Letters in Drug Design & Discovery - Volume 16, Issue 9, 2019

Background: Hydrazide-hydrazones constitute an important class of compounds for new drug development. In this study, a series of 39 new acylhydrazones (3-41), derived from (2S)-3-methyl- 2-[[(4-methylphenyl)sulfonyl]amino]butanoic acid hydrazide were synthesized with further aim to achieve biologically active acylhydrazones carrying an amino acid side chain. Methods: Compounds 3-41 were synthesized by microwave-assisted method. All synthesized compounds have been tested for their anti-HIV activity compound 21 was subjected to a new set of 2DNMR analysis for the characterization of the isomers in solution and determination of its 3D structure. Results: The IC50 values for compounds 2-40 were found between >125-10.90 μg/ml against HIV- 1(IIIB) and HIV-2(ROD) strains in MT-4 cells. Compounds 3, 6, 10, 12, 23, 24, 27, 32, and 37 with CC50 values between 10.90-14.50 μg/ml were selected to evaluate for their antileukemia activity. IC50 values for these mentioned compounds were found as >100μM on human chronic myelogenous leukemia, K562 cell line. Conclusion: Some compounds with IC50 values between 10.90-14.50 μg/ml will be of benefit in the development of novel leads.

Background: Diabetes is the primary cause of fatality and disability all over the world, in recent past, we have reported various classes of compounds as anti-glycating agents and we have also reported benzimidazole and benzothiazole derivatives as a potential class of anti-glycating agents. This encouraged us to evaluate the pyridinyl benzimidazole/pyridinyl benzothiazole derivatives 1-27 for yeast glucose uptake activity. Methods: In the present study, an equimolar mixture of pyridine carboxaldehyde derivatives (1 mmol) and sodium metabisulphite (1 mmol) in DMF (10 mL) was stirred for 10 to 15 min, followed by addition of o-phenylene diamine/2-aminothiophenol (1 mmol) into it and refluxed for 3 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was poured into crushed ice. Precipitates were formed which were collected by filtration to produce compounds 1-27 in good yields. Recrystallization from methanol yielded pure crystals. Results: Our present study showed that all compounds showed a varying degree of yeast glucose uptake activity in the range IC50 = 36.43-272.20 μM, compared to standard metronidazole (IC50 = 41.86 ± 0.09 μM). Compounds 5 (IC50 = 38.14 ± 0.17 μM), 6 (IC50 = 40.23 ± 0.20 μM), and 7 (IC50 = 36.43 ± 0.02 μM) showed an excellent yeast glucose uptake activity better than the standard. Conclusion: Pyridinyl benzimidazole/pyridinyl benzothiazole derivatives 1-27 were synthesized, structurally characterized, and evaluated for in vitro yeast glucose uptake activity. Compounds 5 (IC50 = 38.14 ± 0.17 μM), 6 (IC50 = 40.23 ± 0.20 μM), and 7 (IC50 = 36.43 ± 0.02 μM) demonstrated potent yeast glucose uptake activity as compared to standard metronidazole (IC50 = 41.86 ± 0.09 μM). This study identified a number of potential lead molecules which can be helpful in lowering the blood glucose level in hyperglycemia.

Background: Cancer is a fatal disease for mankind; continuous research is still going on for the invention of potent anticancer drugs. In this view, 1, 3, 4-Oxadiazoles are privileged molecules which attracted medicinal chemists towards their anticancer properties. Methods: A new series of benzo[d]imidazol-5-yl)-5-(substituted)-1,3,4-oxadiazole derivatives was synthesized in an efficient ‘one-pot’ nitro reductive cyclization using sodium dithionite as a cyclizing agent by a conventional method with good yield. All the structures of the synthesized molecules were characterized by IR, 1H NMR, HRMS and Mass spectral analysis. Anticancer activity screening against A375 melanoma cancer cell line and MDA-MB-231 breast cancer cell line along with antimicrobial activity were carried out using agar well diffusion method. Results: Compounds 8a and 8j of the series emerged as potent anticancer agents against A375 melanoma cancer cell line with IC50 47.06 μM and 36.76 μM, respectively. In silico studies also revealed that compounds 8a and 8j showed highest interaction with 2OH4 protein of VEGFR-2 tyrosine kinase. Substantial antibacterial and antifungal activities against the tested microorganism were observed for compounds 8j and 8g. Conclusion: Potent anticancer property has been observed with 1,3,4-Oxadiazole linked tetrafluro substituted benzene ring 8j indicating that future research on these type of molecules can be continued to improve the anticancer activity.

