Letters in Drug Design & Discovery - Volume 14, Issue 2, 2017

The anticancer drug candidate 1,3-dibenzyl-4,5-diphenyl-imidazol-2-ylidene gold(I) chloride (NHC-AuCl) and its 2',3',4',6'-tetra-O-acetyl-β-D-glucopyranosyl-1’-thiolate derivative (NHC-AuSR), which is a potential ligand for glucose transporters, were tested on the NCI 60 cancer cell panel in vitro. NHC-AuCl and NHC-AuSR showed very good activity against a wide range of human cancer cell lines inclusive renal cell cancer with similar average GI50 values of 1.78 and 1.95 μM, respectively. This encouraged maximum tolerable dose (MTD) experiments in mice, where MTD values of 10 mg/kg for NHC-AuCl and 7.5 mg/kg for NHC-AuSR were determined with single injections to groups of 2 mice. In the following tumor xenograft experiment NHC-AuCl and NHC-AuSR were given at MTD in 6 injections to two cohorts of 6 CAKI-1 tumor-bearing NMRI:nu/nu mice, while a control cohort of 6 mice was treated with solvent only. NHC-AuCl at the dose of 10 mg/kg and NHC-AuSR at the lower dose of 7.5 mg/kg induced both low toxicities in the form of abdominal swelling but no significant body weight loss was seen in both groups. The tumor volume growth reduction was significant and almost identical; optimal T/C values of 0.47 were observed on day 19 for NHC-AuCl and on day 29 for NHC-AuSR. Immunohistochemistry for the proliferation marker Ki-67 and the angiogenesis marker CD31 did not show significant changes due to NHC-AuCl or NHC-AuSR treatment in the animals. However, thioredoxin reductase (TrxR) inhibition with IC50 values of 1.5 μM for NHC-AuCl and 3.1 μM for NHC-AuSR seems to indicate that apoptosis induction through elevated oxidative stress is the main mechanism for the two gold compounds.

Urogenital schistosomiasis is a chronic infection caused by the human blood fluke Schistosoma haematobium. Schistosomiasis haematobium is a known risk factor for cancer leading to squamous cell carcinoma of the urinary bladder (SCC). This is a neglected tropical disease endemic in many countries of Africa and the Middle East. Schistosome eggs produce catechol-estrogens. These molecules are metabolized to active quinones that cause alterations in DNA (leading in other contexts to breast or thyroid cancer). Our group have shown that schistosome egg associated catechol estrogens induce tumor-like phenotypes in urothelial cells, originated from parasite estrogen-host cell chromosomal DNA adducts and mutations. Here we review recent findings on the role of estrogen–DNA adducts and how their shedding in urine may be prognostic of schistosome infection and/or represent potential biomarkers for urogenital schistosomiasis associated bladder cancer and infertility.

A series of novel dimethyl ((aryl/heteroarylamino) (4-(pyrrolidin-1-yl) phenyl)) methyl phosphonates were synthesized by simple and an efficient one-pot three component Kabachnik- Fields reaction. Pyrrolidino-4-benzaldehyde (1), different substituted amines 2a-l and dimethylphosphite (3) were reacted at room temperature using aqueous zinc tetrafluoroborate as catalyst under solvent free conditions to obtain the title compounds 4a-l. The anticancer activity was predicted by in silico studies where the best interactions were observed against aromatase, a potential cancer target and even their molecular descriptors and ADME attributes prompted them as safe drug like molecules. Their in vitro evaluation by MTT assay against human prostate cancer cells (PC-3M) revealed their potential anticancer activity when compared with the standard drug cyclophosphamide encouraging their use to control and manage prostate malignancy

In this in vitro study, a series of amino-pyrazole derivatives were designed, synthesized, and evaluated against five human cancer cell lines (PC3, A549, HL60, HCT116, and SW620) for their anti-proliferative effects and inhibition of p53-MDM2 binding. The results of the biological evaluation showed that this series of compounds has improved inhibition of p53-MDM2 binding and anti-proliferative activities compared to previously designed pyrazole derivatives. Compound 6e exhibited the best potency for MDM2 inhibition (FP-IC50 = 9.83 μM). Compound 8e demonstrated a comprehensive potency (FP-IC50 = 15.34 μM) and anti-proliferative activity in all five of the cell lines tested (IC50 = 12.20-32.19 μM).

Some 1(2H)-phthalazinone derivatives were synthesized and their chemical structures were confirmed by 1H-NMR, 13C-NMR, mass and elemental analysis. Subsequently, modified Ellman’s method was used to determine both acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitory activities of the synthesized compounds. The activity results showed that compound 8c was the most active AChE inhibitor with inhibition value of 63% at 100 μM among the tested compounds. In addition, docking of the synthesized compounds into the active sites of AChE and BuChE was carried out in order to predict the binding energies and non-covalent interactions stabilizing the enzyme-ligand complexes.

