Competition and Change

Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has gained significant public health attention owing to its devastating effects on lives and livelihoods worldwide. Due to difficult access to vaccines in many developing countries and the inefficiency of vaccines in providing complete protection even with fully vaccinated persons, there remains the need for the development of novel drugs to combat the disease. This study describes the in vitro activity of a library of fifty-five spiro-fused tetrahydroisoquinoline–oxindole hybrids (spirooxindoles) as potential blocking agents of the interaction between the SARS-CoV-2 viral spike and the human angiotensin-converting enzyme 2 (ACE2) receptor, essential for viral transmission. The synthesis was conducted by the Pictet-Spengler condensation of phenethylamine and isatin derivatives, while the screening against spike-ACE2 interaction was done using our previously described AlphaScreen fluorescent assay. The in vitro screening identified compound (11j) as the most active, showing a 50% inhibitory concentration (IC50) of 3.6 μM against SARS-CoV-2 spike/ACE2 interaction. Structure-activity relationships explained via molecular docking studies and the computation of binding free energy of each compound with respect to the spike/ACE2 protein-protein interaction showed that the most active compound possesses a bulky naphthyl group, which addresses voluminous hydrophobic regions of the ACE2 binding site and interacts with the hydrophobic residues of the target. Therefore, these compounds could be potentially useful in searching for SARS-CoV-2 spike/ACE2 interaction blocking agents.

OfChtI and OfChi-h are ideal targets for developing agricultural inhibitors against Ostrinia furnacalis. In order to further confirm the importance of conjugated systems in rhodanine derivatives, sixteen novel 1,4-benzodioxane-tethered-rhodanine derivatives were designed and synthesized with or without C=C double bond of 5-alkenyl rhodanine skeleton. Among them, compounds 3a–3h, with preserved 5-alkenyl rhodanine skeleton, all exhibited much better inhibitory activities against both OfChtI and OfChi-h, compared to that of the corresponding reduced compounds 4a–4h without its C=C double bond. The inhibitory mechanism demonstrated that the 5-alkenyl rhodanine conjugated plane was conducive to improving the binding affinity with both two chitinases. Compound 3g was identified as the most potential dual-chitinases inhibitor against OfChtI (Ki = 2.57 μM) and OfChi-h (Ki = 2.03 μM). The bioassay study also indicated that compound 3g displayed the best insecticidal activity against O. furnacalis and distinctive sublethal effect in regulating its growth and development. These 1,4-benzodioxane-tethered-rhodanine derivatives deserved further investigation as novel dual-chitinases inhibitor candidates in the control of O. furnacalis.

An α-C–H oxygenation of amides using Togni reagent II and an umpolung strategy is reported. α-Benzoyloxy amides were prepared in moderate-to-high yields from tertiary amides under mild and catalyst-free reaction conditions. All reagents are commercially available, easy to use, and compatible with various functional groups and rings. α-Benzoyloxy amides could be easily transformed into the corresponding α-hydroxy amides in almost quantitative yields. This transformation has significant potential for the synthesis of important compounds in pharmaceutical and agricultural fields.

A series of tetrahydrobenzo[cd]indole derivatives was synthesized by condensation of a fungal metabolite hyphodermin A, a naphtho[1,2-c]furan-3,9-dione derivative, and various anilines in methanol. Using this approach, ten analogs (3a–3j) were synthesized and tested as inhibitors against glycogen phosphorylase (GP). While compounds 3e and 3i bearing hydrophobic bromo and trifluoromethyl groups showed moderated inhibition (Ki = 32.3–57.4 μΜ), compound 3g with hydroxy group had the most potent activity with a Ki value of 7.9 ± 0.7 μΜ against human liver GPa. An X-ray crystallography study of the rabbit muscle GPb-3g complexes revealed that this inhibitor binds at a subsite within the indole binding site of GP which has not been previously observed to bind ligands.

