Letters in Drug Design & Discovery - Volume 15, Issue 5, 2018

Background: A new series of substituted 1,2,4-triazoles derivative were synthesized and characterized by IR, 1HNMR, 13CNMR spectra, mass spectroscopy and elemental analysis. Methods: The isonicotinic acid hydrazide (INH) was used as starting material. These synthesized compounds were screened for antitubercular activities by Luciferase Reporter Phase (LRP) assay against drug sensitive reference strain (H37RV) and on S, H, R & E resistant M. tuberculosis (MDR) clinical isolate. First line drug Rifampicin and Isoniazid were used as standard drugs. Result: The study revealed that all the screened compounds showed good to moderate activity except compounds 5b & 5q. Conclusion: The antitubercular activity indicated that the substitution of groups at third and fourth position of 1,2,4-triazole potentiate the activity as compare to isoniazid and rifampicin.

Background: Cancer is a major health problem worldwide, the relative mortality rate caused by cancer is still very high even in developed countries. Although the remarkable success has been achieved: some small molecule anticancer agents have been approved by the U.S. Food and Drug Administration (FDA) in clinics and some are currently in clinical trials, cancer chemotherapy is still highly inadequate. It is essential to find novel structures, low side effect and more potent anticancer agents. Thieno[2,3-d]pyrimidine derivatives also exhibited a wide range of biological activities, especially thieno[2,3-d]pyrimidine derivatives exhibited potent anticancer activities. Based on our previous good results, we synthesized 21 new structures of thieno[2,3- d]pyrimidine derivatives in current work and evaluated their cytotoxicity to A549, HCT116 and MCF-7 cell lines. Methods: The target compounds were prepared by the reaction of 5-substituted-4-chlorothieno[ 2,3-d]pyrimidine with (3-(substituted-phenyl]-isoxazole-5-yl)-methanol in dry iso-PrOH, catalyzed by Et3N. And then, the in vitro anticancer efficacy against A549, HCT116 and MCF-7 cell lines was evaluated using MTT method. Results: The target compounds were characterized using NMR and MS. Most compounds exhibited good anticancer activity against A549, HCT116 and MCF-7 cell lines. Conclusion: 6-Methyl-4-{[3-(4-chlorophenyl)-isoxazol-5-yl-]-methoxy-}-thieno[2,3-d]-pyrimidine (3e) exhibited the most potent cytotoxicity to A549, HCT116 and MCF-7 cell lines (IC50s: 2.79, 6.69 and 4.210-3 μM, respectively) than the reference drug gefitinib (IC50s: 17.90, 21.55 and 20.68 μM, respectively). 3e can be regarded as the best drug candidates for development of anticancer drugs.

Background: A novel series of 4-[(4,5-diphenyl-2-substituted phenyl/heteryl)-1H-imidazole- 1-yl]pyrimidine-2(1H)-one derivatives 5 (a-o) were synthesized using Green protocol. Methods: The structures of the synthesized derivatives were established by IR, NMR, Mass spectra and elemental analysis. The synthesized coupled derivatives 5 (a-o) were evaluated for their in vitro antifungal activity against six fungi strains. Compounds 5h, 5i and 5j exhibited the most promising antifungal activity. The mode of action of the most promising antifungal compounds 5i and 5j was established by ergosterol extraction and quantitation assay. From the ergosterol extraction and quantitation assay finding that the compounds 5i and 5j act by the inhibition of ergosterol biosynthesis in C. albicans. Results: The molecular docking study of most active compounds 5i and 5j had shown good binding interactions with the lanosterol 14 α-demethylase. The synthesized compounds were also analyzed for ADMET properties and the result showed that compounds could be exploited as an oral drug candidate. To establish the antifungal selectivity and safety, the most active compounds were further tested for cytotoxicity against human cancer cell lines HeLa and PC-3 and showed no significant cytotoxic activity. The in vivo acute oral toxicity study shows that the synthesized active compounds 5i and 5j were non toxic in nature. Conclusion: All the above studies clearly indicated that novel, selective and specific inhibitors against the lanosterol 14 α-demethylase have been synthesized, which can be used as lead antifungal molecules.

