Letters in Drug Design & Discovery - Volume 15, Issue 6, 2018

Background: Now-a-days, the model of “hybrid drugs” has acquired recognition in medicine due to their significant role in the treatment of different health problems. Methods: We have synthesized new series of isoxazole-chalcone conjugates (14a-m) by the Claisen-Schmidt condensation of suitable substituted acetophenones with isoxazole aldehydes (12a-d). In vitro cytotoxic activity of the synthesized compounds was studied against four different selected human cancer cell lines by using sulforhodamine B (SRB) method. Results: The adopted scheme resulted in good yields of new series of isoxazole-chalcone conjugates (14a-m). Potent cytotoxic activity was observed for compounds -14a, 14b, 14e, 14i, 14j and 14k against prostate DU-145 cancer cell line. Conclusion: The observed potent cytotoxic activities were due to the presence of 3,4,5- trimethoxyphenyl group.

A novel, rapid and efficient microwave-assisted synthesis of S-substituted quinazoline derivatives was obtained using 1,4-dihydroquinazoline-2-thiol and various boronic acids with copper catalyst in one-pot reactions. The versatility of the synthetic protocol with various boronic acids and the optimization processes of the microwave irradiation conditions including temperature, solvent, and reaction time were demonstrated.

Background: Improving the gastrointestinal safety profile of Non-Steroidal Anti- Inflammatory Drugs (NSAIDs) is an important goal. An important strategy to develop NSAIDs with minimal Gastrointestinal (GI) toxicity is to target the COX-2 isoform with a selective inhibitor. Methods: In this study we selected ketoprofen as a lead NSAID for development into safer agents. 1, 2, 4-Oxadiazole moiety was employed to mask the free acid group of the ketoprofen to get six different derivatives hypothesized to have minimal GI irritation. In Vivo anti-inflammatory and analgesic activities of these six synthesized derivatives were tested and compared to equivalent dose of the parent drug. Results: Three compounds showed superior anti-inflammatory activity (76.29%, 80.45% &79.06% inhibition) compared to the parent drug (72.71% inhibition), in a carrageenan induced paw edema model (peak at 4h). One compound, 3d also showed moderate analgesic activity (51.14%), in comparison to ketoprofen (63.97%) in an acetic acid induced writhing model. In addition, the tested compounds were found to possess much less degree of ulcerogenic potential (almost half) compared to the parent NSAID, ketoprofen. Their unique selectivity toward the COX-2 enzyme was investigated using molecular modeling techniques. Conclusion: Results of compound 3d which showed highest anti-inflammatory and analgesic activities with much reduced ulcerogenic potential, are highly encouraging and may serve as new COX-2 selective lead and merits further investigation.

Introduction: Metal ions are cofactors found in antioxidant enzymes such as superoxide dismutase (SOD), and are essential in catalytic mechanisms for scavenging the free radicals. Therefore, synthetic compounds containing metal ions coordination are designed for SOD mimic and other biological activities. Objective: This study aimed to synthesize metal (Ni, Cu, Mn) complexes of mixed ligands of 2-thiouracil (2TU) with 8-hydroxyquinoline (8HQ) (1-3) and with 2-hydroxyquinoline (2HQ) (4-6), and to determine antioxidant and antimicrobial activities. Results: The metal complexes 1-6 elicited SOD activity with IC50 of 1.20-500.26 μM, particularly, complex 5 (2TU-Cu-2HQ) showed the highest SOD activity with IC50 of 1.20 μM. In addition, complexes 1 (2TU-Ni-8HQ), 5 and 2 (2TU-Cu-8HQ) displayed radical scavenging activity (RSA) with IC50 of 174.86, 196.54 and 431.65 μM, respectively, whereas the complexes 3, 4 and 6 were shown to be inactive. Furthermore, the metal complex 3 (2TU-Mn-8HQ) exhibited good antimicrobial activity with the minimal inhibitory concentration (MIC) range of 11.07-708.64 μM against gram positive and gram negative bacteria as well as diploid fungus, followed by metal complexes 2 (MIC of 23.68-757.70 μM) and 1 (MIC of 350.67-701.35 μM). Interestingly, among the similar mixed ligands with different metal ions of complexes 1 (Ni), 2 (Cu) and 3 (Mn), the complex 3 has the highest SOD (IC50 = 3.50 μM) and antimicrobial activities, but Cu complex (5) of 2TU and 2HQ showed higher SOD and RSA activities than Ni (4) and Mn (6) complexes. Conclusion: This finding reveals novel transition metal complexes with a potential for further development as medicinal compounds.

