Letters in Drug Design & Discovery - Volume 15, Issue 2, 2018

Background: In this study, we reported the in vitro cytotoxicity activities of a series of N-(2-(arylmethylimino)ethyl)-7-chloroquinolin-4-amine derivatives against four human cancer cell lines. Methods: Good activities were obtained for compounds having aryl groups = 2-hydroxyphenyl, pyridinyl, 5-nitrofuran-2-yl and 5-nitrothiophen-2-yl. Results and Conclusion: The results indicate that this group of compounds is a good starting point for the potential discovery of new prototypes against cancer.

Background: Antioxidants are proficient of stabilizing agents in the target cells and biological systems. The homeostatic equilibrium between the reactive oxygen species and endogenous antioxidants is important in maintaining healthy tissues. As some antioxidant agent's show improved resistance, it is necessary to design the new heterocyclic molecules to form potent antioxidant agents with promising pharmacological applications. Moreover, thienopyrimidine derivatives has been the subject of much research due to their significance in different applications and their extensive potential pharmacological and medicinal activities like antibacterial, antifungal, anticancer, anticonvulsant, anti-inflammatory, analgesic, anti-viral, anti-oxidant, anti-diabetic and antimalarial properties. Although, recently rhodanine was reported as privileged hybrid in drug discovery and exhibited pharmacological activities such as anti-malarial, antibacterial, antiviral, antidiabetic agents. Hence, the development of new molecules within the scope of synthetic procedure of thienopyrimidine scaffold for heterocyclic synthesis would be worthy and well desired. Methods: All the target thienopyrimidine-rhodanine derivatives (5a-l) prepared from the Knoevenagel condensation with different substituted benzaldehydes in the presence of glacial acetic acid and 3-(thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (4). Although, all the synthesized compounds tested for their anti-oxidant activity investigated using DPPH radical scavenging, nitric oxide (NO) and ABTS activity. Results: All the thienopyrimidine-rhodanine derivatives (5a-l) were evaluated for their in vitro anti-oxidant activity. In fact, (Z)-5-(4-methylbenzylidene)-3-(thieno[2,3-d]pyrimidin-4-yl)-2- thioxothiazolidin-4-one (5c) with IC50 value 17.64 ± 0.06 μg/mL and (Z)-5-(2-nitrobenzylidene)-3- (thieno[2,3-d]pyrimidin-4-yl)-2-thioxothiazolidin-4-one (5j) with IC50 value 17.54 ± 0.23μg/mL showed excellent antioxidant activity nearly similar to the standard drug as an ascorbic acid (IC50 = 17.45 ± 0.03μg/mL). Conclusion: The objective of the present work was to design, synthesis and screened for their antioxidant activities of novel thienopyrimidine containing rhodanine derivatives with the hope of discovering new structure leads as the most potent antioxidant agents. Our aim has been achieved by the synthesis of thienopyrimidines with diver functionalities by exploiting 2-thioxothiazolidin-4-one chemistry and tested for antioxidant activity. The compounds 5c and 5j were found most potent activity compare to the standard ascorbic acid. Furthermore, the electron withdrawing groups at position-4 in benzene ring enhanced the activity, whereas the compounds 5d, 5f, 5i and 5l showed good activity all the three radical scavenging methods.

