Letters in Drug Design & Discovery - Volume 14, Issue 12, 2017

Background: Aminopeptidase N also known as APN/CD13 is a zinc-dependent type II membrane-bond ectopeptidase that is overexpressed on cancer cells. APN/CD13 is considered as an attractive target for anti-cancer drug design due to key roles in tumor invasion, angiogenesis and metastasis. Therefore, study of quantitative relationships between activity and structures of APN/CD13 inhibitors can provide useful information for the designing and synthesis of novel APN inhibitors. Methods: In this study, the linear method was used to develop QSAR models in order to predict the activities of APN/CD13 inhibitors. A dataset that consisted of 39 leucine ureido derivatives was divided into the training and test subsets. Genetic algorithm and stepwise methods have been employed for selection of relevant descriptors. Results: Multiple linear regression analysis with GA selection was used to model the structureactivity relationships. In this model, R2 was 0.84 for the training set and 0.67 for the test set. We also applied the SW technique as variable selection procedure to the same data set. With the use of SW, the 6 most relevant descriptors were selected to build the model. The value of R2 of the SWMLR model was 0.87 for the training set and 0.77 for the test set. Both models were validated by leave-one-out (LOO) cross-validation. Conclusion: The results of SW-MLR and of GA-MLR were confirmed and is appeared that the SW-MLR model had more power to predict APN inhibitory activity. On the basis of QSAR models, charge polarization, the atomic masses, polarizability, the atomic van der Waals volumes, the molecular symmetry and aromaticity index were found to be important factors controlling the APN inhibitory activity.

Background: Imidazolones as well as Schiff base are extensively used as building blocks for the synthesis of various pharmaceutically active agents. The use of synthetic antioxidant for use in the diet and therapy demands a great deal of research attention for synthetic antioxidants. It was observed that the π-excessive ring systems are responsible for antioxidant activity of the compounds. Objective: The primary objective of this study was to develop a new method to synthesize imidazalone derivatives which are evaluated for in vitro antioxidant activity in order to check their nutraceutical value. Methods: Novel method for the synthesis of imidazalone derivatives is developed starting from simple easily accessible glycine, thiophene aldehyde and benzoyl chloride. The synthesis of target molecules is achieved in four steps via formation of an intermediate oxazolone which undergoes ring opening on reaction with hydrazine hydrate and subsequent cyclization with aldehydes in presence of acid catalyst. Results: All Imidazolone compounds were evaluated for their in vitro antioxidant activity using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. Almost all the tested imidazalone compounds showed moderate to excellent activity, the substitution on arylidene group substantially influenced their overall activity. The compound 3-{[(E)-(4-chlorophenyl)methylidene]amino}-2- phenyl-5- (thiophen-2-ylmethylidene)-3,5-dihydro-4H-imidazol-4-one (9) showed very high radical scavenging capacity with IC50 value 2.886 μg/ml in comparison with the standard ascorbic acid (1.439 μg/ml). The antioxidant activities of the synthesized compounds appeared in the following order 6 >5> 13> 8>7>20>11>12>10>19>15>14>18>16 and 17. Further in silico studies complement the in vitro antioxidant studies. Conclusion: Compound, 3-{(4-chlorophenyl)methylidene]amino}-2-phenyl-5-(thiophen-2-ylmethylidene)- 3,5-dihydro-4H-imidazol-4-one (9) displayed best antioxidant activity due to the presence of active chloro group. Compounds bearing hydroxyl group at para and ortho position (16 and 18) showed very low activity. This anomalous result could be explained on the basis of intramolecular hydrogen bonding. These results were complement the in silico antioxidant studies.