Background: Antioxidants are compounds that inhibit oxidation in biological systems and in the natural environment as free radical scavengers, reactive oxygen scavengers, or reducing agents. Phenolic acid compounds, such as Protocatechuic Acid (PCA), are one of the most important antioxidants occurring in the natural environment. Methods: In this study, the relationships between structure and antioxidant activities of the phenolic acids including PCA were investigated systematically with a particular focus on electronic substituent effects using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay. The antioxidant activities of the compounds were further investigated at the intracellular level with the DCF-DA assay using a fluorescence microplate reader and a flow cytometry. Results: Electron-donating substituents in an ortho- or para-position to a hydrogen donor in the aromatic structure stabilized the resulting antioxidant-derived radical by delocalization across the entire molecule. A hydrogen-bond donating substituent increased antioxidant activity by stabilizing the incipient phenolic radical. Ascorbic acid and the o-substituted phenolic acids with hydrogenbonding donors and p-substituted 2,5-dihydroxybenzoic acid significantly reduced intracellular ROS levels. Conclusion: The study of relationship between antioxidant properties and hydrogen-bonding ability/ electronic effect of various substituents in the phenolic acids provides a promising strategy to develop sophisticated antioxidant foods and drugs.

Background: Benzimidazolium salts include biologically active benzimidazole ring. Some benzimidazolium salts and their metal complexes, containing different groups, showed remarkable antibacterial, antifungal and antitumor effects. Most of these studies are generally related with the 2-unsubstituted derivatives of benzimidazolium salts which named as N-heterocyclic carbenes (NHCs). To enhance the efficacy of the benzimidazoles in the biological systems, it is very important to overcome the insolubility problem. For this reason and previously indicated structural importance of the benzimidazolium salts, 1,3-dialkyl halide salts of the 2-arylbenzimidazoles, are of focus in this work. To the best of our knowledge, this is the first report that describes the microwave assisted synthesis and antimicrobial activity of 2-arylsubstituted benzimidazolium salts. Methods: A series of novel 1,3-dialkyl-2-arylbenzimidazolium salts (8-28) were synthesized via the N-alkylation of 1-methyl-2-arylbenzimidazole derivatives (1-7) with alkyl halides under microwave conditions by using small amount of DMF. The results were also compared with conventional heating under reflux. Structures of the products were confirmed by using 1H-NMR, 13C-NMR, FTIR spectroscopic techniques. All of the synthesized compounds were screened for their in vitro antimicrobial activities using microbroth tube dilution and disc diffusion methods. Results: Considering the reactions repeated by classical heating, it was determined that the reaction times were decreased from 3-6 hours to 5-35 minutes under microwave. Additionally, yields have increased from 4-71 % to 64-96 % ranges. Considering the whole antimicrobial activity studies, MIC values of newly synthesized benzimidazolium salts 8-28 (1.95->1500 μg/ml) are remarkably smaller than parent benzimidazoles 1-7 (62.5->1500 μg/ml) on the studied microorganisms. Conclusion: The microwave method is advantageous regarding the usage of mild conditions and small amounts of solvent, easy purification and achieving high yields in short times. The antimicrobial activity studies demonstrate that newly synthesized salts (8-28) are effective mostly on grampositives and eukaryotic microorganisms. Compounds 16, 18, 19, 24, 25 and 27 were found to be the most effective inhibitors of growth in both gram-positive bacteria and eukaryotes. Thus, the synthesized compounds in this study may aid the treatment of fungal and bacterial diseases. The results of this study are of great significance in the areas of synthetic organic chemistry, microbiology, pharmaceutical chemistry and chemical catalysis.

