Medicinal Chemistry - Volume 17, Issue 3, 2021

Background: Citrus limon, a Mediterranean-grown citrus species of plants belonging to the Rutaceae family, occupies a place of an impressive range of food and medicinal uses with considerable value in the economy of the fruit of the country. Citrus fruits are economically important with large-scale production of both the fresh fruits and industrially processed products. The extracts and phytochemicals obtained from all parts of C. limon have shown immense therapeutic potential because of their anticancer, anti-tumor and anti-inflammatory nature, and also serve as an important ingredient in the formulation of several ethnic herbal medicines. These properties are mediated by the presence of different phytochemicals, vitamins and nutrients in the citrus fruits. Material and Methods: The methods involved in the preparation of the present article included the collection of information from various scientific databases, indexed periodicals, and search engines such as Medline Scopus google scholar PubMed, PubMed central web of science, and science direct. Results: This communication presents an updated account of different pharmacological aspects of C. limon associated with its anti-oxidative, antiulcer, antihelmintic, insecticidal, anticancer, cytotoxic, and estrogenic activities. In addition, C. limon extracts possess hepatoprotective, anti-hyperglycemic, and antimicrobial properties. The present article includes the structure and function of different key chemical constituents from different parts of C. limon. Also, the possible molecular mechanisms of actions of bioactive compounds from C. limon are displayed. Conclusion: The traditional and ethno-medicinal literature revealed that C. limon is very effective in different pathologies. Most of these compounds possessing antioxidant properties would be implicated in offering health benefits by acting as potential nutraceuticals to humans with special reference to disease management of health and disease.

Background: Privileged 4H-chromenes possess potent anticancer and anticonvulsant activities. By the inspiring potency of 4H-chromenes and demands of the present era of scaffolds, an effective molecule was discovered for the treatment of cancer and related diseases. Objective: This study designed and synthesized a novel series of 4H-chromene derivatives from one-port synthesis for the treatment of cancer and other such diseases. Methods: A side amide chain was substituted in multiple steps on the amine group of chromene. Later, the anticancer activity of synthesized compounds was investigated against the human colon adenocarcinoma cell line (HT-29) using sulforhodamine B (SRB) assay. Moreover, anticonvulsant activity was also detected using maximal electroshock seizure (MES) model and subcutaneous Metrazol Seizure Threshold Test (scMET) in albino Wistar rats. Neurotoxicity was evaluated by using the rotarod test. Before the synthesis, docking studies were performed using various molecular targets. Subsequently, the computational study of the titled compounds was performed to predict the pharmacokinetic profile. Results: Among the fifteen tested compounds, A4 and A9 were found to be active against HT-29 cells (growth inhibitory dose 50% (GI50) <11μM). Moreover, compounds A4 showed the protection at 300mg/kg in scMET (h) for albino Wistar rats and compounds A9, A11, and A15 exhibited the anticonvulsant effect at the doses 100, 300 and 300 mg/kg, respectively in MES screen (h). Conclusion: Due to these encouraging results, we concluded that both A4 and A9 may be effective for treatement against colon cancer, while compound A9 may be used as a considerable effective molecule for the treatment of epilepsy.

Background: A series of novel 5-substituted benzylidene rhodanine derivatives using four different amines were designed based on our previously developed CoMSIA (Comparative molecular similarity indices analysis) model for the anticancer activity. Methods: The designed rhodanines were synthesized via dithiocarbamate formation, cyclization and Knoevenagel condensation. The structures of the synthesized compounds were confirmed and analyzed by spectral studies. Results: The synthesized rhodanines were investigated for in vitro anticancer activities and the analogs have displayed mild to significant cytotoxicity against MCF-7 breast cancer cells. The compounds with benzyloxy substitution at the fifth position of rhodanine ring (Compounds 20, 33 and 38) system showed significant cytotoxic activity against MCF-7 cells. CoMSIA, a three-dimensional quantitative structureactivity relationship (3D-QSAR) technique was accomplished to elucidate structure-activity relationships. Conclusion: Based on the information derived from CoMSIA contour plots, some key features for increasing the activity of compounds have been identified and used to design new anti-cancer agents. The present developed CoMSIA model displayed good external predictability, r2pred of 0.841 and good statistical robustness.

Background: 1α,25-dihydroxy vitamin D3 (calcitriol) shows potent growth-inhibitory properties on different cancer cell lines, but its hypercalcemic effects have severely hampered its therapeutic application. Therefore, it is important to develop synthetic calcitriol analogues that retain or even increase its antitumoral effects and lack hypercalcemic activity. Based on previous evidence of the potent antitumor effects of the synthetic alkynylphosphonate EM1 analogue, we have now synthesized a derivative called SG. Objective: The aim of the present work is to evaluate the calcemic activity and the antitumor effect of SG, comparing these effects with those exerted by calcitriol and with those previously published for EM1. In addition, we propose to analyze by in silico studies, the chemical structure-biological function relationship of these molecules. Methods: We performed the synthesis of vinylphosphonate SG analogue; in vitro assays on different cancer cell lines; in vivo assays on mice; and in silico assays applying computational molecular modeling. Results: The SG compound lacks hypercalcemic activity, similar to the parent compound EM1. However, the antitumor activity was blunted, as no antiproliferative or anti-migratory effects were observed. By in silico assays, we demonstrated that SG analogue has a lower affinity for the VDRligand- binding domain than the EM1 compound due to lack of interaction with the important residues His305 and His397. Conclusion: These results demonstrate that the chemical modification in the lateral side chain of the SG analogue affects the antitumoral activity observed previously for EM1 but does not affect the calcemic activity. These results contribute to the rational design and synthesis of novel calcitriol analogues.

