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Natural products represents an important source of new lead compounds in drug discovery research. Several drugs currently used as therapeutic agents have been developed from natural sources; plant sources are specifically important. In the past few decades, pharmaceutical companies demonstrated insignificant attention towards natural product drug discovery, mainly due to its intrinsic complexity. Recently, technological advancements greatly helped to address the challenges and resulted in the revived scientific interest in drug discovery from natural sources. This review provides a comprehensive overview of various approaches used in the selection, authentication, extraction/isolation, biological screening, and analogue development through the application of modern drug-development principles of plant-based natural products. Main focus is given to the bioactivity-guided fractionation approach along with associated challenges and major advancements. A brief outline of historical development in natural product drug discovery and a snapshot of the prominent natural drugs developed in the last few decades are also presented. The researcher’s opinions indicated that an integrated interdisciplinary approach utilizing technological advances is necessary for the successful development of natural products. These involve the application of efficient selection method, well-designed extraction/isolation procedure, advanced structure elucidation techniques, and bioassays with a high-throughput capacity to establish druggability and patentability of phyto-compounds. A number of modern approaches including molecular modeling, virtual screening, natural product library, and database mining are being used for improving natural product drug discovery research. Renewed scientific interest and recent research trends in natural product drug discovery clearly indicated that natural products will play important role in the future development of new therapeutic drugs and it is also anticipated that efficient application of new approaches will further improve the drug discovery campaign.

The programmed death-1 receptor (PD-1) acts as a T-cell brake, and its interaction with ligand-1 (PD-L-1) interferes with signal transduction of the T-cell receptor. This leads to suppression of T-cell survival, proliferation, and activity in the tumor microenvironment resulting in compromised anticancer immunity. PD-1/PD-L-1 interaction blockade shown remarkable clinical success in various cancer immunotherapies. To date, most PD-1/PD-L-1 blockers approved for clinical use are monoclonal antibodies (mAbs); however, their therapeutic use are limited owing to poor clinical responses in a proportion of patients. mAbs also displayed low tumor penetration, steep production costs, and incidences of immune-related side effects. This strongly indicates the importance of developing novel inhibitors as cancer immunotherapeutic agents. Recently, advancements in the small molecule-based inhibitors (SMIs) that directly block the PD-1/PD-L-1 axis gained attention from the scientific community involved in cancer research. SMIs demonstrated certain advantages over mAbs, including longer half-lives, low cost, greater cell penetration, and possibility of oral administration. Currently, several SMIs are in development pipeline as potential therapeutics for cancer immunotherapy. To develop new SMIs, a wide range of structural scaffolds have been explored with excellent outcomes; biphenyl-based scaffolds are most studied. In this review, we analyzed the development of mAbs and SMIs targeting PD-1/PD-L-1 axis for cancer treatment. Altogether, the present review delves into the problems related to mAbs use and a detailed discussion on the development and current status of SMIs. This article may provide a comprehensive guide to medicinal chemists regarding the potential structural scaffolds required for PD-1/PD-L-1 interaction inhibition.

Plants have been extensively studied since ancient times and numerous important chemical constituents with tremendous therapeutic potential are identified. Attacks of microorganisms including viruses and bacteria can be counteracted with an efficient immune system and therefore, stimulation of body’s defense mechanism against infections has been proven to be an effective approach. Polysaccharides, terpenoids, flavonoids, alkaloids, glycosides, and lactones are the important phytochemicals, reported to be primarily responsible for immunomodulation activity of the plants. These phytochemicals may act as lead molecules for the development of safe and effective immunomodulators as potential remedies for the prevention and cure of viral diseases. Natural products are known to primarily modulate the immune system in nonspecific ways. A number of plant-based principles have been identified and isolated with potential immunomodulation activity which justify their use in traditional folklore medicine and can form the basis of further specified research. The aim of the current review is to describe and highlight the immunomodulation potential of certain plants along with their bioactive chemical constituents. Relevant literatures of recent years were searched from commonly employed scientific databases on the basis of their ethnopharmacological use. Most of the plants displaying considerable immunomodulation activity are summarized along with their possible mechanisms. These discussions shall hopefully elicit the attention of researchers and encourage further studies on these plant-based immunomodulation products as potential therapy for the management of infectious diseases, including viral ones such as COVID-19.

