Letters in Drug Design & Discovery - Volume 17, Issue 5, 2020

Background: Natural occurring β-Carbolines alkaloids are abundant in the plant kingdom or other organisms, and they were found to possess good antitumor activity through multiple mechanisms. Based on previous summarized SARs of β-carboline derivatives, the modification on pyridine ring would have a great impact on their antitumor activities. Therefore, we plan to synthesized arylated β-carboline-3-amides to find more valuable β-Carbolines derivatives. Methods: A novel bimetallic Pd(OAc)2/AgOAc catalyst system was developed for the amidation of aryl iodides under acid condition. A series of N-arylated β-carbolines derivatives were synthesized using this method. The structures of these compounds were confirmed by 1H NMR, 13C NMR and HRMS, and their in vitro antiproliferative activity was investigated against HepG2 and Hela tumor cell lines by MTT assay. Results: Eleven N-arylated β-carboline-3-amides were synthesized using this bimetallic catalyzed method in 58-98% yields. These synthesized N-arylated compounds showed no antiproliferative activity at 20 μM. Conclusion: We have discovered an efficient and bimetallic catalytic system allowing the Narylation of secondary acyclic amides. This is the first report that N-arylation of aliphatic secondary acyclic amides under acid condition.

Background: Oxime compounds, including oxime ethers and oxime esters, possess various biological activities. Many oxime ethers have been widely used in the fields of pesticides and medicines. However, oxime ethers are rarely used in the field of pesticides. Methods: We chose the excellent fungicide pyrifenox as the lead compound, integrated pyridinyl, adamantyl and benzoyl moieties into one molecule, while also designed and synthesized ten 1- (adamantan-1-yl)ethanone oxime esters containing pyridinyl moiety. Moreover, we also evaluated their preliminary antifungal activities against S. sclerotiorum and B. cinerea. Results: The target compounds were characterized by NMR, IR and HRMS. The preliminary bioactivity test showed that they exhibited some antifungal activity to S. sclerotiorum and B. cinerea, and EC50 values were in the range of 14.16-32.97 and 27.60-52.82 μg/mL, respectively. Conclusion: Some target compounds such as 3d, 3e, 3h and 3i, exhibited moderate activities against S. sclerotiorum, with EC50 values of 14.16-18.18 μg/mL.

Background: Diabetes is the foremost health problem worldwide predisposing to increased mortality and morbidity. The available synthetic drugs have serious side effects and thus, emphasize further need to develop effective medication therapy. GPR40 represents an interesting target for developing novel antidiabetic drug. In the current study, searching of potential natural hit candidate as agonist by using structure based computational approach. Methods: The GPR40 agonistic activity of natural compounds was searched by using Maestro through docking and Molecular Dynamics (MD) simulation application. Virtual screening by using IBScreen library of natural compounds was done and the binding modes of newer natural entity(s) were investigated. Further, MD studies of the GPR40 complex with the most promising hit found in this study justified the stability of these complexes. Results: The silicone chip-based approach recognized the most capable six hits and the ADME prediction aided the exploration of their pharmacokinetic potential. In this study, the obtained hit (ZINC70692253) after the use of exhaustive screening having binding energy -107.501 kcal/mol and root mean square deviation of hGPR40-ZINC70692253 is around 3.5 Å in 20 ns of simulation. Conclusion: Successful application of structure-based computational screening gave a novel candidate from Natural Product library for diabetes treatment. So, Natural compounds may tend to cure diabetes with lesser extent of undesirable effects in comparison to synthetic compounds and these novel screened compounds may show a plausible biological response in the hit to lead finding of drug development process. To the best of our knowledge, this is the first example of the successful application of SBVS to discover novel natural hit compounds using hGPR40.