The use of natural plants as powerful sources for the treatment of chronic illnesses has drawn more attention from researchers to herbal remedies. Silybum marianum, a naturally occurring plant, is the source of silymarin, a flavonolignan which is used to guard against a range of illnesses in both clinical and experimental contexts. Silymarin is easily absorbed and metabolised in phases I and II, according to its pharmacokinetics. Phase II is the site of its conjugation, and it is finally excreted in bile and urine. In a variety of tissues, the primary active components, silymarin and silibinin, provide protection against cancer. Silibinin has been shown to have anti-inflammatory, anti-angiogenic, antioxidant, and anti-metastatic properties. This further helps to block many oncogenic pathways from being activated such as NF-κB, Wnt/β-catenin, PI3K/Akt, and MAPK pathways. Hence, silibinin helps in preventing proliferation of the tumor cells, initiating the cell cycle arrest, and induce cancer cells to die. This review gives the thorough analysis of silibinin in distinct types of cancer such as lung, liver, breast, bladder, prostate, skin and ovarian cancer.

Trypanosomiasis, which is brought on by trypanosome parasites, is still a serious but often ignored health issue, especially in nations with limited resources. It is necessary to create novel, safe, effective, and alternative anti-trypanosomal chemical substances because current treatments have significant adverse reactions, low potency, high levels of toxicity, and drug resistance. Drug regimens that constitute the fundamental basis of contemporary pharmacological therapy have been largely derived from substances that are natural. Plants are mainly revered as ancient medicines worldwide and have contributed to the development of important pharmaceuticals for widespread medical conditions. An innovative approach for obtaining a reliable and potentially rich source of treatment against a variety of infectious diseases has been demonstrated by plant-focused research. This review discusses various phytoconstituents that have been utilized in the treatment of trypanosomiasis. Various recent and earlier studies that have investigated the in-vitro or in-vivo potential of medicinal plants for anti-trypanosomal properties have been discussed. The presence of bioactive plant-based compounds like quinones, flavonoids, phenols, etc., in the essential oils and unrefined extracts of various medicinal herbs, is part of a significant approach associated with the development of novel therapeutics. These substances have been found to be a reliable source of medicinal substances to aid in the treatment of trypanosomiasis. This review emphasizes the use of various plants with their phytoconstituents as an avenue of novel and potent medications against Trypanosomiasis. It discusses various studies of trypanocidal properties of alkaloids, essential oils, phenols, flavonoids, etc., that have been widely utilized against Trypanosoma. The results from both in vitro and in vivo studies demonstrate these natural compounds’ potential as therapeutics for the management of Trypanosoma infections.

Three series of (dimethyl-, dibutyl-, and diphenyl-) new organotin(IV) complexes based on chlorine substituted aryl ligands were synthesized and characterized by UV, 1H NMR, 13C NMR, 119 Sn NMR, HRMS, and X-ray crystallography analysis. MTT results showed that chlorine substitution at different positions on the aryl group exhibited different anticancer activities. Among them, 5-chloro substituents > 3,5-dichloro substituents > 3-chloro substituents on the aryl ring of salicylaldehyde on Schiff base ligand. In addition, different substituents on the tin atom also demonstrated extreme differences in anticancer activities, where dibutyltin > diphenyltin > dimethyltin. Interestingly, the complex LTDB2 exhibited excellent anti-proliferative activity against breast cancer MDA-MB-231 cells (superior to cisplatin) and lower toxicity against human embryonic kidney HEK-293 cells in vitro. Flow cytometry showed that LTDB2 not only induced apoptosis, but also induced cell cycle arrest in G2 phase. These findings provide new insights for further research and development of novel organotin(IV) complexes as anticancer drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly prescribed for pyrexia, dysmenorrhea, operative pain, and arthritic pain due to their analgesic, antipyretic, and anti-inflammatory properties. A recent investigation indicates that NSAIDs may possess prophylactic properties against mammary tumor. Their anti-neoplastic potential is associated with chronic inflammation in the development of tumors. NSAIDs exhibit anti-breast cancer activity potentially by targeting COX-2, an enzyme overexpressed in many solid tumors, or by altering several pathways, including NF-κB, JAK-STAT, MAPK, PI3K/Akt, mTOR, Wnt/β-catenin, and CREB, involved in cell cycle regulation, development, and progression of the tumor. In addition, NSAIDs can alter the expression of pro- and anti-apoptotic proteins that regulate cell survival. Researchers have developed a variety of derivatives, such as ester, phospho-ester, thioester, amide, hydrazide, metal complexes, and salt derivatives, to improve the anticancer activity and selectivity of NSAIDs. These novel derivatives exhibited excellent outcomes in preclinical investigations against various breast cancer cell lines, highlighting enhanced cytotoxicity and bioavailability and minimizing adverse effects as compared to standard NSAIDs. This review emphasizes the anti-breast cancer potential of NSAIDs and their novel derivatives by targeting novel molecular targets in mammary tumorigenesis, focusing on both COX-dependent and independent pathways. Investigating these NSAID derivatives offers an optimistic approach to the development of safer, more efficient anticancer agents for the treatment of breast cancer.