Background: The main issue is finding the most efficient method in the treatment of cancer in terms of early and accurate diagnostic. One of the most modern diagnostic techniques is imaging methods. The accuracy and detection speed of MRI and CT SCAN are high. Methods: The most important complication of iodinated contrast agents in medical imaging is severe renal toxicity Nephrogenic Systemic Fibrosis (NSF). In order to reduce the cytotoxicity of kidney cells caused by the usage of iodized contrast agents a complex agent should be designed. The two drugs which have been used for the synthesis of this compound are L -lysine amino acid and NAcetyl- Cysteine (NAC). Results: The synthesis of this complex due to two dimer molecules with each other and NAC greatly a helper for an antioxidant activity and L-lysine amino acid helps in drug entry into the cells. However, helping for an antioxidant activity heavily reinforce and eventually will successfully reduce the cytotoxicity. When its exposure to HEK 293 cell line (P<0.05). The reduction in toxicity at the dosage of 100 μM has been showed as the greatest reduction. The amount of renal toxicity was reported 40% in Omniscan. Conclusion: Omniscan was tested when iodinated contrast medium was combined with the synthesized 2NAC-LYS-OMNISCAN complex and the human embryonic kidney 293 (HEK293) cell line. Then, the cytotoxicity was reduced to 10 %. On the other hand, the viability increased from 60 % to 90 %, or in other words, the cytotoxicity was reduced from 40 % to 10 %.

Background: Several series of pyrazole derivatives containing (thio) semicarbazide (4a-4h, 5a-5l, 6a-6f, 7a-7c) were designed and synthesized to screen dual inflammatory and antimicrobial activities. Methods: The products were characterized by1H NMR, 13C NMR and HRMS. In vitro LPS-induced TNF-α model and in vivo xylene-induced ear-edema model were used to evaluate their antiinflammatory activity. Their in vitro antimicrobial activities were evaluated using a serial dilution method against several gram-positive strains, gram-negative strains and a fungi strain. Results: Bioassays indicated that most of the compounds markedly inhibited the expression of TNF- α at the concentration of 20 μg/mL Compounds 5i, 6b, and 7b had comparable in vivo antiinflammatory activity to the reference drug dexamethasone at the dose of 50 mg/kg. In addition, several compounds showed antimicrobial activity against different strains, and compounds 5g and 5h exhibited potent inhibitory activities with the MIC value of 8 μg/mL against the Streptococcus pneumoniae CMCC 31968 and Staphylococcus aureus CMCC 25923, respectively. Compound 7b, which exhibited both anti-inflammatory and antimicrobial activities, should be studied as it is or after derivatization. Conclusion: It can be concluded that pyrazoles, with (thio)-semicarbazone moieties, have the potential to be developed into new anti-inflammatory agents.

Background: There has been increased interest in the research of proteasome inhibitors for more than two decades. Hotspots in this field are constantly changing. Objective: This study aimed to investigate trends in proteasome inhibitors research from 1992 to 2018 and compare the contributions of such research from different countries and authors. Methods: We used Excel 2013 and VoSviewer to analyze bibliometric data on the subject of proteasome inhibitors, including the number of publications, citations frequency, H-index, and country contributions and hotspots (keywords of popular scientific fields). Results: A total of 3646 articles were included. The USA contributed the largest percentage of articles (1742), with the most citations (90666) and the highest H-index (139). The journal Blood had the most articles. Dana Farber Cancer Institute and Millennium Pharmaceuticals Incorporation were the most contributive institutions. Keywords could be divided into three clusters: Basic experiment, clinical research, and others. Conclusion: The number of proteasome inhibitors articles has been increasing for the past 27 years. The USA made the largest contribution in this field. Recent studies on the topic of “carfilzomib” are relatively new and should be closely followed in proteasome inhibitors research.

Objective: According to the principles of drug design, the structures of picotamide and betrixaban were combined to design novel series of 2-methoxy-5-aminobenzamides. A total of twenty new compounds 1a-1t have been synthesized and evaluated for their antiplatelet aggregation activities in vitro. Methods: In the structural design of target compounds 1a-1t, the betrixaban was retained group characteristics and the picotamide was retained its 1, 3, 4-substitution position. With 2-methoxybenzoic acid as starting material, compounds 1a-1t were synthesized after 5 steps of nitration, acylation, ammoniation, reduction and secondary ammoniation. And their antiplatelet aggregation activities in vitro were assessed by the Born test with ADP, arachidonic acid and collagen as inducing agents, respectively, and with aspirin and picotamide as two reference drugs. Results: The compound 1f (46.14%±0.07) had the highest activity for ADP and its IC50 value was 0.17 μM, far better than the two control drugs aspirin (0.44 μM) and picotamide (0.47 μM). The IC50 value of four compounds 1i (0.24 μM), 1j (0.22 μM), 1r (0.25 μM) and 1t (0.24 μM), displayed higher antiplatelet activities in vitro for AA than aspirin (0.43 μM) and picotamide (0.34 μM). Evaluation of cytotoxicity activity of the compounds against L929 cells line revealed that at lower concentration of 10 μmol·L-1, compound 1p had lower effect on L929 cells, and its cell survival rate (88.24%±4.16) was higher than that (82.35%±4.16) of picotamide. Conclusion: Novel series of 2-methoxy-5-aminobenzamides has shown higher in vitro antiplatelet activities and lower effect on L929 cells at lower concentration.