Background: Diabetes Mellitus (DM) is a complex metabolic disease illustrated by abnormally high levels of plasma glucose or hyperglycaemia. Accordingly, several α-glucosidase inhibitors have been developed for the treatment of diabetes and other degenerative disorders. While, a coumarin ring has the privilege to represent numerous natural and synthetic compounds with a wide spectrum of biological activities e.g. anti-cancer, anti-HIV, anti-viral, anti-malarial, anti-microbial, anti-convulsant, anti-hypertensive properties. Besides this, coumarins have also shown potential to inhibit α-glucosidase leading to a generation of new promising antidiabetic agents. However, the testing of O-substituted coumarins for α-glucosidase inhibition has evaded the attention of medicinal chemists. Methods: For O-alkylation/acetylation reactions, the hydroxyl coumarins (A-B) initially activated by K2CO3 in dry DMF were reacted with variedly substituted haloalkanes at room temperature under nitrogen. The synthesized compounds were tested for their α-glucosidase (from Saccharomyces cerevisiae) inhibitory activity and anti-oxidant activity using DPPH radical scavenging activity. In silico docking simulations were conducted using CDocker module in DS (Accelrys) to explore the binding modes of the representative compounds in the catalytic site of α-glucosidase. Results: All the coumarin analogues (A1, B1, A2-A10, B2-B8) including their precursors (A-B) were evaluated for their in vitro α-glucosidase inhibition using acarbose as a standard inhibitor. All the mono O-alkylated coumarins (except A1) showed significant (p <0.05) α-glucosidase inhibition relative to the hydroxyl coumarin (A) with IC50 values ranging between 11.084±0.117 to 145.24± 29.22 μg/mL. Compound 7-(benzyloxy)-4, 5-dimethyl-2H-chromen-2-one (A9) bearing a benzyl group (Ph-CH2-) at position 7 showed a remarkable (p <0.05) increase in the activity (IC50 = 11.084±0.117 μg/mL), almost four-fold more than acarbose (IC50 = 40.578±5.999 μg/mL). The introduction of –NO2 group dramatically improved the anti-oxidant activity of coumarin, while the O-alkylation/acetylation decreased the activity. Conclusion: The present study describes the synthesis of functionalized coumarins and their evaluation for α-glucosidase inhibition and antioxidant activity under in vitro conditions. Based on IC50 data, the mono O-alkylated coumarins were observed to be stronger inhibitors of α-glucosidase with respect to their bis O-alkylated analogues. Coumarin (A9) bearing O-benzyloxy group displayed the strongest α-glucosidase inhibition, even higher than the standard inhibitor acarbose. The coumarin (A10) bearing –NO2 group showed the highest anti-oxidant activity amongst the synthesized compounds, almost comparable to the ascorbic acid. Finally, in silico docking simulations revealed the role of hydrogen bonding and hydrophobic forces in locking the compounds in catalytic site of α-glucosidase.

Background: Calmodulin (CaM) is a ubiquitous, calcium-binding protein that can bind to and regulate a multitude of different protein targets, thereby affecting many different cellular functions. Binding ofsmall, hydrophobic molecules alter its function, as in the case of Phenothiazine (PTZ). PTZ isan organic compound with a history of use as an antihelminth and frequently quoted as a classic example of a pharmaceutical lead structure.Its derivatives are currently used as antipsychotic drugs. Triflouperazine (TFP) is a phenothiazine derivative and a dopamine antagonist, with antiemetic and antipsychotic activities. TFP exerts its antipsychotic effect by blocking central dopamine receptors, thereby preventing effects like delusions and hallucinations caused by an excess of dopamine. This agent also functions as a calmodulin inhibitor, thereby leading to an elevation of cytosolic calcium. We have attempted to screen the extent of CaM specificity towards different classes of TFP and PTZ. Methods: Molecular docking approach using the Lamarckian Genetic Algorithm was used to elucidate the basis of structural similarity of TFP and PTZ with CaM. In total, 3000 compounds were studied. All of the antagonists were taken from PubChem database on the basis of the structural similarity of TFP and PTZ. Results: The docking result of these molecules with CaM demonstrated favored binding energies in the range of -11.50 kcal/mol to -4.51 kcal/mol, with 8 molecules showing hydrogen bonds with the active site residue Met124. Compound 1 was found to be the best CaM inhibitor. The Drug like and chemical toxicity was also predicted for this compound. Conclusion: Computational docking is a feasible method to screen inhibitor compounds against a biomolecule of interest.

Background: Aroylindole derivatives, the structural analogs of Combretastatin A-4 has been found to possess potent growth inhibitory activity on several cancer cell lines due to its excellent antitumor and antivascular activities. The aim of present research work is to identify lead and establish structure activity correlation of trimethoxyaroylindole derivatives, using integrated ligand and structure based computational approaches. Materials and Methods: A correlation between structure and biological activity was established using computational approaches i.e., structure activity correlation by pharmacophore and atom based 3D QSAR, molecular docking and energetic based pharmacophore mapping studies of trimethoxyaroylindole derivatives. Results and Discussion: The 3D-QSAR on trimethoxyaroylindole derivatives generated and showed best statistical result for CPHs AAARR.182 was validated by Q2 (0.6929), R2 (0.82). The Comp. 1 of the training set was employed as template for hydrogen bond donor, hydrophobic and hydrogen bond acceptor field prediction features and visualization of the 3D-QSAR model provides details of relationship between structure and biological activity of trimethoxyaroylindole derivatives. Pharmacophore model was developed by Phase and e-pharmacophore on comp. 1, the trimethoxy group with ring A, keto group, N-H group with ring B and ring C are pharmacophoric group important for the lead generation and coincide with various chemical features that may facilitate non-covalent binding between the ligand and its target receptor. Molecular docking studies showed critical interactions between Cys241, Val318 and meta, para-methoxy group at ring A while and Thr179 and NH of indole (distance 3.5 Å). The para position of trimethoxyphenyl ring bind to SH group of CYS 241 receptor molecule via hydrogen bond. Conclusion: The lead identification and establish structure activity correlation of trimethoxyaroylindole derivatives, were performed using integrated ligand and structure based computational approaches i.e., atom based 3D QSAR and pharmacophore study, molecular docking, energetic based pharmacophore mapping studies showed promising results. The outcomes of present studies could be utilized for the design of novel aroylindole derivatives including its lead optimization as potential anticancer agent.