Background: Dolutegravir sodium is a HIV-1 integrase strand transfer inhibitor (INSTI) and in combination with other anti-retroviral agents, is recommended for the treatment of HIV-1 infection. Moreover, it is a second generation HIV integrase inhibitor designed to deliver potent antiviral activity. Originally, collaboration between Shionogi and Glaxo Smith Kline (GSK) led to dolutegravir sodium which is marketed under the trade name Tivicay®. Its synthesis involves the reaction of (R)-3-aminobutanol (1) with 3-benzyloxy-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine- 2,5-dicarboxylic acid 2-methyl ester. Later, the (R)-3-aminobutanol became a key intermediate for the synthesis of Dolutegravir sodium. Methods: In our method the (R)-3-aminobutanol is synthesized in a three/four-step synthetic protocol using 4-Hydroxy 2-butanone as starting material, initial formation of oxime with hydroxyl amine, followed by replacement of developed lithium aluminum hydride (LAH) for reduction of oxime using Raney ‘Ni’, which provided the enantiomeric mixture of 3-aminobutanol in about 85-90 % yield, which is more significant compared to earlier approach (yield: 70 %). Further the mixture was resolved with D-(-)-tartaic acid to obtain the R-isomer as an ester. The ester is then hydrolyzed with potassium carbonate in methanol to give pure (R)-3-amino butanol in 90 % yield and chiral purity was found to be 99.89 % by HPLC. Results: The present method is highly economical and eliminates the use of expensive catalysts. Moreover, the reaction conditions adopted in this process are mild and suitable for industrial applications and is further supported by our study with a large scale (up to 30 Kg) and the yields obtained are quite good. It is our claim that the present methodology is extremely useful for preparation of (R)-3-aminobutanol on commercial scale. Conclusion: We have developed a simple and efficient method for the synthesis of (R)-3- aminobutanol in industrial scale from 4-hydroxy-2-butanone. The process also involves the use of Raney Ni as an eco friendly reagent for the conversion of oxime to amine which is superior to reported LAH approach. Further, the process also uses an inexpensive D-(-)-tartaric acid as a chiral reagent. The developed method involves very cheap reagents, experimental procedures are highly convenient and the yields are impressive.

Background: Hepatitis C Virus (HCV) infection is one of the causes for liver cirrhosis and hepatocellular carcinoma leading to liver failure. An estimated 2-3% of the world population is chronically infected with HCV. HCV is a positive single stranded RNA virus encoding for a single polypeptide, which cleaves into structural and non-structural proteins. The non-structural (NS) proteins play critical roles in viral replication and have become the targets for HCV chemotherapy. The current treatment involves pegylated interferon-α/ribavirin-based treatment and a combination of direct-acting antivirals. NS5B is a critical enzyme for the replication of HCV RNA and is an interesting target for the screening and design of small molecule inhibitors to interfere in the HCV viral replication. Methods: Screening of a library of compounds in a replicon assay, a thiazolone derivative was identified as a NS5B enzyme inhibitor (IC50: 11 μM). Based on the structure of this lead compound, few libraries of compounds were designed and synthesized following a fragment based approach. Structural features of both peptide-based and non-peptide-based protease inhibitors such as lopinavir and tipranavir were considered while designing novel compounds. Results: Several novel protease inhibitors were designed and synthesized based on the structural fragments of lopinavir and tipranavir. This resulted in identification of compounds with thiazolone scaffold as having good anti-HCV NS5B enzyme activity. However, to improve their cellular activity, the thiazolone scaffold was then tethered with several amino acids and then screened for their anti-HCV activity which led to finding a tethered thiazolone as novel hepatitis C NS5B polymerase inhibitor with good cellular potency (EC50 = 1.2 μM). Conclusion: Systematic modification of lead compound (EC50 = 35 μM) from an enzyme assay and by tethering with a suitable amino acid improved the cellular potency of the lead compound. This resulted in a compound 18c with nearly 30 fold (EC50 = 1.2 μM) potent compound in cellular assay than the original lead compound. It's believed that this improvement was possible because of better transport of the active compound into the cell due to its amino acid tether.