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen, aspirin, indomethacin, flufenamic acid and phenylbutazone are used to treat most of the inflammatory disorders. These NSAIDs are also associated with serious side effects including gastric ulceration, nephrotoxicity, and bleeding, mainly due to acidic nature. Hence, there is a need to identify highly potent and safer treatment for inflammatory disorders. Methods: Herein, synthetic hydrazinyl thiazole substituted coumarins and chromones 1-48 were evaluated for ROS inhibitory activity. ROS were generated from zymosan activated whole blood phagocytes. Results: Among all tested compounds, compounds 1 (IC50 = 38.3 ± 7.1 μM), 2 (IC50 = 5.7 ± 0.2 μM), 5 (IC50 = 28.3 ± 3.5 μM), 23 (IC50 = 12.5 ± 3.1 μM), 27 (IC50 = 32.8 ± 1.1 μM), 39 (IC50 = 20.2 ± 1.6 μM), and 42 (IC50 = 43.2 ± 3.8 μM) showed potent ROS inhibition as compared to standard ibuprofen (IC50 = 54.3 ± 1.9 μM). Whereas, compounds 3 (IC50 = 134.7 ± 1.0 μM), 16 (IC50 = 75.4 ± 7.2 μM), 24 (IC50 = 102.4 ± 1.0 μM), and 31 (IC50 = 86.6 ± 1.5 μM) were found to be moderately active. Compounds 1, 2, 5, 23, 27, 39, and 42, having potent ROS inhibitory activity were also screened for their nitric oxide (NO) inhibition. Cytotoxicity was also checked for all active compounds on NIH-3T3 cell line. Cyclohexamide (IC50 = 0.13 ± 0.02 μM) was used as standard. Conclusion: Identified active compounds from these libraries may serve as lead candidates for future research in order to obtain a more potent, and safer anti-inflammatory agent.

Background: Biological system complexity impedes the drug target identification by biological experiments. Thus drugs, rather than acting on target site only, can interact with the entire biological system. Study of this phenomenon, known as network pharmacology, provides grounds for biological target identification of new drugs or acts as a foundation for the discovery of new targets of present drugs. No publication is available on the interaction network of CAPE. Aim: This study was aimed at the investigation of the candidate targets and possible interactions of caffeic acid phenethyl ester (CAPE) involved in its osteoimmunological effects. Methods: This study encompasses the investigation of candidate targets and possible interactions of CAPE by analyzing through PASS Prediction and constructing a biological network of CAPE. Results: In response to input (CAPE), PASS Prediction generated a network of 1723 targets. While selecting the probability to be active (Pa) value greater than 0.7 brought forth only 27 targets for CAPE. Most of these targets predicted the therapeutic role of CAPE as an osteoimmunological agent. Apart from this, this network pharmacology also identified 10 potential anti-cancer targets for CAPE, out of which 7 targets have been used efficiently in developing potent osteoimmunological drugs. Conclusion: This study provides scientific prediction of the mechanisms involved in osteoimmunological effects of CAPE, presenting its promising use in the development of a natural therapeutic agent for the pharmaceutical industry. CAPE targets identified by web-based online databases and network pharmacology need additional in silico assessment such as docking and MD simulation studies and experimental verification to authenticate these results.

Background: Thiophene ring forms important building block in medicinal chemistry. Literature reveals that thiophene ring in combination with different groups shows different activity. By keeping these things in mind we have designed and synthesized a new series of amide and sulfonamide coupled thiophene. A series of novel substituted 3-sulfamoylbenzo[b]thiophene-4- carboxamide molecules containing sulfonamide and amide group were designed, synthesized and used for anti-proliferative activity study. Methods: The final compounds 16-36 were synthesized by using series of reactions comprising sulfonation, sulfonamide coupling, hydrolysis and peptide coupling. The yields of compounds 16- 36 are in the range of 90-98%. The structures of the synthesized compounds were elucidated and confirmed by 1H NMR, 13C NMR, LCMS and the purity was checked through HPLC analysis. The compounds were further tested for their in vitro anticancer activity against a series of cell lines A549, HeLa, MCF-7 and Du-145. Results: The intermediates 8-13, 15 and final compounds 16-36 were synthesized in good yields. The synthesized compounds were further tested for their anticancer activity and most of compounds showed moderate to good anticancer activity against all four cell lines. Conclusion: We have synthesized 21 compounds and were screened for anticancer activity against MCF-7, HeLa, A-549 and Du-145 cancer cell lines. Most of the compounds were active for tested cell lines with IC50 value in the range of 1.81 to 9.73 μM. The compounds 18, 19, 21, 25, 30, 31 and 33 are most active in cell line data with IC50 value in the range of 1.81 to 2.52 μM.

