Medicinal Chemistry - Volume 15, Issue 2, 2019

Background: Low molecular weight 1,2,3-triazoles and naphthoquinones are endowed with various types of biological activity, such as against cancer, HIV and bacteria. However, in some cases, the conjugation of these two nuclei considerably increases their biological activities. Objective: In this work, we decided to study the synthesis and screening of bis-naphthoquinones and xanthenes tethered to 1,2,3-triazoles against cancer cell lines, specifically the human breast cancer cell line MCF-7. Results: Starting from lawsone and aryl-1H-1,2,3-triazole-4-carbaldehydes (10a-h) several new 7- (1-aryl-1H-1,2,3-triazol-4-yl)-6H-dibenzo[b,h]xanthene-5,6,8,13(7H)-tetraones (12a-h) and 3,3'- ((1-aryl-1H-1,2,3-triazol-4-yl)methylene)bis(2-hydroxynaphthalene-1,4-diones) 11a-h were synthesized and evaluated for their cytotoxic activities using the human breast cancer cell line MCF-7 and the non-tumor cell line MCF10A as control. We performed test of cell viability, cell proliferation, intracellular ATP content and cell cytometry to determine reactive oxygen species (ROS) formation. Conclusions: Based on these results, we found that compound 12a promotes ROS production, interfering with energy metabolism, cell viability and proliferation, and thus promoting whole cell damage.

Background: IDX-184 is a guanosine derivative having a potent inhibitory performance against HCV NS5b polymerase. Objective: To test three different groups of 2'C - modified analogues of guanosine nucleotide against HCV polymerase. Method: Using combined Quantitative Structure-Activity Relationships (QSAR) and molecular docking, the suggested compounds are studied. Results: Examining the docked structures of the compounds with experimentally solved NS5b structure (PDB ID: 2XI3) revealed that most of the compounds have the same mode of interaction as that of guanosine nucleotide and hence, NS5b inhibition is possible. Conclusion: It is revealed that sixteen modifications have a better binding affinity to NS5b compared to guanosine. In addition, seven more compounds are better in NS5b binding compared to the approved drug, sofosbuvir, and the compound under clinical trials, IDX-184. Hence, these compounds could be potent HCV NS5b inhibitors. Summary Points: Novel guanosine modifications were introduced in silico and optimized using QM. QSAR and docking calculations are performed to test the binding affinity of the compounds to HCV NS5b active site. Comparison between the binding affinities and the mode of interactions of the compounds and both GTP and IDX-184 is performed. Structural mining to quantify the mode of binding of the compounds to NS5b active site pocket.

Background: Natural product, osthol has been found to have important biological and pharmacological roles particularly having inhibitory effect on multiple types of cancer. Objective: The unmet needs in cancer therapeutics make its derivatization an important and exciting field of research. Keeping this in view, a whole new series of diverse analogues of osthol (1) were synthesized. Method: All the newly synthesized compounds were made through modification in the lactone ring as well as in the side chain of the osthol molecule and were subjected to anti-proliferative screening through 3-(4,5-Dimethylthiazol-yl)-diphenyl tetrazoliumbromide (MTT) against four different human cancers of diverse origins viz. Colon (Colo-205), lung (A549), Leukemia (THP- 1) and breast (MCF-7) including SV40 transformed normal breast epithelial cell (fR-2). Results: Interestingly, among the tested molecules, most of the analogs displayed better antiproliferative activity than the parent Osthol 1. However, among all the tested analogs, compound 28 exhibited the best results against leukemia (THP1) cell line with IC50 of 5μM.Compound 28 induced potent apoptotic effects and G1 phase arrest in leukemia cancer cells (THP1). The population of apoptotic cells increased from 13.8% in negative control to 26.9% at 8μM concentration of 28. Compound 28 also induced a remarkable decrease in mitochondrial membrane potential (ΛΨm) leading to apoptosis of the cancer cells. Conclusion: A novel series of molecules derived from natural product osthol were synthesized, wherein compound 28 was found to be most effective against leukemia and with 10 fold less toxicity against normal cells. The compound induced cancer inhibition mainly through apoptosis and thus has a potential in cancer therapeutics.