Background: Thiazolopyrimidines possessed their structural diversity and various biological activity. Up to date, thiazolopyrimidines derivatives have widespread applications in pharmaceutical fields. In this article, a series of thiazolopyrimidine derivatives were designed based on the lead compound structure in our previous studies. Methods: All the target compounds were synthesized with the coupling reaction, Biginelli reaction and “one-pot” aldol condensation. Their structures were identified by 1H NMR, 13C NMR spectra and HRMS. Antitumor activities of the target compounds were evaluated by MTT. Results: 25 new target compounds were synthesized and they primarily screened through testing their inhibitory rates against two human tumor cell lines and Compounds 15, 17, 20, 22, 40 exhibited more than 70% inhibitory rate against both MDA-MB-231 and K562. Further assessing their IC50 against five tumor cell lines, 15 and 22 show advantage over lead compound I in MDAMB- 231, K562 and PC-3. Conclusion: A series of thiazolopyrimidine derivatives were synthesized and the preliminary biological evaluation suggest that target compound 22 exhibited better antiproliferative activity against K562 than gossypol.

Background: Elevated levels of serum LDL and total cholesterol are considered important risk factors for the development of atherosclerosis. Cholesteryl ester transfer protein inhibition raises HDL levels and reduces atherosclerotic lesions. Objective: Consequently, there is a great interest in developing new CETP inhibitors. Methods: Herein, synthesis of four chlorobenzyl benzamides 8a-d that aim at CETP inhibition was performed. Results: Benzamide 8a showed the best CETP inhibitory activity with an IC50 of 1.6 μM. In vitro biological data shows that the presence of p-trifluoromethoxy group enhances CETP inhibitory activity more than m-trifluoromethyl groups. QPLD docking shows that the verified compounds accommodate the binding cleft of CETP and are enclosed by hydrophobic lining. The scaffold of 8a-d matches the pharmacophoric points of CETP inhibitors; particularly hydrophobic and aromatic functionalities. Conclusion: Future structural modification is needed to improve CETP inhibitory activity and to enhance understanding of the structure-activity relationship.

Introduction: Currently, there are a significant number of drugs getting approval with poor biopharmaceutical characteristics, as low solubility and bioavailability. These facts lead to a decrease of the therapeutic effect and to an increase of the drug dosage. In this regard, there is a need to overcome this problem, in which the development of new drug delivery systems (DDS) arises as a promising strategy, since these systems could improve some drug characteristics, like solubility and dissolution rate, increasing their therapeutic effect with a lower dose. Therefore, the aim of this work consisted in the development and characterization of a new formulation of mixed polymeric micelles based on Pluronics® P123 and F68 to improve the administration of meloxicam (MLX). Methods: Firstly, polymeric micelles were prepared by the thin-film method. Secondly, it was performed the physicochemical characterization of the systems through the evaluation of their size, increment of solubility (IS) and encapsulation efficiency (EE) by DLS and UV spectroscopy, respectively. Besides this, it was also evaluated the morphology of the polymeric micelles by transmission electronic microscopy (TEM) and their chemical structure by FTIR spectroscopy and differential scanning calorimetry (DSC). Moreover, it was determined the physical stability of these systems and their cytotoxicity in vitro. Results: The obtained results show that the formulation FM2, (Pluronic P123 and MLX) and the formulation FM3, (Puronic P123 and F68 and MLX) have presented the better results for size, polydispersion index (PDI), IS and EE. Being, these results related to the capacity of these formulations to protect and to avoid the sequestration of MLX by the liver and spleen and, consequently, to improve the bioavailability of MLX. Besides this, these systems have the better results for the assay representing the physical stability in the passage for the gastrointestinal (GI) tract and they have a low toxicity for the cells, even at bigger concentrations. Conclusion: Thus, these formulations can be considered promising systems to improve the solubility of MLX and other poor soluble drugs in an oral administration.