Background: Pyrazolines, electron-rich nitrogen carriers, are of great importance due to their potential applications for the treatment of many diseases including inflammation, infectious diseases and neurodegenerative disorders. Objectives: The purpose of this work was to synthesize new pyrazoline derivatives and evaluate their anticholinesterase effects. Methods: 1-Aryl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (1-7) were synthesized via the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(piperidin-1-yl)phenyl]prop-2- en-1-one with arylhydrazine hydrochloride derivatives in acetic acid, whereas 1-aryl-5-[4- (morpholin-4-yl)phenyl]-3-(3,4-dimethoxyphenyl)-4,5-dihydro-1H-pyrazoles (8-14) were obtained by the treatment of 1-(3,4-dimethoxyphenyl)-3-[4-(morpholin-4-yl)phenyl]prop-2-en-1-one with arylhydrazine hydrochloride derivatives in acetic acid. Their inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) were determined using a modification of Ellman’s spectrophotometric method. In silico docking and Absorption, Distribution, Metabolism and Excretion (ADME) studies were performed using Schrödinger’s Maestro molecular modeling package. Results: In general, piperidine derivatives were found to be more effective than morpholine derivatives on cholinesterases (ChEs). 1-Phenyl-5-[4-(piperidin-1-yl)phenyl]-3-(3,4-dimethoxyphenyl)- 4,5-dihydro-1H-pyrazole (1) and 1-(4-cyanophenyl)-5-[4-(piperidin-1-yl)phenyl]-3-(3,4- dimethoxyphenyl)-4,5-dihydro-1H-pyrazole (7) were identified as the most effective AChE inhibitors in this series with 40.92% and 38.98%, respectively. Compounds 1 and 7 were docked into the active site of human AChE (PDB code: 4EY7). Both the compounds were found to be capable of forming π-π stacking interactions with Trp286. Based on in silico ADME studies, these compounds are expected to have reasonable oral bioavailability. Conclusion: In the view of this work, the structural modification of the identified agents is going on for the generation of new anticholinesterase agents with enhanced efficacy.

Background: FMS-like tyrosine kinase-3 (FLT3) belongs to the class III Receptor Tyrosine Kinase (RTK) family. FLT3 is involved in normal hematopoiesis and is generally expressed in early hematopoietic progenitor cells. Mutations either with an internal tandem duplication of FMS-like tyrosine kinase-3 (FLT3-ITD) or point mutation at the activation loop leads to the Acute Myeloid Leukemia (AML), a highly heterogeneous disease. Thus, FLT3 is an important therapeutic target for AML. Methods: In the present work, docking and 3D-QSAR techniques were performed on a series of diaminopyrimidine derivatives as FLT3 kinase antagonists. Results: Docking study recognized important active site residues such as Leu616, Gly617, Val624, Ala642, Phe830, Tyr693, Cys694, Cys695, Tyr696 and Gly697 that participate in the inhibition of FLT3 kinase. Receptor-based CoMFA, RF-CoMFA and CoMSIA models were developed. RFCoMFA model revealed relatively better statistical results compared to other models. Furthermore, the selected RF-CoMFA model was evaluated using various validation techniques. Contour maps of the RF-CoMFA illustrated that steric and electronegative substitutions were favored at R1 position whereas steric and electropositive substitutions were favored at R2 position to enhance the potency. Conclusion: Based on the designed strategy, we derived from the contour map analysis, 14 novel FLT3 inhibitors were designed and their activities were predicted. These designed inhibitors exhibited more potent activity than the most active compounds of the dataset.

Background: A wide range of thiazole, pyrazole and pyran derivatives gained special attention due to pharmacological activities especially therapeutic activities. Many pharmacological drugs containing the thiazole and pyrazole nuclei are known in the market. Methods: The 2-arylidencyclohexan-1,3-dione 3a-c were the key starting compounds for many heterocyclic reactions to produce substituted heterocyclic derivatives. Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 were measured in which the compounds showed high inhibition. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by assessing the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition. Conclusion: Thirty compounds were synthesized. Ten of them (3a, 3c, 5a, 5c, 7a, 10f, 11a, 13c, 16a and 16c) were the most active compounds for selected cancer cell lines. Compounds 3c, 5c, 7a, 10f, 13c and 16c showed high inhibition toward the tyrosine kinases while compounds 3c, 5c and 10f were the most potent to inhibit Pim-1.