Introduction: The enzyme called dipeptidyl peptidase IV (DPP-IV) is related to the glycemic control associated with the stimulation of the pancreas to produce insulin. So, its inhibition is a good strategy for the treatment of type 2 diabetes mellitus. Methods: In this study, we have employed molecular modeling strategies such as CoMFA, molecular docking, molecular dynamics, and binding free energy calculations of a set of DPP-IV inhibitors in order to understand the main characteristics related to the biological activity of these ligands against the enzyme. Results: The models obtained from CoMFA presented significant values of internal (0.768) and external (0.988) validations. Important interactions with some residues, such as Glu205, Tyr666, Arg125, Ser630, Phe357 and Tyr662, were also identified. In addition, calculations of the electronic properties allowed relating the LUMO and HOMO energies with the biological activity of the compounds studied. The results obtained from the molecular dynamics simulations and the SIE calculations (ΔG) indicated that the inhibitor 40 increases the stability of the DPP-IV target. Conclusions: Therefore, from this study, it is possible to propose molecular modifications of these DPP-IV inhibitors in order to improve their potential to treat type 2 diabetes.

Background: α-Glucosidase is a hydrolyzing enzyme that plays a crucial role in the degradation of carbohydrates and starch to glucose. Hence, α-glucosidase is an important target in carbohydrate mediated diseases such as diabetes mellitus. Objective: In this study, novel coumarin containing dithiocarbamate derivatives 4a-n were synthesized and evaluated against α-glucosidase in vitro and in silico. Methods: These compounds were obtained from the reaction between 4-(bromomethyl)-7- methoxy-2H-chromen-2-one 1, carbon disulfide 2, and primary or secondary amines 3a-n in the presence of potassium hydroxide and ethanol at room temperature. In vitro α-glucosidase inhibition and kinetic study of these compounds were performed. Furthermore, a docking study of the most potent compounds was also performed by Auto Dock Tools (version 1.5.6). Results: Obtained results showed that all the synthesized compounds exhibited prominent inhibitory activities (IC50 = 85.0 ± 4.0-566.6 ± 8.6 μM) in comparison to acarbose as a standard inhibitor (IC50 = 750.0 ± 9.0 μM). Among them, the secondary amine derivative 4d with pendant indole group was the most potent inhibitor. Enzyme kinetic study of the compound 4d revealed that this compound competes with a substrate to connect to the active site of α-glucosidase and therefore is a competitive inhibitor. Moreover, a molecular docking study predicted that this compound interacted with the α-glucosidase active site pocket. Conclusion: Our results suggest that the coumarin-dithiocarbamate scaffold can be a promising lead structure for designing potent α-glucosidase inhibitors for the treatment of type 2 diabetes.

Background: ATP-binding cassette Super-family G member 2 protein is an active ATPbinding cassette transporter with the potential to combat cancer stem cells. Objective: Due to the lack of potential ATP-binding cassette Super-family G member 2 inhibitors, we screened natural inhibitors, which could be a safe source to control multidrug resistance by blocking the regulation of ATP-binding cassette Super-family G member 2 protein. Methods: Three-dimensional structure of ATP-binding cassette Super-family G member 2 protein downloaded from the protein databank and chemical structures of 166 selected compounds of the training dataset were retrieved from PubChem. Drug-likeness and docking analysis was conducted to shortlist the dataset for pharmacophore generation. LigandScout 4.1.5 used for pharmacophorebased screening of Zbc library of ZINC database and Autodock Vina were utilized for molecular docking against the predicted active pocket of the target protein to evaluate the potential association of protein and ligands. The physiochemical properties of novel compounds were calculated by admetSAR respectively. Results: Through pharmacophore-based screening, ZINC4098704 (Rhein) was identified as a lead compound which demonstrates the least binding energy (-8.5) and the highest binding affinity with the target protein and showed optimal physiochemical profile. This compound is highly recommended for a laboratory test to confirm its activity as an ATP-binding cassette Super-family G member 2 inhibitors. Conclusion: Our computer-based study systematically selected natural lead compounds, which could be effective in inhibiting ATP-binding cassette Super-family G member 2 and may help reverse the effect of multidrug resistance to increase the effectiveness of chemotherapy in cancer treatment.

Background: Moderate to severe asthma could be induced by diverse proinflammatory cytokines, as IL-17 and IFN-γ, which are also related to treatment resistance and airway hyperresponsiveness. Oxazolidines emerged as a novel approach for asthma treatment, since some chemical peculiarities were suggested by previous studies. Objective: The present study aimed to evaluate the IL-17A and IFN-γ modulatory effect of two new oxazolidine derivatives (LPSF/NB-12 and -13) on mononucleated cells of patients with moderate and severe asthma. Methods: The study first looked at potential targets for oxazolidine derivatives using SWISS-ADME. After the synthesis of the compounds, cytotoxicity and cytokine levels were analyzed. Results: We demonstrated that LPSF/NB-12 and -13 reduced IFN-γ and IL-17 production in peripheral blood mononucleated cells from asthmatic patients in a concentrated manner. Our in silico analysis showed the neurokinin-1 receptor as a common target for both compounds, which is responsible for diverse proinflammatory effects of moderate and severe asthma. Conclusion: The work demonstrated a novel approach against asthma, which deserves further studies of its mechanisms of action.