Background: Pyrimidine-based drugs stimulate tissue regeneration and immunity, two components that need to be improved in a number of respiratory diseases of different etiology (e.g. influenza and asthma). In the present study we investigated relationships between the character of substitutions in the uracil structure and the impact of the respective uracil derivatives on the immortalized lung cells. Methods: The level of cell proliferation, maximum tolerated dose and toxic effect of 5-substituted uracil derivatives (12 compounds) were studied on the immortalized lung epithelial cells and compared with the ones of 6-methyluracil. Results: 5-Carboxyuracil and 1,3-dimethyl-5-carboxyuracil had the lowest cytotoxicity among the studied compounds. Their maximal tolerated dosage values were 5 times higher whereas the proliferation index was increased by 25% and 75%, respectively, compared to 6-methyluracil, known for its positive effects on cell regeneration. Conclusion: 5-Carboxyuracil and 1,3-dimethyl-5-carboxyuracil have the best perspectives for further studies on their biological effects.

Background: Brominated 8-hydroxy, 8-methoxy, 8-amino quinolines 5, 6, 8, 9 and novel cyano 8-hydroxyquinolines 11, 12 were evaluated in vitro for their anticancer effects on various cell lines. 5,7-Dibromo- 5, 7-bromo- 6, 7-cyano- 11 and 5,7-dicyano-12 8-hydroxyquinolines were shown to have strong antiproliferative activity against various tumor cell lines, including C6 (rat brain tumor), HeLa (human cervix carcinoma), and HT29 (human colon carcinoma) with IC50 values ranged from 6.7 to 25.6 μg/mL. Methods: A structure activity relationship (SAR) was conducted that quinoline core containing hydroxly group at C-8 positon led to more anti cancer potentials. Results: The results of Lactate Dehydrogenase (LDH) cytotoxic, DNA laddering and inhibition assays indicated that 5, 6, 11 and 12 have high cytotoxic effects and appototic potentials. Conclusion: Furthermore, 5 and 12 have inhibitory effects on relaxation of supercoiled plazmid DNA by supressed the Topoisomerase I enzyme. As a result, 5, 6, 11 and 12 may have promising anticancer drug potential and 5 and 12 may be novel topoisomerase inhibitors.

Background: Curcumins were reported to possess anti-inflammatory and antiangiogenic. Furthermore, Curcumin is a very potent free radical scavenger than vitamin E. Moreover, cyanoacetamides were reported to possess, antimicrobial antifungal, insulin releasing, antiinflammatory and antitumor. Thus the present study focuses on the synthesis of some novel structure hybrids incorporating either curcumin or cyanoacetamide with sulphonamide, aiming to reach a more potent antioxidant agent. Methods: 4-arylazoenol derivatives 12-16 and E-hydrazo derivatives 19-23 were prepared and their structure was confirmed by variable spectra analysis. The newly synthesized compounds were screened for their antioxidant activity using ABTS and Bleomycin-dependent DNA damage methods. Results: Coupling of the diazonium salts 7-11 of different sulpha drugs with curcumin 1 or with cyanoacetamide 18 afforded the corresponding 4-arylazoenol derivatives 12-16 and E-hydrazo derivatives 19-23. Among all the synthesized compounds, 12-16, 18, 20 and 22 were the most potent antioxidant compounds. Conclusion: The objective of the present study was to synthesize and evaluate the antioxidant activity of some novel sulfonamides structure hybrids incorporating either curcumin or N-[4- (aminosulfonyl) phenyl]-2-cyanoacetamide moiety with the hope of discovering new structure serving as antioxidant agent. The data showed clearly that most of compounds displayed good in vitro antioxidant activities.