Background: Considering that AD is multifactorial in nature, novel series of imidazo [2,1-b][1,3,4] thiadiazole derivatives were designed to address the basic factors responsible for the disease. Methods: These compounds were investigated as inhibitors of beta-site APP cleaving enzyme 1, acetylcholinesterase and butyryl cholinesterase. Results: The BACE1 inhibitory results indicated that nitro phenyl substituted derivatives of imidazo [2,1-b][1,3,4] thiadiazole scaffold (R2 = m-NO2) demonstrated superior BACE1 inhibitory activity compared to other substituted moieties. In the BuChE assay, compounds 4h and 4l carrying meta NO2 at R2 of phenyl ring turned out to be potent inhibitors. Conclusion: In conclusion, these novel synthesized derivatives seem to be promising anti-Alzheimer agents.

Introduction: G protein-coupled receptor kinase 2 (GRK2) is known to be implicated in heart failure, and therefore serves as an important drug target. GRK2 belongs to the protein kinase A, G, and C family and shares high sequence similarity with its closely related protein, the Rhoassociated coiled-coil protein kinase 2 (ROCK2). Therefore, selective inhibition of GRK2 over ROCK2 is considered crucial for heart failure therapy. Objective: To understand the structural factors for enhancing the inhibitory activity for GRK2 and selectivity over ROCK2, we analyzed and compared molecular interactions using the same set of ligands against both receptors. Methods: We have performed molecular docking and three-dimensional quantitative structure activity relationship (3D-QSAR) studies on a series of hydrazone and triazole derivatives. Results: The presence of hydrophobic substituents at the triazole ring, electronegative substituents between the pyridine and triazole ring and hydrophobic substituents near the benzene ring increases the activity of both kinases. Whereas, having non-bulky substituents near the triazole ring, bulky and hydrophobic substations at the benzene ring and electronegative and H-bond acceptor substituents at the triazole ring showed a higher inhibitory preference for GRK2 over ROCK2. Conclusion: The outcome of this study may be used in the future development of potent GRK2 inhibitors having ROCK2 selectivity.

Background: Bubonic plague is amongst the diseases with the highest potential for being used in biological warfare attacks today. This disease, caused by the bacterium Yersina pestis, is highly infectious and can achieve 100% of fatal victims when in its most dangerous form. Besides, there is no effective vaccine, and the chemotherapy available today against plague is ineffective if not administered at the beginning of the infection. Objective: Willing to contribute for changing this reality we propose here new phenylureas as candidates for the drug design against plague meant to target the enzyme dihydrofolate reductase from Y. pestis (YpDHFR). Methods: Seven phenylureas, four of them new, were synthesized, following synthetic routes adapted from procedures available in the literature, and using microwave irradiation. After, they were submitted to docking studies inside YpDHFR and human DHFR (HssDHFR) in order to check their potential as selective inhibitors. Results: Our results revealed four new phenylureas and a new synthetic route for this kind of molecule using microwave irradiation. Also, our docking studies showed that these compounds are capable of binding to both HssDHFR and YpDHFR, with U1 - U4 and U23 showing more selectivity for HssDHFR and U7, U8 being more selective towards YpDHFR. Conclusion: We reported the synthesis with good yields of seven phenylureas, following a simple and clean alternative synthetic route using microwave irradiation. Further molecular docking studies of our compounds suggested that two are capable of binding more selectivity to YpDHFR, qualifying as potential candidates for the drug design of new drugs against plague.

Background: Chromene and anilinopyrimidine heterocyclics are attractive anticancer compounds that have inspired many researchers to design novel derivatives bearing improved anticancer activity. Methods: A series of pyrimidine-fused benzo[f]chromene derivatives 6a-x were synthesized as anticancer hybrids of 1H-benzo[f]chromenes and anilinopyrimidines. The inhibitory activity of the synthesized compounds 6a-x against cell viability of human chronic myelogenous leukemia (K562), human acute lymphoblastic leukemia (MOLT-4) and human breast adenocarcinoma (MCF-7) cell lines was evaluated using MTT assay. The interaction of the most promising compound with calf-thymus DNA was also studied using spectrometric titrations and Circular Dichroism (CD) spectroscopy. Results: Most compounds showed promising activity against tested cell lines. Among them, 2,4- dimethoxyanilino derivative 6g exhibited the best profile of activity against tested cell lines (IC50s = 1.6-6.1 μM) with no toxicity against NIH3T3 normal cell (IC50 >200 μM). The spectrometric studies exhibited that compound 6g binds to DNA strongly and may change DNA conformation significantly, presumably via a groove binding mechanism. Conclusion: The results of this study suggest that the prototype compound 6g can be considered as a novel lead compound for the design and discovery of novel anticancer agents.