In the present study, a series of new 6-benzamide containing 4-phenylquinazoline derivatives were designed and synthesized as PI3Kδ inhibitors. The preliminary SAR for this series of compounds was established. PI3Kδ inhibitory assay showed that most of the synthesized compounds achieved significant activity against PI3Kδ. Compound 12h was the most potent PI3Kδ inhibitor, displaying an IC50 value of 17 nM. These results reveal that the 6-benzamide containing 4-phenylquinazoline is an encouraging chemical substructure, deserving further structural exploration to identify novel and highly potent PI3Kδ inhibitors.

CD38 is regarded as a potential target. Inhibitors against CD38 can regulate calcium metabolism in human body to impede the occurrence of disease, including diabetes and myeloma. In this work, 47 thiazoloquin(az)olin(on)es analogues with high pIC50 values in the micromolar ranges are studied by three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking. The comparative molecule field analysis (i.e., CoMFA q2 = 0.790; r2 = 0.967; rpred 2 = 0.872) and comparative molecular similarity indices analysis (i.e., CoMSIA q2 = 0.723; r2 = 0.969; rpred 2 = 0.815) are applied. Then, the Topomer CoMFA method is performed to validate these models, and the results show that this model has q2 = 0.662, r2 = 0.915 and rpred 2 = 0.704. These results indicate that the three models have good predictive abilities. Subsequently, molecular docking highlights the important interactions between the ligand and the CD38 receptor protein.

A new series of 3-aryl/heteroaryl-5-benzofurnyl pyrazoles [5(a-l)] were synthesized from 1,3-β-monothiodiketones through the cyclocondensation reaction with phenyl hydrazine in good yield and characterized by IR, 1H and 13C NMR, Mass and elemental analyses. All compounds were subjected to evaluate antimicrobial activity against various bacteria viz Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, Escherichia coli and Klebsiella pneumoniae and fungal strains viz Fusarium oxysporum and Aspergillus flavus. Further, the inhibition of biofilm formation of Pseudomonas aeruginosa was also carried out. The results showed that some of the synthesized compounds displayed significant antimicrobial activity against tested pathogens. Compounds bearing 3,4,5-trimethoxy (5c) and 4-chloro (5j) substituents on phenyl ring of pyrazole showed the prominent activity against all strains except Lactobacillus species. Among the compounds screened for antibiofilm activity, compounds 5b-d recorded good antibiofilm potential with <50% biofilm formation at 100 μM of which 5b recorded MIC as low as 20 μM.

Some novel pyrazole derivatives were designed and synthesized through multi-step reactions from substituted phenol as starting material. Their structures were confirmed by 1H NMR, FTIR, MS and elemental analysis. All these compounds were evaluated their herbicidal activity. The preliminary bioassay results indicated that some of title compounds displayed moderate herbicidal activity at 200 μg/mL. Among them, compounds 4-chloro-N'-(2-(2,5-dimethyl-phenoxy) acetyl)-3-ethyl-1-methyl-1H-pyrazole-5-carbohydrazide, 4-chloro-N'-(2-(2,4-dichlorophenoxy)acetyl)- 3-ethyl-1-methyl-1H-pyrazole-5-carbohydrazide, 4-chloro-3-ethyl-1-methyl-N'-(2-(m-tolyloxy) acetyl)-1H-pyrazole-5-carbohydrazide and 4-chloro-3-ethyl-1-methyl-N'-(2-(3-nitrophenoxy)acetyl)- 1H-pyrazole-5-car-bohydrazide possessed 95%, 100%, 95% and 95% inhibition against Brassica campestris respectively. In the further bioassay, the compound 6l exhibited excellent herbicidal activity either monocotyledon or dicotyledon plant at 150 g/ha.

Various benzimidazole compounds containing a triazole nucleus were synthesized and screened for their antioxidant activies. The structures of newly synthesized compounds were characterized by 1H NMR, 13C NMR and elemental analysis data. Antioxidant features of the synthesized compounds were investigated by different processes such as 2,2-diphenyl picryl hydrazyl (DPPH),2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) and CUPric reducing antioxidant capacity (CUPRAC) methods. Significant antioxidant activity was achieved by some of the synthesized compounds demonstrated as much activity as standards (AA and BHT). Correlation analysis between the CUPRAC antioxidant and ABTS radical scavenging assays revealed positive correlation (R2= 0.926), indicating differing antioxidant activities based on the reaction mechanism