Background: Salmonella typhimurium is a pathogen, causing a threat to human health worldwide. The severity in treatment raises as the pathogen develops resistance against wellestablished drugs. To combat these multidrug-resistant pathogens, novel target and antimicrobial agents are needed. The literature supports the potency of L-asparaginase as a novel target as it provides survival benefit to the pathogen. The plant-derived molecules holds remarkable potential and therefore, their antimicrobial properties are explored in the present study. Methods: In the present work in silico studies were performed to test the efficacy of chemoconstituents of spices as antimicrobial agents against the novel target l-asparaginase. The pharmacokinetic profile of the lead molecules were also studied by determining their ADMET properties. Results: The results obtained through in silico studies suggest the efficacy of 27 ligands (spices chemoconstituents) as anti-microbial agents that were effective in blocking the virulent protein lasparaginase. The lowest docking score obtained for piperic acid derivative 1 was -7.591 while for ampicillin (the standard drug) was -5.797. Piperic acid derivative 2, drupanin, ent-copalic acid, 4- amino cinnamic acid, 3-O-prenyl coumaric acid also displayed good results in terms of docking score and ADMET profiling. The amino acid residues commonly involved in the interaction within the druggable pockets are Thr35, Thr55, Thr115, Gly34, Gly83, Asp116. Conclusion: The molecular docking and ADMET profiling of spices chemoconstituents pave the path for future drug development against the multidrug resistant S. typhimurium via L-asparaginase targeting.

Background: High attrition rate in late drug discovery and development stages leads to financial loss to industries and Governments. Despite the global prevalence of HIV infection and lack of promising treatment for AIDS patients, there are only a few drugs approved for the management of infected patients. There is an urgent need to discover newer anti-HIV drugs with novel mechanism of action and with efforts to reduce attrition rate in early drug discovery stages. Objective: Prioritization of reported potential anti-HIV-1 leads according to their quantitative estimation of druglikeness (QED), carcinogenicity, mutagenicity, absorption, metabolism and toxic properties. Synthesis of analogs of the best lead and evaluation of their anti-HIV-1 activity is shown. Methods: In silico anti-HIV lead prioritization was performed on a set of known anti-HIV natural products in order to obtain a lead with better druglikeness and ADMET properties. Prioritized lead tembamide and its four analogs were synthesized and their anti-HIV-1 activity was evaluated. Results: Tembamide was found to be a lead with better QED, absorption and metabolism properties and with no carcinogenicity, mutagenicity and toxic potential. (+)-Tembamide is previously reported to show potent anti-HIV-1 activity against laboratory adapted strains HIV-1IIIB (X4, subtype B) and HIV-1Ada5 (R5, subtype B) in H9 cell line. It was observed during this study that synthesized tembamide and its four analogs were weakly active against primary isolates HIV-1UG070 (X4, subtype D) and HIV-1VB59 (R5, subtype C) in TZM-bl cell line. Conclusion: The results showed that there is scope for the improvement of activity of tembamide analogs to discover a potent anti-HIV compound.

Background: Many studies support the involvement of the substance P (SP)/neurokinin-1 receptor (NK-1R) system in cancer. SP, after binding to the NK-1R, regulates cancer cell proliferation, induces cell migration and invasion, which are steps of the metastatic process, exerts an antiapoptotic effect, and triggers endothelial cell proliferation necessary for neoangiogenesis. Lung cancer is the first cause of cancer-related deaths in the western world and despite trials using cytotoxic chemotherapeutic agents, no significant progress in extending the survival of patients suffering the disease has been reported. New strategies must be developed. The NK-1R is involved in the viability of lung cancer cells. In lung cancer, SP and NK-1Rs are expressed in human samples while human non-small-(NSCLC) and small (SCLC)-cell lung cancer cells overexpress these receptors. Non-peptide NK-1R antagonists (aprepitant (Emend), L-733,060, L-732,138) and the peptide NK- 1R antagonist [D-Arg1, D-Phe5, D-Trh7,9, Leu11]-SP exert, via the NK-1R and in a concentrationdependent manner, an antiproliferative action against human lung cancer cells (inhibit cell proliferation and induce the death of tumor cells by apoptosis). NK-1R antagonists also inhibit the migration of tumor cells and exert an antiangiogenic action. The SP/NK-1R system is an important target for the treatment of lung cancer and NK-1R antagonists could act as specific drugs against lung cancer cells. The use of NK-1R antagonists (e.g., the drug aprepitant, used as antiemetic in clinical practice) as antitumor agents could be a promising therapeutic innovation. Conclusion: In this review, we update and discuss the data regarding the possible use of NK-1R antagonists in the treatment of lung cancer.