The pharmacological characteristics of secondary metabolites and their promising use in agriculture, medicine and industry has attracted immense attention from the scientific community. Glycyrrhizin, a triterpenoid saponin from Glycyrrhiza glabra (licorice), has also garnered substantial attention due to its diverse range of biological activities and therapeutic potential. This review provides a comprehensive overview of glycyrrhizin and its derivatives, accentuating their pharmacological activities along with their primary mechanisms of action. Glycyrrhizin exhibits notable antidiabetic, antiviral, anti-inflammatory, antifungal and anticancer activities. All these activities are attributed to its ability to modulate various cellular pathways and immune responses. Its anti-inflammatory effects are primarily facilitated through the inhibition of NF-κB and other pro-inflammatory cytokines, while its antiviral efficacy has been shown to extend to a broad spectrum of viruses, including SARS-CoV-2. Glycyrrhizin explores anticancer potential through its capacity to inhibit proliferation, induce apoptosis, and suppress metastasis. Future studies should be focussed on the development of novel derivatives and formulations, particularly nano-formulations, to enhance efficacy and safety, positioning glycyrrhizin and its derivatives as emerging arsenal candidates in the dominion of natural product-based therapeutics.

One of the most common types of Dementia mostly affecting people over the age of 65 is Alzheimer’s Disease. Characterized by various Neuropsychiatric Symptoms such as, memory loss, cognitive impairment, mood and behavioral disturbances leading to a poor life style. WHO 2021 Global status report states that the cases of dementia will drastically increase from 55 million in 2019 to 139 million in 2050 and the total amount paid for health care, long-term care and hospice services by dementia patients is $360 billion (estimated) in 2024. This is alarming and requires serious attention. To do so, first and foremost, identification of the targets involved in the pathogenesis of the disease is necessary. In Alzheimer’s disease, there are two highly accepted hypothesis, Tau and Amyloid beta (Aβ). Extensive research on these Hypothesis has revealed some potential target enzymes such as, Beta-site amyloid precursor protein cleaving enzyme 1 (BACE-1), Monoamine oxidases (MAO), GSK-3 (Glycogen synthase kinase-3) and Cholinesterases. Scientists tried to leverage, enzyme inhibition as a way to modulate the activity of these enzymes and modulation of enzymes was perceived to be affecting the progression and symptoms of the disease significantly. From there, enzyme inhibition has been thought to therapeutically affect the pathogenesis of disease. Some drugs which have undergone clinical trials but were not able to complete them due to side effects and lack of efficacy are Crenezumab (targeting Aβ), LMTM (TRx0237) (targeting Tau) and verubecestat (BACE-1 inhibitor) were terminated in clinical trials. In this review we have inquired the role of BACE-1, MAO, GSK-3 and Cholinesterases in Alzheimer’s Disease and unveiled Potential Inhibitors, which may fulfill the demand of a novel drug.

Bromodomain-containing protein 4 (BRD4), as the reader of epigenetics, could regulate gene transcription by recognizing acetylated lysine of histones. In recent years, researchers have found that dysregulation of BRD4 leads to the occurrence and development of various cancers, making BRD4 a promising target for cancer therapy. To identify novel BRD4 inhibitors from natural products, a hierarchical virtual screening method including pharmacophore modeling, molecular docking, and molecular dynamic simulation was performed to obtain five hit compounds with potential BRD4 inhibitory activity. Subsequently, structural optimization of the hit compound (ZINC2648030) with chromone structure was conducted to afford a series of derivatives (8a–13e), and their BRD4 inhibitory activities were evaluated. Among them, 13b showed remarkable BRD4 inhibitory activity (IC50 = 0.60 μM). Moreover, 13b displayed a potent inhibitory effect on A549 cells with an IC50 value of 0.79 μM, and further investigations demonstrated that it has the potential to induce apoptosis, inhibit colony formation, and suppress cell invasion. These findings indicated that 13b might be a candidate for cancer treatment.