Background: Search for new antiviral and anticancer agents are essential because of the emergence of drug resistance in recent years. In continuation of our efforts in identifying the new small molecule antiviral and anticancer agents, we identified chalcones as potent antiviral and anticancer agents. Objective: With the aim of identifying the broad acting antiviral and anticancer agents, we discovered substituted aryl/heteroaryl derived thienyl chalcones as antiviral and anticancer agents. Method: A focused set of thienyl chalcone derivaties II-VI was screened for selected viruses Hepatitis B virus (HBV), Herpes simplex virus 1 (HSV-1), Human cytomegalovirus (HCMV), Dengue virus 2 (DENV2), Influenza A (H1N1) virus, MERS coronavirus, Poliovirus 1 (PV 1), Rift Valley fever (RVF), Tacaribe virus (TCRV), Venezuelan equine encephalitis virus (VEE) and Zika virus (ZIKV) using the National Institute of Allergy and Infectious Diseases (NIAID)’s Division of Microbiology and Infectious Diseases (DMID) antiviral screening program. Additionally, a cyclopropylquinoline derivative IV has been screened for 60 human cancer cell lines using the Development Therapeutics Program (DTP) of NCI. Results: All thienyl chalcone derivatives II-VI displayed moderate to excellent antiviral activity towards several viruses tested. Compounds V and VI were turned out be active compounds towards human cytomegalovirus for both normal strain (AD169) as well as resistant isolate (GDGr K17). Particularly, cyano derivative V showed very high potency (EC50: <0.05 μM) towards AD169 strain of HCMV compared to standard drug Ganciclovir (EC50: 0.12 μM). Additionally, it showed moderate activity in the secondary assay (AD169; EC50: 2.30 μM). The cyclopropylquinoline derivative IV displayed high potency towards Rift Valley fever virus (RVFV) and Tacaribe virus (TCRV) towards Rift Valley fever virus (RVFV). The cyclopropylquinoline derivative IV is nearly 28 times more potent in our initial in vitro visual assay (EC50: 0.39 μg/ml) and nearly 17 times more potent in neutral red assay (EC50: 0.71 μg/ml) compared to the standard drug Ribavirin (EC50: 11 μg/ml; visual assay and EC50: 12 μg/ml; neutral red assay). It is nearly 12 times more potent in our initial in vitro visual assay (EC50: >1 μg/ml) and nearly 8 times more potent in neutral red assay (EC50: >1.3 μg/ml) compared to the standard drug Ribavirin (EC50: 12 μg/ml; visual assay and EC50: 9.9 μg/ml; neutral red assay) towards Tacaribe virus (TCRV). Additionally, cyclopropylquinoline derivative IV has shown strong growth inhibitory activity towards three major cancers (colon, breast, and leukemia) cell lines and moderate growth inhibition shown towards other cancer cell lines screened. Conclusion: Compounds V and VI were demonstrated viral inhibition towards Human cytomegalovirus, whereas cyclopropylquinoline derivative IV towards Rift Valley fever virus and Tacaribe virus. Additionally, cyclopropylquinoline derivative IV has displayed very good cytotoxicity against colon, breast and leukemia cell lines in vitro.