Background: The Gastric H+/K+-ATPase is also known as proton pump is the enzyme responsible for the acidification of gastric juice. H+/K+ GastroEsophageal Reflux Disease (GERD) and other acid related diseases mainly depend on the inhibition of the gastric H+/K+- ATPase which will finally result in acid secretion in stomach. GERD is one of the diseases that have significant effect on the quality of human life and are the major burden on health care systems is that leads to heart burn, acid regurgitation, chest pain, epigastric pain, and respiratory conditions such as chronic cough. Hence the study of the inhibitors of Gastric H+/K+-ATPase is desired. Methods: Research and online content related to imidazo [1, 2-a]pyrazine and heterocyclic ring analogues (I) that were synthesized and evaluated for their Gastric H+/K+-ATPase inhibitory activity is reviewed, and in order to design and develop still better and more effective H+/K+-ATPase inhibitors, we have made Quantitative Structure Activity Relationship (QSAR), docking and ADMET studies on these compounds. Results: The best MLR equation based on four descriptors along with statistical parameters is obtained using Statistica dataminer software. Using the model expressed by this study we predicted some new compounds of high H+/K+-ATPase inhibition potency. Each predicted compound has very high potency with which only a few compounds of existing series can match. Conclusion: The QSAR and molecular modelling studies suggested that still better compounds can be designed if the flexibility of the molecules can be increased for which attempts can be made to have more saturated atoms in the molecules. Such a compound predicted by us was found to have interactions with the enzyme H+/K+-ATPase almost in the same manner as the FDA approved compounds, lansoprazole, pantaprazole.

Background: Drugs that interfere with microtubule dynamics are used widely in cancer chemotherapy. Microtubules are composed of αβ-tubulin heterodimers, and the colchicine binding site of tubulin is an important pocket for designing tubulin polymerization inhibitors. We have previously designed and synthesized a series of colchicine binding site inhibitors (CBSIs). However, these compounds showed no anticancer activity in vivo. Then, we have used a deconstruction approach to obtain a new derivative MT189, which showed in vivo anticancer activity. Methods: We crystallized a protein complex including two tubulins, one stathmin-like domain of RB3 and one tubulin tyrosine ligase, and soaked MT189 into the crystals. We collected the diffraction data and determined the tubulin-MT189 structure to 2.8 Å. Results: Here, we report the crystal structure of tubulin complexed with MT189, elucidate how the small-molecular agent binds to tubulin and inhibits microtubule assembly, and explain previous results of the structure-activity-relationship studies. Conclusion: The tubulin-MT189 complex structure reveals the interactions between this agent and tubulin and provides insights into the design of new derivatives targeting the colchicine binding site.

Background: Diabetes is a chronic endocrine associated metabolic ailment. It is chiefly characterized by hyperglycemia, which results due to deficient insulin levels caused by either obliteration of pancreatic beta cells or the incompetent sensitivity of insulin at the target tissue. Methods: In the present study, selected compounds (Abrotandiol, Abrotanone, Lariciresinol, Pinoresinol, Syringaresinol and Taxiresinol) from Perovskia atriplicifolia were evaluated for antidiabetic potentials using molecular docking simulations and computational tools. Results: All selected compounds possess moderate to strong respective activities against aldose reductase, DPP-IV, PTPB, insulin receptor and PPAR-g. Selected compounds that include Abrotandiol, Lariciresinol, Pinoresinol, Syringaresinol, Abrotanone and Taxiresinol have shown highest binding energies of ΔG = -9.3 kcal/mol, -8.9 kcal/mol, -8.9 kcal/mol, -8.8 kcal/mol, -8.8 kcal/mol and -7.6 kcal/mol respectively against PPAR-g. However, out of six compounds, Abrotanone has shown strong potential binding energy against all selected targets, i.e. ΔG = -7.8 kcal/mol with aldose reductase, ΔG = -10.3 kcal/mol with DPP-IV, ΔG = -9.3 kcal/mol with PTPB and ΔG = -8.3 kcal/mol with insulin receptors. Conclusion: The present study proposed that all selected compounds possess antidiabetic activity. However, Abrotanone has a strong antidiabetic potential. This assumption provides better insight to evaluate further these compounds for in vitro and in vivo testing against diabetes in future.