Background: Due to multi-drug, extended-drug, and pandrug resistance phenotypes, bacterial resistance to antibiotics and fungal infections are a general health issue. Particulary, increase of fungal infections due to secondary cause of human diseases have been observed. An extensive variety of benzimidazole derivatives have been characterized for their chemotherapeutic significance. Benzimidazole derivatives have received important attention because of pharmacological significance during current years, especially antimicrobial, anti-fungal, antitubercular, antioxidant, anti-Alzheimer's disease and antihypertension activities. Methods: Some N-(1H-benzimidazol-2-yl)-2-mercaptoacetamide derivatives (2a-h) were synthesised and evaluated for their antimicrobial activity. The title compounds were gained by reacting N-(1H-benzimidazol-2-yl)-2-chloroacetamide with some substituted 2-mercapto heterocyclic rings. The synthesised compounds were investigated for their antimicrobial activities against C. albicans (ATCC 24433), C. krusei (ATCC 6258), C. glabrata (ATCC90030), C. parapsilosis (ATCC 22019), E. coli (ATCC 25922), E. coli (ATCC 35218), E. feacalis (ATCC 51299), E. feacalis (ATCC 29212), S. aureus (ATCC 25923), K. pneumoniae (ATCC 700603), P. aeruginosa (ATCC 27853). Results: The compounds showed high antifungal activity when compared with standard drug ketoconazole. In addition, all compounds (MIC 100 μg/mL) showed inhibitor activity against P. aeruginosa at two fold concentration of chloramphenicol (MIC 50 μg/mL). Also, compounds 2a, 2c and 2e (MIC: 50 μg/mL) have equal effect against E. coli (ATCC 35218) and more effective than other compounds (MIC of chloramphenicol: 100 μg/mL). Conclusıon: All compounds showed notable activity. Compounds have determined to possess higher antifungal activity than antibacterial activity. Additionally, compounds 2a with 1-methyltetrazole, 2c with benzothiazole and 2e with 6-chlorobenzothiazole moieties were found as the most active compounds.

Background: We report the design, synthesis and evaluation of a series of 4-biaryl substituted 2-amino benzo[h]chromene derivatives as potential cytotoxic agents. Methods: The one-pot synthesis of this class of compounds was carried out under ultrasound irradiation using an MCR involving Pd/C-catalyzed Suzuki-Miyaura coupling as a key step. Result and Conclusion: Several of these compounds showed promising cytotoxicities when tested against cancer cell lines but no or little effects on non-cancerous cell lines.

Background: The Janus enzyme family is regulated by various cytokines together with interleukins, interferons, and hormones like glycoprotein, thromboprotein, and hormone. Metamorphosis and translocations in the Janus Kinase genes leading to constitutively active Janus Kinase proteins are associated with a variety of hematopoietic malignancies, comprising the myeloproliferative disorders, acute lymphoblastic leukemia, acute myeloid leukemia (JAK2, JAK1), acute megakaryoblastic leukemia (JAK2, JAK3). Hence the study of the inhibitors of Janus Kinase is desired. Methods: Research and online content related to 1-amino-5H-pyrido [4,3-b]indol-4-carboxamide analogues (I) that were synthesized and evaluated for their JAK2 inhibitory activity is reviewed, and in order to design and develop still better and more effective JAK inhibitors, we have made Quantitative Structure Activity Relationship (QSAR), docking and ADMET studies on these compounds Results: The best GA-MLR equation based on four descriptors along with statistical parameters is obtained using QSARINS software. Using the model expressed by this study we predicted some new compounds of high JAK2 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 JAK2 almost in the same manner as the FDA approved compound, Momelotinib.

Background: In the present study, new triazine derivatives 3, 4, 5, 6, 8 and 10 were synthesized starting from readily available cyanuric chloride 1 via nucleophilic displacement with morpholine followed by Suzuki or Stille coupling reactions and then the thermal displacement of chlorine atom with diverse substituted amines. Methods: All synthesized compounds were screened for their cytotoxic activity against HT-29, MDA-MB-231, and HEK293 cell lines. Results and Conclusion: Compounds 6a (IC50 (μM): 0.32 for HT-29 and 2.92 for MDA-MB-231) and 8c (IC50 (μM): 1.40 for HT-29 and 1.60 for MDA-MB-231) have been identified and compared with Doxorubicin and ZSTK474 as the reference standards.