Background: Inflammation is a biological rejoinder of vascular tissues against destructive agents e.g. irritants, damaged cell or pathogens. During inflammation, respiratory burst occurs by activated phagocytes which help to destroy invading pathogens. Phagocytic cells such as neutrophils and macrophages are one of the major sources of reactive oxygen species (ROS) and nitric oxide (NO). Normally, the redox environment is maintained by various antioxidant defense systems, however, these reactive oxygen species may be destructive and can lead to various pathological conditions. Methods: Benzophenone esters and sulfonates (1-18) were synthesized through one pot synthesis by reacting 4-hydroxy benzophenone either different benzoyl chloride or sulfonyl chloride. These synthetic compounds were evaluated for their in vitro immunosuppressive potential on two parameters of innate immune response including inhibition of intracellular reactive oxygen species (ROS) and nitric oxide (NO). ROS were induced in polymorphonuclear leukocytes (PMNs) isolated from human whole blood by serum opsonized zymosan stimulation, whereas NO were produced in J774.2 cells by lipopolysachharides (LPS) stimulation. Moreover, cytotoxicity of compounds was also determined using NIH-3T3 fibroblast cells (ATCC, Manassas, USA) was evaluated by using the standard MTT colorimetric assay. Results: All compounds inhibited the production of ROS at various extent among which compounds 2, 5, 6, 8, 10, 13 and 16 were found to be the potent inhibitors of ROS with IC50 values ranging between (1.0 - 2.2 μg/mL) as compared to ibuprofen (IC50 = 2.5 ± 0.6 μg/mL) as the standard drug. Compounds 2, 7, 11, 13, 14 and 18 showed good inhibition of NO production with % inhibition values ranging between (63.6% - 76.7%) at concentration of 25 μg/mL as compared to NG-monomethyl-Larginine (L-NMMA 65.6 ± 1.1 μg/mL) as the standard. All other derivatives showed moderate to low level of inhibition on both tested parameters. Cytotoxicity activity also showed nontoxicity of synthetic compounds. Structures of all the synthetic compounds were confirmed through 1H-NMR, 13C-NMR, EI-MS and HREI-MS spectroscopic techniques. Conclusion: Compounds 2 and 13 were found to be good dual antiinflammatory (ROS and NO) agent. However, compounds 5, 6, 8, 10 and 16 were found to be selectively active for ROS inhibitory studies. Compounds 7, 11, 14 and 18 were discriminatory active at NO inhibition assay. These initial findings of antiinflammatory activity concluded that these compounds might have the potential to develop a novel non-steroidal antiinflammatory drugs (NSAIDs), non-acidic antiinflammatory agent. Most active compounds 2, 5-8, 10, 13, 14 and 16 showed nontoxicity of synthetic compounds.

Background: Barbituric acid derivatives are a versatile group of compounds which are identified as potential pharmacophores for the treatment of anxiety, epilepsy and other psychiatric disorders. They are also used as anesthetics and have sound effects on the motor and sensory functions. Barbiturates are malonylurea derivatives with a variety of substituents at C-5 position showing resemblance with nitrogen and sulfur containing compounds like thiouracil which exhibited potent anticancer and antiviral activities. Recently, barbituric acid derivatives have also received great interest for applications in nanoscience. Objective: Synthesis of 5-arylidene-N,N-diethylthiobarbiturates, biological evaluation as potential α-glucosidase inhibitors and molecular modeling. Methods: In the present study, N,N-Diethylthiobarbituric acid derivatives were synthesized by refluxing of N,N-diethylthiobarbituric acid and different aromatic aldehydes in distilled water. In a typical reaction; a mixture of N,N-diethylthiobarbituric acid 0.20 g (1 mmol) and 5-bromo-2- hydroxybenzaldehyde 0.199 g (1 mmol) mixed in 10 mL distilled water and reflux for 30 minutes. After completion of the reaction, the corresponding product 1 was filtered and dried and yield calculated. It was crystallized from ethanol. The structures of synthesized compounds 1-25 were carried out by using 1H, 13C NMR, EI spectroscopy and CHN analysis used for the determination of their structures. The α-glucosidase inhibition assay was performed as given by Chapdelaine et al., with slight modifications and optimization. Results: Our newly synthesized compounds showed a varying degree of α-glucosidase inhibition and at least four of them were found as potent inhibitors. Compounds 6, 5, 17, 11 exhibited IC50 values (Mean±SEM) of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 μM, respectively, as compared to standard acarbose (IC50, 38.25 ± 0.12 μM). Conclusion: Our present study has shown that compounds 6, 5, 17, 11 exhibited IC50 values of 0.0006 ± 0.0002, 18.91 ± 0.005, 19.18 ± 0.002, 36.91 ± 0.003 μM, respectively. The studies were supported by in silico data analysis.