N-acetylcysteine (NAC) exhibits diverse pharmacological effects due to the free radical scavenging ability of the reduced thiol. Extensive deacetylation in liver, high protein binding and poor permeability results in low bioavailability of NAC. These setbacks are also the contributing factors in failure to confirm the benefits of NAC in prevention of diseases involving oxidative stress. Present study was aimed at improving the bioavailability of NAC by conjugating it with morpholinoethanol into a morpholinoethyl ester conjugate (A-2). A-2 was synthesized by DCC coupling and the structure was confirmed by IR, 1H-NMR, 13C-NMR, elemental analysis and mass spectroscopy. This conjugate was screened in ovalbumin-induced airway hyperresponsiveness for various lung function parameters where it exhibited significant ameliorating effect; interestingly at half the equimolar dose of NAC. Thus, A-2 has the potential to be used as a substitute for NAC in conditions involving airway hyperresponsiveness and airway eosinophilia.

A series of new biologically potent N-substitutedpyrazoline derivatives have been synthesized by reacting hydrazine hydrate and its derivatives with (2)-1-(4-chlorophenyl)-3-[4-(propan-2- yl)phenyl]prop-2-en-1-one, which in turn prepared by the base catalysed Claisen-Schmidt condensation reaction of 4-(propan-2-yl)benzaldehyde and 4-chloroacetophenone. All the synthesized compounds, 2a-e, 3a-d, 4a,b and 5a-c were screened for their in vitro antibacterial, antioxidant, antiproliferative properties and compounds 3b, 4b were evaluated for in vivo anti-inflammatory activity. The docking studies were carried out for these compounds against α-amylase with TREX1 (PDB:3B60) to predict their putative interactions. Some of the tested compounds showed significant antibacterial, antioxidant, antiproliferative, anti-inflammatory activity and molecular binding.

Aryloxy phenoxy propionic acid esters (APP) chiral herbicide is a kind of acetyl coenzyme A carboxylase enzyme (Acetyl CoA Carboxylase) inhibitor. Sulfonylureas and diphenylethers herbicide are the acetohydroxyacid synthase (ALS) inhibitors and 4,6-dimethoxypyrimidine is the major active group. Bioisosterism and active group combination principle were the primary and effective ways to develop novel pesticides. By using the above principles, we synthesized phenoxy propionate and phenoxy acetamide compounds which containing 4,6-dimethoxypyrimidine. Bioassay results showed that these compounds have no obvious herbicidal activities, but some of them showed higher inhibitory activities for cucumber downy mildew (Pseudoperonospora cubensis) and tomato late blight (Phytophthora infestans), the individual compounds showed milder inhibitory activities for wheat powdery mildew (Blumeria graminis) and rice blast (Pyricularia grisea).

The benzyloxy-benzyl moiety is a valuable building block in medicinal chemistry, e.g. in case of the voltage gated sodium channel blockers Safinamide and Ralfinamide. To prepare further derivatives a series of (iodobenzyl)oxybenzaldehydes (3a-3i) useful intermediates for the synthesis of biologically active compounds were synthesized in high yields by O-benzylation of 2-, 3- and 4- hydroxybenzaldehydes (2a-2c) with a variety of iodobenzylbromides (1a-1c). The title compounds were obtained in 77-100 % yield in 2-5 hours. Longer reaction time or addition of water favoured the formation of aldol-type by-products, mainly 4-hydroxy-4-{[(iodophenyl)methoxy]phenyl}butan-2-one derivatives (5a-5g), which contained the iodine group and the 4-hydroxy-butan-2-one moiety in various positions. In one case (3E-)-4-{3-[(2-iodophenyl)methoxy]phenyl}but-3-en-2-one (6c) with a double bond has been isolated. These side-reactions could be avoided by using acetonitrile as solvent. The structures of the new products were established by high resolution MS and NMR measurements, where 1H-1H, direct 1H-13C, long-range 1H-13C scalar spin-spin connectivities were established from 1D 1H, 13C, 2D gHSQCAD, zTOCSY and gHMBCAD NMR experiments.

Inflammation and its treatment has been studied for thousands of years and is characterized as a nonspecific but beneficial response of tissues to injury. Inflammation is distinguished by symptoms such as redness, pain, and swelling. The anti-inflammatory agents are used to encounter inflammation. It has been found that conventional synthetic nonsteroidal anti-inflammatory drugs (NSAIDs) are effective in various inflammatory conditions but associated with gastrointestinal, liver and kidney problems. Therefore, natural products could be an ideal therapeutic alternative. Our review encounters all the alkaloids with anti-inflammatory effect and/or possible mechanism where reported. It is concluded that further detail mechanistic and clinical studies could lead to the discovery of more effective therapeutic agents in the class.