Background: In medicinal chemistry, thiazoles have gained great importance in antifungal and anticancer drug design and development. Objectives: The aim of this study was to synthesize new quinoline-based thiazolyl hydrazone derivatives and evaluate their anticandidal and anticancer effects. Methods: New thiazolyl hydrazone derivatives were evaluated for their anticandidal effects using disc diffusion method. Ames MPF assay was carried out to determine the genotoxicity of the most effective antifungal derivative. MTT assay was also performed to assess the cytotoxic effects of the compounds on A549 human lung adenocarcinoma, HepG2 human hepatocellular carcinoma, MCF- 7 human breast adenocarcinoma and NIH/3T3 mouse embryonic fibroblast (healthy) cell lines. Results: 4-(4-Fluorophenyl)-2-(2-((quinolin-4-yl)methylene)hydrazinyl)thiazole (4) showed antifungal activity against Candida albicans and Candida krusei in the concentration of 1 mg/mL. In MTT and Ames MPF tests, it was determined that compound 4 did not show cytotoxic and genotoxic effects. MTT assay indicated that 4-(naphthalen-2-yl)-2-(2-((quinolin-4-yl)methylene) hydrazinyl)thiazole (10) showed more selective anticancer activity than cisplatin against A549 and MCF-7 cell lines. Besides, 4-(4-chlorophenyl)-2-(2-((quinolin-4-yl)methylene)hydrazinyl)thiazole (5) exhibited more selective anticancer activity than cisplatin against HepG2 cell line. Conclusion: Due to their high selectivity index, these compounds are considered as candidate compounds to participate in further research.

Background: Mustard gas or sulfur mustard (dichloro-3-thiapentane-1,5) is a chemical compound consisting of chlorine and sulfur which was used as a chemical weapon in the First World War and during the war between Iran and Iraq. Mustard gas is a lipophilic compound that is highly poisonous and can quickly penetrate into body tissues. Eye is one of the body organs that is quite vulnerable to this compound. The present study was conducted to review the effectiveness of various treatments for ocular injuries caused by sulfur mustard. Methods: In this review, therapeutic effects of anti-inflammatory drugs such as dexamethasone, diclofenac, betamethasone and their combination, as well as surgical interventions based on stem cells and different methods of keratoplasty [e.g. penetrating keratoplasty (PKP), lamellar keratoplasty (LKP), and deep anterior lamellar keratoplasty (DALK)] were assessed. Results: As the results indicated, combinatorial therapeutic approaches are more successful compared with single therapeutic measures. It has been reported that utilization of anti-inflammatory drugs such as diclofenac, dexamethasone and betamethasone can control the initial symptoms. In addition, keratolimbal allograft stem cell transplantation methods along with LKP and PKP keratoplasty methods can lead to considerable therapeutic success. Conclusion: Considering the involvement of multiple abnormalities in the pathogenesis of sulfur mustard-induced chronic ocular complications, combinatorial therapeutic approaches appear to be more efficacious.

Background: The anti-plasmin activity of Tranexamic Acid (TA) is considered to be the main mechanism of hypopigmentation. Several studies have found TA to be effective for both oral and topical application. When used to lighten stains, TA is effective even at low concentrations, ideally in the range of 2 to 5%. Increasing the duration of treatment is more effective than increasing the concentration of TA: Higher concentrations of TA (> 5%) do not improve the effect but rather cause irritation. The TA formulations were applied once or twice a day, and the average duration was eight to twelve weeks: advantageous therapeutic effects were observed after this period. Other studies gave intradermal injections once weekly for 12 weeks, also with an acceptable efficiency. The compound may be administered topically to the skin in the form of emulsions, creams and solutions, and formulations containing liposomes. Encapsulation of TA in liposomes may reduce potential skin irritation, and it ensure high formulation stability, decrease the risk of leakage and allow long-term sustained release. Intradermal injections of TA produce relatively quick bleaching results without significant side effects. Conclusion: In conclusion it should be stated that the lightening effect of tranexamic acid in topical and intradermal applications has been most extensively studied in the case of melasma, and most studies have been performed in Asia. Therefore, the final evaluation of TA, in the cases other than melasma and hyperpigmentation, requires further studies. However, further studies are needed in order to optimize the frequency of application of TA and to determine the long-term benefits from its use, especially concerning stains other than chloasma.