Background: Postprandial hyperglycemia can be reduced by inhibiting major carbohydrate hydrolyzing enzymes, such as α-glucosidase and α-amylase which is an effective approach in both preventing and treating diabetes. Objective: The aim of this study was to synthesize a series of 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl] benzoic acid derivatives and evaluate α-glucosidase and α-amylase inhibitory activity along with molecular docking and in silico ADMET property analysis. Method: Chlorosulfonation of 2,4-dichloro benzoic acid followed by reaction with corresponding anilines/amines yielded 2,4-dichloro-5-[(N-aryl/alkyl)sulfamoyl]benzoic acid derivatives. For evaluating their antidiabetic potential α-glucosidase and α-amylase inhibitory assays were carried out. In silico molecular docking studies of these compounds were performed with respect to these enzymes and a computational study was also carried out to predict the drug-likeness and ADMET properties of the title compounds. Results: Compound 3c (2,4-dichloro-5-[(2-nitrophenyl)sulfamoyl]benzoic acid) was found to be highly active having 3 fold inhibitory potential against α-amylase and 5 times inhibitory activity against α-glucosidase in comparison to standard drug acarbose. Conclusion: Most of the synthesized compounds were highly potent or equipotent to standard drug acarbose for inhibitory potential against α-glucosidase and α-amylase enzyme and hence this may indicate their antidiabetic activity. The docking study revealed that these compounds interact with active site of enzyme through hydrogen bonding and different pi interactions.

Background: There is an urgent need to develop novel inhibitors against clinically widespread extended-spectrum β-lactamases (ESBLs) to meet the challenges of the ever-evolving threat of antibiotic resistances. Most existing ESBL inhibitors sharing a common chemical feature of β-lactam ring in their molecule, this structural characteristic makes them intrinsically susceptible to enzymatic breakdown by the resistance mechanisms employed by the bacteria. Objective: The aim of this study was to screen and discover novel lead compounds by using Lproline as initial scaffold to create a “non-sulfur, non-β-lactam” new chemotypes for potential ESBL inhibitors. Methods: Structure-based molecular docking and virtual screening were employed in the novel inhibitor generation process for lead compound screening and SAR analysis. Evaluation of the ESBL inhibitory activity of the lead compounds was performed in combination with three of the most susceptible antibiotics: ceftazidime, meropenem and ampicillin, against thirteen ESBL enzymes including four new CTX-M harboring strains and four KPC-2 producing species. Results: L-proline derived (S)-1-(2-sulfamoylbenzoyl)pyrrolidine-2-carboxylic acid (compound 6) as a “non-sulfur, non-β-lactam” and the most potential ESBL inhibitor was identified. Compound 6 possesses ideal anti-resistance activities by reducing MICs of ceftazidime, meropenem and ampicillin by 16-133, 32-133 and 67-267 fold respectiveily. The inhibitory mechanism of 6 with CTX-M, KPC-2 and penicillinase were proposed and probed with molecular docking analysis. Conclusion: Given that the simple proline derivative but promising synergistic antibacterial properties of compound 6 augers well for further investigations into its in vivo efficacy.

Background: The search for natural inhibitors of snake venom toxins is essential to supplement or even replace the serum therapy. The aim of this work was to evaluate the pharmacological properties of essential oil from Lippia origanoides Kunth. (Verbenaceae). Methods: The oil was extracted by hydrodistillation and the constituents were identified and quantified by GC-MS and GC-FID. The essential oil from L. origanoides was evaluated in hemolysis tests, on the activities of phospholipases A2 and serine proteases and in coagulation and thrombolysis induced by different snake venoms. Results: The major constituents of essential oil were carvacrol, p-cymene, γ-terpinene, and thymol. The oil inhibited approximately 10 % of the phospholipase A2 activity induced by Bothrops atrox, Bothrops jararaca, Bothrops jararacussu and Bothrops moojeni venoms and was not cytotoxic against erythrocytes. However, previous incubation of the oil with B. jararacussu, B. moojeni, and Crotalus durissus terrificus (C.d.t.) venoms resulted in potentiation of hemolytic activity (30 % and 50 % for 0.6 μL mL-1 and 1.2 μL mL-1, respectively). The essential oil presented a procoagulant effect on human citrated plasma, potentiated the thrombolytic action of proteases and phospholipases A2 present in B. jararacussu venom, and serine protease activity induced by B. jararaca and Lachesis muta venoms. When pre-incubated with the C.d.t. venom, however, prothrombotic activity was observed. Conclusion: The results obtained in this work amplify the pharmacological characterization of the essential oil from L. origanoides. However, new studies are fundamental to define the action mechanisms and determine pharmaceutical applications.