Background: Diabetes being among the most prevalent disease is being studied widely to achieve most potent drug with lesser side-effects. Numerous targets have been explored and several drugs have been developed to combat type-2 diabetes. Worldwide scenario depicts an increase in the number of diabetics at an alarming rate. Due to this critical need in the current scenario, the focus has been shifted to natural products. Amongst which flavonoids have been extensively studied for their anti-diabetic potential. Among various targets inhibition of DPP-4, α-glucosidase arose as an advantageous methodology for the management of type-2 diabetes. DPP-4 inhibitor helps to maintain the insulin levels in the body and α-glucosidase inhibitor aids in the control of the postprandial glycemia. Methods: In the present study, the molecular modeling of 155 flavonoids has been performed using GLIDE against Dipeptidyl Peptidase-4 (DPP-4) (PDB ID:2ONC) and α-glucosidase (PDB ID: 2QMJ) so as to achieve lead compounds that can be further used to develop a new drug. Results: Rutin and Theaflavin-3,3'-di-O-gallate were observed to possess the best docking score for α-glucosidase and DPP-4 respectively. Conclusions: The top scoring flavonoids show promising results, but further studies are required to be carried out including the pharmacophore mapping, SAR and QSAR studies. The results illustrated that the hydrogen bonding plays a crucial role in the binding and positioning of the molecules into the active site. Further, the rescoring of the docking values mentioned as MMGB/SA also reconfirmed that these compounds show favorable results.

Background: Quinoline nucleus is found in a vast range of biologically active compounds. The quinoline group of compounds which are anti-infective in nature are found to act by inhibiting different enzymes. DNA gyrase being one of the more common site of action. Methods: Taking the mechanism into consideration, we have designed and synthesised some novel 6-substituted quinoline-4-caboxylic acid derivatives. The designed compounds were studied for their interaction with the proposed target DNA gyrase's active site and binding energies were calculated. These compounds were synthesized, characterized and evaluated for antibacterial activity against S. aureus. The MIC values were calculated and the in-vitro antibacterial activity was compared with the in silico binding energies. Results: The results suggested that SDS-49, SDS-70, SDS-78, SDS-79 compounds which have shown higher affinity towards the DNA gyrase, have shown good biological activity. Conclusion: Some of the synthesized compounds and have shown better docking score and in vitro activity also. DNA gyrase binding activity study shows the prospect of further research in this area.

Background: Cluster of differentiation 38 (CD38) is major NADase and regulates the intracellular level of NAD. It uses NAD as substrate to produce ADP Ribose (ADPR) and cyclic ADP ribose (cADPR) and converts NADP to NAADP. Its inhibition can be utilized to treat several condition. Methods: In this research, for identifying new potent CD38 inhibitors both structure and ligand based virtual screening approaches were used to search 1,064,166 and 23,129,083 clean compounds, respectively. Both Structure Based Virtual Screening (SBVS) and Ligand Based Virtual Screening (LBVS) approaches were performed in istar website. Results: Based on SBVS and LBVS results, 53 and 20 molecules, respectively, were selected. In next step iGEMDOCK software was used to dock these 73 molecules to the NMN binding site of CD38 and finally 7 molecules were selected. For more validation of iGEMDOCK software results, AutoDock software was used to dock these 7 molecules to the NMN binding site of CD38. Auto- Dock results indicated only 5 molecules of these 7 molecules can be considered as CD38 inhibitors. These compounds are zinc68054028, zinc78782163, zinc63259986, zinc34792490 and zinc63260004. Conclusion: SBVS and LBVS are useful tools to identify new CD38 inhibitors with greater activity.

Background: Sirtuin 2 is a deacylase enzyme which has a significant role in the treatment of neurodegenerative diseases. A reported series of novel thieno[3,2-d]pyrimidine-6- carboxamide derivatives has been chosen as sirtuin inhibitors. Methods: A pharmacophore and atom-based 3D-QSAR studies were carried out in order to understand the molecular features and structural requirement of these molecules to selectively inhibit the SIRT-2. Results: The analysis of pharmacophore model revealed two hydrogen bond acceptors, two hydrogen bond donors and one hydrophobic feature as crucial molecular features that predict binding affinity to the SIRT-2 enzyme. The pharmacophore hypothesis (AADDH.7073) derived a 3D-QSAR model with significant Partial Least Square (PLS) statistics values as r2= 0.9604, SD= 0.2568, F= 137.5, for training set and Q2= 0.9515, RMSE= 0.2045, Pearson-R= 0.9758, for the test set. Conclusion: The results provide a detailed structural insights of thieno[3,2-d]pyrimidine-6- carboxamide derivatives which can provide guidance to develop novel potent and selective SIRT-2 inhibitors.

