(III) complex and its application in time-resolved luminescence assays and live cell imaging.

A novel "turn-on" phosphorescent chemodosimeter based on a cyclometalated Ir(III) complex has been designed and synthesized, which displays high selectivity and sensitivity toward Hg(2+) in aqueous media with a broad pH range of 4-10. Furthermore, by time-resolved photoluminescence techniques, some interferences from the short-lived background fluorescence can be eliminated effectively and the signal-to-noise ratio of the emission detection can be improved distinctly by using the chemodosimeter. Finally, the chemodosimeter can be used to monitor Hg(2+) effectively in living cells by confocal luminescence imaging.

2,4-Dihydroxychalcone derivatives as novel potent cell division cycle 25B phosphatase inhibitors and protein tyrosine phosphatase 1B inhibitors.

Eleven 2,4-dihydroxychalcone compounds were synthesized and identified as reversible and competitive cell division cycle 25 (CDC25) B and protein tyrosine phosphatase (PTP) 1B inhibitors with inhibition values in the micromolar range. The results showed that nine compounds significantly inhibited CDC25B phosphatase, whereas seven compounds inhibited the activity against PTP1B in vitro. Compound 8 had the greatest inhibition activity against CDC25B and PTP1B in vitro, with percentage inhibition values of 97.5% and 96.3% at a dose of 20 microg/mL, respectively. Cytotoxic activity assays revealed that compound 8 was the most potent against HCT116, HeLa, and A549 cells. Furthermore, compound 8 exhibited potent antitumor activity in a colo205 xenograft model.

Novel compound heterozygous mutations in the MYO15A gene in autosomal recessive hearing loss identified by whole-exome sequencing.

BACKGROUND: Inherited genetic defects play an important role in congenital hearing loss, contributing to about 60% of deafness occurring in infants. Hereditary nonsyndromic hearing loss is highly heterogeneous, and most patients with a presumed genetic etiology lack a specific molecular diagnosis. METHODS: By whole exome sequencing, we identified responsible gene of family 4794 with autosomal recessively nonsyndromic hearing loss (ARNSHL). We also used DNA from 56 Chinese familial patients with ARNSHL (autosomal recessive nonsyndromic hearing loss) and 108 ethnicity-matched negative samples to perform extended variants analysis. RESULTS: We identified MYO15A c.IVS25+3G>A and c.8375 T>C (p.V2792A) as the disease-causing mutations. Both mutations co-segregated with hearing loss in family 4794, but were absent in the 56 index patients and 108 ethnicity-matched controls. CONCLUSIONS: Our results demonstrated that the hearing loss of family 4794 was caused by novel compound heterozygous mutations in MYO15A.

Muscle hypertonia after permanent focal cerebral ischemia in rats: a qualitative and quantitative behavioral and electrophysiological study.

OBJECTIVES: To examine the level of peripheral muscle resistance after cerebral ischemia. METHODS: A total of 326 healthy male Sprague-Dawley rats were used in the present experiments. We used a modified method to establish peripheral muscle resistance in rat model of stroke, and qualified the recovery of motor functional deficits by behavioral measures and quantified the level of peripheral muscle resistance by electrophysiological test. RESULTS: Neurological score started to go up from day 0, achieved its peak on day 3 (1.49 ± 0.56) and kept at a high level within 10 days after surgery. Compared with 1 day before surgery, both the turn score in corner test and asymmetry score in cylinder test were increased significantly on day 3, day 6 and day 9 after surgery (p < 0.01). On day 6 and day 9 after surgery, the Hmax:Mmax ratio of hemiplegic side of middle cerebral artery occlusion (MCAO) rats was obviously higher than the same side in healthy rat (p < 0.01) and the ratio on the contralateral side of MCAO rats (p < 0.05). CONCLUSIONS: There is a progressive increase in peripheral muscle resistance on day 6 to day 9 after surgery in a rat model of postischemic stroke.

Protective effects of chalcone derivatives for acute liver injury in mice.

The hepatoprotective effects of chalcone derivatives were evaluated in D-galactosamine/lipopolysaccharide (D-GalN/LPS)-induced fulminant hepatic failure in mouse. Thirteen chalcone derivatives were synthesized for study and their hepatoprotective effects were evaluated by assessing aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in serum. Chalcone preparations were injected into mice at 12 h and 1 h before intraperitoneal injection of D-GalN/LPS. After abdominal administration, changes in AST and ALT between the control and treated groups were observed. Ten of the synthesized chalcone derivatives exhibited inhibitory effects on D-GalN/LPS-induced levels of AST and ALT in mice. Compounds 2, 3, 8, 9, and 12 markedly reduced serum AST and ALT at 8 h, inhibited hepatocyte necrosis and showed significant hepatoprotective activities. The activity of compound 3 was compared with the bifendate (DDB) through oral administration. Compound 3 showed much higher inhibitory effects than bifendate for decreasing AST and ALT activity. The results indicate that compound 3 has strong hepatoprotective activity through suppression of tumor necrosis factor-alpha (TNF-alpha) preduction, reduction of the histological change in the liver, and attenuated of hepatocyte apoptosis confirmed by DNA fragmentation assay.