The popularity of energy beverages among young adult population is high. These drinks are claimed to boost energy and performance and contain high concentration of caffeine as one of the several ingredients. Discrepancies have been encountered by some of the previous studies between the actual quantity of caffeine present in the product and the amount mentioned on the label, making the determination of caffeine content in these drinks very important. Thus, in this study, we analyzed the caffeine concentration in most popular energy drinks available in Saudi Arabia. The energy drink samples (n = 9) were procured from retail outlets. Sample solutions were prepared in methanol and analyzed for caffeine content by GC-MS. Chromatographic parameters were optimized to achieve optimum resolution and various validation parameters were evaluated. The method was successfully applied for the quantification of caffeine in energy drinks by directly injecting the multifold diluted samples in methanol. The method was linear (r2 = 0.999) over a concentration range of 5–25 µg/mL, specific, precise (%RSD of peak area = 0.56–0.78), and accurate (%recovery = 99.3–101.2%). The amounts of caffeine determined were found in the range of 20.82–33.72 mg/100 mL (52.05–84.3 mg/pack). Results revealed that the amount of caffeine actually present in the tested drinks varied within ±10% range from the amount specified on the product labels. The amounts of caffeine detected in tested beverages were within the USFDA safe upper limit of per-day caffeine consumption, which has indicated that the consumption of one serving of energy drink is unlikely to produce any adverse health effect.

The aim of this study was to develop and validate a fast and simple reversed-phase HPLC method for simultaneous determination of four cardiovascular agents—atorvastatin, simvastatin, telmisartan and irbesartan in bulk drugs and tablet oral dosage forms. The chromatographic separation was accomplished by using Symmetry C18 column (75 mm × 4.6 mm; 3.5 μ) with a mobile phase consisting of ammonium acetate buffer (10 mM; pH 4.0) and acetonitrile in a ratio 40:60 v/v. Flow rate was maintained at 1 mL/min up to 3.5 min, and then suddenly changed to 2 mL/min till the end of the run (7.5 min). The data was acquired using ultraviolet detector monitored at 220 nm. The method was validated for linearity, precision, accuracy and specificity. The developed method has shown excellent linearity (R2 > 0.999) over the concentration range of 1–16 µg/mL. The limits of detection (LODs) and limits of quantification (LOQs) were in the range of 0.189–0.190 and 0.603–0.630 µg/mL, respectively. Inter-day and intra-day accuracy and precision data were recorded in the acceptable limits. The new method has successfully been applied for quantification of all four drugs in their tablet dosage forms with percent recovery within 100 ± 2%.

Transferrin belongs to a class of monomeric glycoproteins, which sequestrate and transport iron inside the body. Apart from iron, transferrin binds with various other metal ions and is assumed to deliver medicinally important metal ions to cells. Hence, the investigation of binding characteristics may provide crucial information for new drug developments. To study the biological impacts of medicinally important metal ions, in this work, we explored the binding behavior of Rh(III) ion with serum apo-transferrin (ApoHST) using FT-IR and UV-Vis spectroscopy. In FT-IR, interaction of Rh(III) with ApoHST was studied at three concentrations (0.25, 0.5, and 1 mM) of metal ion at different time intervals (15, 30, and 60 min). The IR spectra of Rh(III)-ApoHST coordinates revealed a marked reduction in amide I and II band intensities with alterations in band positions. The α-helical part of protein secondary structure reduced considerably (from 53% to 49%, 42%, and 39%), followed by an increment in β-sheet and β-turn components with the increasing concentrations of metal ion. Saturation level reached at 1 mM concentration of Rh(III) ion. In the UV-Vis spectroscopic study, absorption of metal ion-protein coordinates successively raised as concentration of Rh(III) ion increased. The binding constant (K) was calculated as 1.16×104 M−1, which showed a strong binding of the test metal ion with the protein. Upon coordination with a metal ion, the microenvironment of aromatic protein residues changed, which was detected by these spectroscopic techniques. The results revealed the existence of a significant interaction between Rh (III) ion and ApoHST. These research outcome may present new insight into the possible utilization of Rh(III) ion-based compounds in biomedicine. However, more investigations are needed to interpret the exact cellular mechanism.

This study was performed to evaluate phytochemical composition of Khaya senegalensis stem bark and Azadirachta indica leaf hydroethanolic (80%) extracts using GC-MS technique as a tentative identification method and screen for antioxidant and antidiabetic properties in Wistar rats. Diabetes was induced by intraperitoneal injection of alloxan (150 mg/kg·bw). Animals were divided into groups of six and treated by extracts (400 mg/kg·bw) for 28 days. The results compared with positive and negative control groups of animals. After treatment, blood samples were collected to determine the blood glucose level, lipid profile, liver and kidney function markers, and DPPH free radical scavenging activity was evaluated. Phytochemical investigations revealed that extracts were enriched with a wide range of secondary metabolites such as phenols, saponins, triterpenes, alkaloids, flavonoids, sterols, fatty acids, siloxane derivatives, and anthraquinones in diverse concentrations with reported antioxidant and antidiabetic properties. Biological screening results indicated that both extracts exhibited free-radical scavenging property in DPPH screening, and in that, K. senegalensis stem bark extract (91 ± 0.02%) showed greater reduction than A. indica leaf extract (55 ± 0.03%), with an IC50 of 0.023 ± 0.03 g/mL, which was lower than the reference drug propylgallate (0.077 ± 0.03 g/mL). Both the extracts remarkably reduced the blood glucose concentration in diabetic rats (p<0.05). However, A. indica leaf extract showed greater reduction (52%) than K. senegalensis stem bark extract (37%). Similarly, the cholesterol, LDL, triglyceride, total protein, albumin, urea, creatinine, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels decreased significantly (p<0.05), in comparison to diabetic control animals. However, the concentrations of HDL slightly increased. Overall, both extracts showed significant antidiabetic and antioxidant potential in diabetic rats. As oxidative stress is associated with the hyperglycemia, the antioxidant activity displayed by the extracts will provide additional benefits in the antidiabetic therapy.

