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Kinases are a group of therapeutic targets involved in the progression of numerous diseases, including cancer, rheumatoid arthritis, Alzheimer's disease, and viral infections. The majority of approved antiviral agents are inhibitors of virusspecific targets that are encoded by individual viruses. These inhibitors are narrow-spectrum agents that can cause resistance development. Viruses are dependent on host cellular proteins, including kinases, for progression of their life-cycle. Thus, targeting kinases is an important therapeutic approach to discovering broadspectrum antiviral agents. As there are a large number of FDA approved kinase inhibitors for various indications, their repurposing for viral infections is an attractive and time-sparing strategy. Many kinase inhibitors, including baricitinib, ruxolitinib, imatinib, tofacitinib, pacritinib, zanubrutinib, and ibrutinib, are under clinical investigation for COVID-19. Herein, we discuss FDA approved kinase inhibitors, along with a repertoire of clinical/ preclinical stage kinase inhibitors that possess antiviral activity or are useful in the management of viral infections.

: Bryostatins are complex macrolactones isolated from marine organisms Bryozoan Bugula neritina. They are potent modulators of protein kinase C isozymes (PKCα: ki = 1.3-188 nM), and are one of the most extensively investigated marine natural products in clinical trials. Although ~21 natural bryostatins have been isolated, however only bryostatin-1 (1) has received much interest among medicinal chemists and clinicians. The structure-activity relationship of bryostatins has been well established, with the identification of key pharmacophoric features important for PKC modulation. The low natural abundance and the long synthetic route have prompted medicinal chemists to come-up with simplified analogs. Bryostatin skeleton comprises three pyran rings connected to each other to form a macrocyclic lactone. The simplest analog 27 contains only one pyran, which is also able to modulate the PKCα activity; however, the cyclic framework appears to be essential for the desired level of potency. Another simplified analog 17 ("picolog") exhibited potent and in-vivo efficacy against lymphoma. Bryostatin-1 (1) has shown an acceptable intravenous pharmacokinetic profile in mice and displayed promising in-vivo efficacy in mice models of various cancers and Alzheimer's disease. Bryostatin-1 was investigated in numerous Phase I/II oncology clinical trials; it has shown minimal effect as a single agent, however, provided encouraging results in combination with other chemotherapy agents. FDA has granted orphan drug status to bryostatin-1 in combination with paclitaxel for esophageal cancer. Bryostatin-1 has also received orphan drug status for fragile X syndrome. Bryostatin-1 was also investigated in clinical studies for Alzheimer's disease and HIV infection. In a nutshell, the natural as well as synthetic bryostatins have generated a strong hope to emerge as treatment for cancer along with many other diseases.

The complex and multifaceted nature of Alzheimer’s disease has brought about a pressing demand to develop ligands targeting multiple pathways to combat its outrageous prevalence. Embelin is a major secondary metabolite of Embelia ribes Burm f., one of the oldest herbs in Indian traditional medicine. It is a micromolar inhibitor of cholinesterases (ChEs) and β-site amyloid precursor protein cleaving enzyme 1 (BACE-1) with poor absorption, distribution, metabolism, and excretion (ADME) properties. Herein, we synthesize a series of embelin–aryl/alkyl amine hybrids to improve its physicochemical properties and therapeutic potency against targeted enzymes. The most active derivative, 9j (SB-1448), inhibits human acetylcholinesterase (hAChE), human butyrylcholinesterase (hBChE), and human BACE-1 (hBACE-1) with IC50 values of 0.15, 1.6, and 0.6 μM, respectively. It inhibits both ChEs noncompetitively with k i values of 0.21 and 1.3 μM, respectively. It is orally bioavailable, crosses blood–brain barrier (BBB), inhibits Aβ self-aggregation, possesses good ADME properties, and protects neuronal cells from scopolamine-induced cell death. The oral administration of 9j at 30 mg/kg attenuates the scopolamine-induced cognitive impairments in C57BL/6J mice.

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Berberrubine is a naturally occurring isoquinoline alkaloid and a bioactive metabolite of berberine. Berberine exhibits a wide range of pharmacological activities, including cholinesterase inhibition. The cholinesterase inhibitors provide symptomatic treatment for Alzheimer's disease; however, multitarget-directed ligands have the potential as disease-modifying therapeutics. Herein, we prepared a series of C9-substituted berberrubine derivatives intending to discover dual cholinesterase and beta-site amyloid-precursor protein cleaving enzyme 1 (BACE-1) inhibitors. Most synthesized derivatives possessed balanced dual inhibition (AChE and BChE) activity in the submicromolar range and a moderate inhibition against BACE-1. Two most active ester derivatives, 12a and 11d, display inhibition of AChE, BChE, and BACE-1. The 3-methoxybenzoyl ester derivative, 12a, inhibits electric eel acetylcholinesterase (EeAChE), equine serum butyrylcholinesterase (eqBChE), and human hBACE-1 with IC 50 values of 0.5, 4.3, and 11.9 μM, respectively and excellent BBB permeability (P e = 8 × 10 −6 cm/s). The ester derivative 12a is metabolically unstable; however, its ether analog 13 is stable in HLM and exhibits inhibition of AChE, BChE, and BACE-1 with IC 50 values of 0.44, 3.8, and 17.9 μM, respectively. The ether analog also inhibits self-aggregation of Aβ and crosses BBB (P e = 7.3 × 10 −6 cm/s). Administration of 13 at 5 mg/kg (iv) in Wistar rats showed excellent plasma exposure with AUC 0−∞ of 28,834 ng min/ml.In conclusion, the multitargeted berberrubine ether derivative 13 is CNS permeable and has good ADME properties.

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Background The genus Lycium is commercially known for its nutrient dense goji-berries, among these berries, black goji-berries obtained from Lycium ruthenicum Murr are highly valued and widely used as traditional medicine in trans-himalayan cold desert Ladakh and as functional food in several countries. Methods The current collection of data and literature was done by exploring different scientific portals like SciFinder, Google scholar, PubMed, Dictonary of Natural Products, Institute for Scientific Information, Web of Science and Scopus by searching keywords like black goji berry, crystal pearl, and trans-Himalayan plant. Results Fruits of L. ruthenicum Murr, are overwhelmingly enriched in anthocyanins, proanthocyanidins, polysaccharides, spermine and spermidine alkaloids. The presence of these bioactive phyto-chemicals has been linked with reported anti-diabetic, anti-inflammatory, anti-fatigue, anti-atherosclerosis and neuro-protective properties of black goji berries. A unique color of these berries makes them exceptional as compared to other berries. Conclusions In this article, we have reviewed the variety of high value phytochemicals of Lycium ruthenicum Murr, with a special focus on health promoting anthocyanins which will provide an insight to the readers for exploring novel applications of L. ruthenicum Murr in field of medicine and food industries.