To obtain a multipotent framework that can target simultaneously COX-2, 5-LOX, acetylcholinesterase (AChE), and butyrylcholinesterase (BChE) to treat neuroinflammation, a series of derivatives containing pyrimidine and pyrrolidine cores were rationally synthesized and evaluated. Pyrazoline–pyrimidine hybrid (23g), (3-acetylcoumarin derivative of pyrrolidin-1-yl)­benzenesulfonamide (27), and tacrine derivatives of (pyrrolidin-1-yl)­benzenesulfonamide (31, 38) displayed excellent in vitro COX-2 inhibition having IC50 value in the nanomolar range. Tacrine–pyrrolidine hybrids 36 and 38, and tacrine–pyrimidine hybrid (46) emerged as the most potent eeAChE inhibitors with IC50 values of 23, 16, and 2 nM, respectively. However, compounds 27, 31, and 38 possessed excellent simultaneous and balanced inhibitory activity against all of the four tested targets and thus emerged as optimal multipotent hybrid compounds among all of the synthesized series of the compounds. In the ex vivo, transgenic animal models treated with compounds 36 and 46 displayed a significant decline in both AChE and BChE potentials in the hippocampus and cortical tissues. In anti-inflammatory activities, animals treated with compounds 36 and 46 displayed a significant % inhibition of edema induced by carrageenan and arachidonic acid. Biochemical analysis and histopathological examination of mice liver indicate that tacrine derivatives are devoid of hepatotoxicity and neurotoxicity against SH-SY5Y neuroblastoma cell lines. In vivo acute toxicity study showed the safety of synthesized compounds up to 1000 mg/kg dose. The inhibitory manner of interaction of these potent drugs on all of the studied in vitro targets was confirmed by molecular docking investigations.

Objectives The recent viral pandemic poses a unique challenge for healthcare providers. Despite the remarkable progress, the number of novel antiviral agents in the pipeline is woefully inadequate against the evolving virulence and drug resistance of current viruses. This highlights the urgent need for new and improved vaccines, diagnostics and therapeutic agents to obviate the viral pandemic. Key findings Benzothiazole plays a pivotal role in the design and development of antiviral drugs. This is evident from the fact that it comprises many clinically useful agents. The current review is aimed to provide an insight into the recent development of benzothiazole-based antiviral agents, with a special focus on their structure-activity relationships and lead optimisation. One hundred and five articles were initially identified, and from these studies, 64 potential novel lead molecules and main findings were highlighted in this review. Summary We hope this review will provide a logical perspective on the importance of improving the future designs of novel broad-spectrum benzothiazolebased antiviral agents to be used against emerging viral diseases. Benzothiazoles as antiviral agents Yahya I. Asiri et al.

Over the past two decades, there has been a notable rise in the use of antipsychotic drugs, as they are used to treat an increasing number of neuropsychiatric disorders. This rise has been led predominantly by greater use of the second generation antipsychotic (SGA) drugs, which have a low incidence of neurological side-effects. However, many SGAs cause metabolic dysregulation, including glucose intolerance and insulin resistance, thus increasing the risk of cardiometabolic disorders. The metabolic effects of the novel SGA lurasidone, which was approved by the Food and Drug Administration in 2010, remain largely unknown. As rodent models accurately predict the metabolic effects of SGAs in humans, the aim of the present study was to use sophisticated animal models of glucose tolerance and insulin resistance to measure the metabolic effects of lurasidone. In parallel, we compared the SGA olanzapine, which has established metabolic effects. Adult female rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (10.0 mg/kg, s.c.) and subjected to the glucose tolerance test (GTT). Separate groups of rats were treated with vehicle, lurasidone (0.2, 0.8 or 2.0 mg/kg, s.c.) or olanzapine (1.5 and 15 mg/kg, s.c.) and tested for insulin resistance with the hyperinsulinemic-euglycemic clamp (HIEC). Compared to vehicle treated animals, lurasidone caused mild glucose intolerance in the GTT with a single dose, but there was no effect on insulin resistance in the GTT, measured by HOMA-IR. The HIEC also confirmed no effect of lurasidone on insulin resistance. In contrast, olanzapine demonstrated dose-dependent and potent glucose intolerance, and insulin resistance in both tests. Thus, in preclinical models, lurasidone demonstrates mild metabolic liability compared to existing SGAs such as olanzapine. However, confirmation of these effects in humans with equivalent tests should be confirmed.

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Background. Pyrazoles are an interesting class of compounds showing potent anticancer activities. Our previous studies have demonstrated the potent anticancer activity of pyrazole analogues. Therefore, we focused on developing anticancer agents through structure optimization of the pyrazolyl lead molecule. Methods. The pyrazole derivatives were prepared by the appropriate synthetic protocols. The antiproliferative activities were evaluated using a sulforhodamine B assay against three cancer cell lines. In vitro and in silico molecular docking studies employing xanthine oxidase were used to explore the mechanism by which pyrazole derivatives exert anticancer effects. Results. One of the pyrazole derivatives demonstrated the greatest promise as an anticancer agent against the human colon cancer cell line (IC50 4.2 μM), with a potent xanthine oxidase inhibitory activity (IC50 0.83 μM). Conclusion. In summary, our findings suggest that these pyrazolyl analogues containing a pyridine nucleus could serve as a promising lead molecule in the development of novel anticancer agents.