Background: Aromatase inhibitors emerged as a pivotal moiety to selectively block estrogen production, prevention and treatment of tumour growth in breast cancer. De novo drug design is an alternative approach to blind virtual screening for successful designing of the novel molecule against various therapeutic targets. Objective: In the present study, we have explored the de novo approach to design novel aromatase inhibitors. Methods: The e-LEA3D, a computational-aided drug design web server was used to design novel drug-like candidates against the target aromatase. For drug-likeness ADME parameters (molecular weight, H-bond acceptors, H-bond donors, LogP and number of rotatable bonds) of designed molecules were calculated in TSAR software package, geometry optimization and energy minimization was accomplished using Chem Office. Further, molecular docking study was performed in Molegro Virtual Docker (MVD). Results: Among 17 generated molecules using the de novo pathway, 13 molecules passed the Lipinski filter pertaining to their bioavailability characteristics. De novo designed molecules with drug-likeness were further docked into the mapped active site of aromatase to scale up their affinity and binding fitness with the target. Among de novo fabricated drug like candidates (1-13), two molecules (5, 6) exhibited higher affinity with aromatase in terms of MolDock score (-150.650, -172.680 Kcal/mol, respectively) while molecule 8 showed lowest target affinity (-85.588 Kcal/mol). Conclusion: The binding patterns of lead molecules (5, 6) could be used as a pharmacophore for medicinal chemists to explore these molecules for their aromatase inhibitory potential.

Introduction: Topoisomerase II alpha (Topo IIα) has become one of the extensively exploited targets in chemotherapy due to its role in regulating the topological constraints of DNA during replication and transcription. Small molecules targeting Topo IIα’s activity such as etoposide (VP-16) and doxorubicin are extensively used in the treatment of many different types of cancer. Objective: Here, the effects of three small molecules, named as azacyanines, on Topo IIα have been assessed. Methods: In-vitro Topoisomerase IIα drug screening kit and agarose gel imaging were used for the assessment of Topo IIα’s activity. Results: Our results revealed that all the azacyanines investigated decreased the catalytic activity of Topo IIα dramatically. More importantly, the decrease in the catalytic activity of Topo IIα in the presence of azacyanines was higher than the presence of VP-16, which is a commercially available chemotherapy drug. Upon further investigation, it has been observed that Azamethyl’s catalytic inhibition of Topo IIα was concentration dependent and the catalytic activity of Topo IIα was almost completely abolished in the presence of 100.0 μM of Azamethyl. Conclusion: These findings reveal the potential of azacyanines as effective Topo IIα inhibitors and chemotherapeutic agents.

The pandemic spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2) that causes COVID-19 calls for global health emergency with wide prevalence across 94 countries, and around 3073 deaths reported in china on 7th March 2020 which created red alert zone in the country. It was further noticed other than China, countries like the republic of Korea ranked first with 6767 cases, Italy with 4747 and Iran with 3513 cases. The spread of COVID-19 made a historical transition between December 2019 to March 2020 by extending the paradigm to a newer territory every day with the highest predicted reproductive number <2. Hence, while combating the epidemic spread, there are spectra of strategies that require crucial validation, some of which include drug repurposing, enzyme inhibition, target drug delivery etc. Among these, the category of drugs called enzyme inhibitors has a unique opportunity in the process of new drug discovery as these enzymes possess structural versatility starting from the host viral interface and up to the release of a new virus. Drugs entrapped within liposomes are highly effective against intracellular microorganisms as per published observations. Regulatory authorities like World Health Organization (WHO) and Centre for disease control and prevention (CDC) strongly recommend the need for the PPE’s like N95 respirator to avoid person to person contact. In this context, Electrospun Nanofiber Technology (ENT) offers ultrathin fibres (20-200 nm) with close proximity of 99.97% of high efficient air filtration. Fabrication of ultrafine nano mask by utilizing electospun technology will surely benefit millions of people in a time-dependent manner.