Caffeine is a well-known central nervous system stimulant, which can cause anxiety, insomnia and nervousness. Domestic wastes of caffeinated drinks, beverages and chocolates are the major sources for entry of caffeine in the environmental system. Caffeine has been widely detected in natural water resources. The current study describes a method for efficient removal of caffeine from aqueous solution by a laboratory scale dielectric barrier discharge (DBD) in open air. Caffeine concentrations in various sample solutions were monitored by high-performance liquid chromatography, and the degradation products were identified by directly injecting the sample to mass spectrometer. The consequences of varied parameters such as input power, initial concentration and initial pH of the solution on the degradation of caffeine were investigated. Removal efficiency of caffeine from aqueous solution was 72.6% and 96.6% for the initial concentrations of 100 and 1 µg/mL, respectively, at initial pH 7 after 4 min treatment in DBD plasma system with 60 W input powers. Caffeine removal efficiency was less in acidic solutions (initial pH 4), and insignificant degradation was observed in alkaline solutions (initial pH 10). Furthermore, the degradation of caffeine was also enhanced by increasing the input power in DBD system. The DBD system used in this study has been considered to be fast, effective and economical. It was operated at atmospheric condition in open air without using catalyst, expensive gases or organic solvents, and significant degradation of caffeine was achieved in a short (4 min) treatment time.

The interaction behavior of Fe3+ with transferrin and apotransferrin (iron-free form) was investigated in this study using affinity capillary electrophoresis. Change in the mass and charge of protein upon binding to the metal ion in the capillary tube led to variation in its migration time and was used to measure the noncovalent binding interactions by fast screening method. Acetanilide was used as the electroosmotic flow (EOF) marker to avoid possible errors due to the change in EOF during the experiment. The binding results were calculated from the mobility ratios of protein (Ri) and EOF marker (Rf) using the formula (Ri − Rf)/Rf or ∆R/Rf. For more comprehensive understanding, the kinetics of the interaction was studied and binding constants were calculated. Results showed that the Fe3+ displayed insignificant interaction with both proteins at lower metal ion concentrations (5–25 μmol/mL). However, transferrin exhibited significant interactions with the metal ion at 50 and 100 μmol/mL (ΔR/Rf = 0.0114 and 0.0201, resp.) concentrations and apotransferrin showed strong binding interactions (ΔR/Rf = −0.0254 and 0.0205, resp.) at relatively higher Fe3+ concentrations of 100 and 250 μmol/mL. The binding constants of 18.968 mmol−1 and −13.603 mmol−1 were recorded for Fe3+ interaction with transferrin and apotransferrin, respectively, showing significant interactions. Different binding patterns of Fe3+ with both proteins might be attributed to the fact that the iron-binding sites in transferrin have already been occupied, which was not the case in apotransferrin. The present study may be used as a reference for the investigation of protein-metal ion, drug-protein, drug-metal ion, and enzyme-metal ion interactions and may be helpful to provide preliminary insight into the new metal-based drug development.

Shammah is a locally manufactured form of smokeless tobacco (ST) which is traditionally used in Middle Eastern countries including Saudi Arabia, Sudan, and Yemen. Presence of a high concentration of nicotine, in addition to various other toxic and carcinogenic constituents, makes it a serious human health threat. It is an admixture containing powdered tobacco, along with several additives, such as lime, ash, black pepper, volatile oils, and flavoring agents. This study was conducted to investigate the constituents of eight different samples of widely used shammah varieties in the Jazan region of Saudi Arabia using GC-MS and to evaluate their cytotoxic effect against three cancer cell lines representing most of the top malignancies in the region including MCF-7, A2780, and HT29 cancer cells, in addition to MRC5 cells (normal human fetal lung fibroblast) using the MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay. GC-MS analysis showed the presence of nicotine or 3-(1-methyl-2-pyrrolidinyl)pyridine (2.1–91.9% of total constituents detected) in all ST samples, whereas its derivative (1s,2s)-nicotine-N-oxide (0.23–1.62%) was detected in four samples. In addition, several known carcinogenic constituents were also identified, and their carcinogenicity was confirmed by MTT results, in which, all the eight samples promoted the growth of MCF7, A2780, and HT29 cancer cells. The cytotoxic effects of samples against the normal cells MRC5 was proportional to the number of components detected by GC-MS. The ingestion of these constituents through saliva of shammah consumers could be the reason for many cancers including breast, ovary, and colon cancers. These results support the urgent local and international call to educate the users regarding the deleterious effects of shammah to avoid its use.