Background: Aedes aegypti is an important mosquito vector for the transmission of several infectious diseases. Current insecticides play a vital role in controlling mosquitoes; however, the frequent use of insecticides has led to the development of insecticide resistance. In order to control mosquito populations, new and effective bioactive molecules are urgently needed. Methods: In the current work, N-(benzylidene)-3-cyclopentylpropionic acid hydrazide derivatives (2a-p) were synthesized and evaluated for their larvicidal and adulticidal effects on Ae. aegypti. Results: N-(Benzylidene)-3-cyclopentylpropionic acid hydrazide (2a) and N-(4-isopropylbenzylidene)- 3-cyclopentylpropionic acid hydrazide (2i) were identified as the most potent larvicides in this series with LC50 values of 0.0097 (0.005-0.017, 95%CI) μg/μL and 0.2729 (0.223- 0.336, 95%CI) μg/μL, respectively against 1st instar A. aegypti. On the other hand, compounds 2a-p showed weak adulticidal activity against adult female A. aegypti. Conclusion: Due to their notable larvicidal activity, compounds 2a and 2i stand out as promising candidates for further studies.

Background: Illicium verum Hook. f. (Star anise) has been traditionally used for the treatment of abdominal colic, vomiting, pain, nervousness, insomnia and rheumatism. Objective: The present study was conducted to investigate the anti-inflammatory properties of Illicium verum extracts. Methods: Different extracts of I. verum (IV-Ext-1, IV-Ext-3 and IV-Ext-4) were screened for their anti-inflammatory potential using carrageenan-induced paw edema in mice. The mechanism of action was explored using paw edema tests (carrageenan, histamine, serotonin and prostaglandins) in rats and anti-oxidant activity (DPPH assay). Reverse phase HPLC was used for chemical characterization of extracts. Results: The IV-Ext-3 was found to be the most potent anti-inflammatory agent (38% inhibition) using carrageenan-induced paw edema. The anti-inflammatory effect was observed during both the initial (IC50: 260 mg/kg) and late phases (IC50: 200 mg/kg). Similar IC50 of 200 mg/kg was observed in both phases of histamine-induced paw edema. However, the extract failed to cause 50% inhibition in serotonin-induced edema (IC25: 400 mg/kg) and was also ineffective against Prostaglandin- E2 induced edema. Furthermore, the IV-Ext-3 appeared to be an effective antioxidant (IC50: 12 μg/ml). The HPLC chromatogram of IV-Ext-3 showed the presence of anti-inflammatory constituents such as shikimic acid (1.6%) and anethole (0.25%), 3, 4-dihydroxybenzoic acid (0.003%) and p-hydroxy methyl benzoate (0.117%) along with some polar hydroxyl derivatives of benzoic acids. Conclusion: Among all the extracts of I. verum, IV-Ext-3 was found to be the most effective antiinflammatory agent which can be attributed to multiple anti-inflammatory constituents, antihistamine and antioxidant potentials.

Background: The use of laser methods to irradiate currently used drugs in order to obtain photo-products with antimicrobial and anti-tumour activity constitutes a new approach in fighting antimicrobial resistance acquired by bacteria and tumours. Methods: The interaction of UV laser radiation with phenothiazine derivatives, such as chlorpromazine, thioridazine and promethazine, and a hydantoin derivative, SZ-2, was evaluated using analytical techniques: UV-Vis-NIR absorption, FTIR, and laser induced florescence. Results: The investigation of photo-products mixtures suggested the photo-generation of sulfoxide and hydroxyl compounds when phenothiazine derivatives were irradiated and the braking of molecule and detachment of radical attached to thio-hydantoin ring when SZ-2 was irradiated. As for application of laser irradiated drug solutions on pseudo-tumours induced in rabbit eyes using Schmidt-Erfurth method, it was observed a decrease of inflammations related to pseudo-tumours and a fast recovery of corneal tissues. Conclusion: The best effect concerning the recuperation of healthy corneal tissue quality in the pseudo-tumour was observed for 10 mg/mL chlorpromazine irradiated 20 min with 266 nm laser beam. This new method offers the possibility to combat antimicrobial resistance acquired by tumours or bacteria by flexible development of new agents using laser systems and techniques.