Background: Head and neck squamous cell carcinoma (HNSCC) is one of the most common malignancies in humans and the average 5-year survival rate is one of the lowest among aggressive cancers. Protein kinase C zeta (PKCZ) is highly expressed in head and neck tumors, and the inhibition of PKCZ reduces MAPK activation in five of seven head and neck tumors cell lines. Considering the world-wide HNSCC problems, there is an urgent need to develop new drugs to treat this disease, that present low toxicity, effective results and that are relatively inexpensive. Methods: A unified approach involving homology modeling, docking and molecular dynamics simulations studies on PKCZ are presented. The in silico study on this enzyme was undertaken using 10 compounds from latex of Euphorbia tirucalli L. (aveloz). Results: The binding free energies highlight that the main contribution in energetic terms for the compounds-PKCZ interactions is based on van der Waals. The per-residue decomposition free energy from the PKCZ revealed that the compounds binding were favorably stabilized by residues Glu300, Ileu383 and Asp394. Based on the docking, Xscore and molecular dynamics results, euphol, sitosterol and taraxasterol were confirmed as the promising lead compounds. Conclusion: The present study should therefore play a guiding role in the experimental design and development of euphol, ß-sitosterol and taraxasterol as anticancer agents in head and neck tumors. They are potential lead compounds, better than other ligands based on the best values of docking and MM-PBSA energy.

Background: Diabetes mellitus, a chronic disease, has grown wide concern in today's world. Majority of the world's population is affected by this disease. All the existing drugs have some side effects such as weight gain, risk of liver disease, skin problems etc. This situation demands the need of more and more potent drugs. Demand for new and faster acting drugs is great and as such it necessitated search for new drug targets. Keeping such a situation in view we wanted to screen out some non-toxic anti-diabetic molecules by applying computational tools. In the present work Protein Tyrosine Phosphate (PTP1B) was taken as the drug target and methoxime-3, 4-dephostatin (MXD) was chosen as the desired inhibitor. Methods: 100 derivatives were generated as combinatorial library taking MXD as the parent molecule with the help of iLib diverse. Non-toxicity of the compounds was assured using online portal Mobyle@rpbs. Molecular docking was performed with the non-toxic derivatives using BiosolveIT LeadIT 2.1.3 and validated using Autodock 4.2. Activity profiling (IC50) was analysed with the help of QSAR study to find the potency of the best compound. Results: ADMET screening confirmed that out of 100(hundred) derivatives generated, 95 (ninetyfive) were non-toxic and satisfy Lipinski rule. From molecular docking, the best pose was selected on the basis of their rank. Analysis of the result showed that Mol: 44 is the best option for PTP1B inhibition as it shows a good score of -30.5615. The other drug-likeness property for Mol: 44 have been screened with the help of Osiris Property Explorer. For QSAR model, activities were correlated with descriptors such as molar volume, parachor, molecular weight, logP and polarizability. The IC50 value of the compound Mol 44 which was found to have the highest score is 0.04μM which was moderate to that of controls. Conclusion: Therefore the designed analogue of methoxime-3, 4-dephostatin, Mol: 44 (5-(4-{2,3- dihydroxy-5-[(E)-(methoxy-imino)methyl]phenyl}piperazin-1-yl)pyrimidine-2,4(1H,3H)-dione) was found to have increased efficacy than the parent compound and also the known inhibitors reported. Thus, Mol: 44, a derivative of Methoxime-3, 4-dephostatin may be considered as an antidiabetic drug lead followed by in vitro and in vivo validation in future. If confirmed, the lead will be able to meet up some of the challenges of present diabetes treatment. Thus the study is of immense significance.

Background: High rate of bacterial infection potentiates scientists to search natural products for new antimicrobial agents. Methods: This research determines the antimicrobial activity of tannins isolated from Pimenta dioica leaves on Gram-positive and Gram-negative infectious organisms using agar diffusion method. Results: All tested compounds were effective against Staphylococcus epidermidis, particularly pedunculagin and nilocitin exhibited broad spectrum antibacterial effects against tested isolates as quantified by microtiter plate dilution method. Conclusion: This will open the era for in-vivo assessment of such compounds for clinical applications.

Background: Pyrazoline scaffold is a key structural motif found among pharmaceutically active molecules including synthetic and natural products. The molecules with pyrazoline backbone from natural as well as synthetic origin are investigated worldwide for the development of efficient and potent drugs. Over the past few years, pyrazoline derivatives are used for the treatment of diverse dreadful diseases including malaria, cardiovascular, tumor, HIV, diabetes, tuberculosis, infections, inflammation, etc. Objective: The main objective of this review article is to emphasize on the recent efforts of researchers to study and understand the pharmacological aspects of various pyrazolines and their analogues derived from chalcone derivatives. Methods: A well known synthetic method for the preparation of pyrazolines is the ring closure reaction of α, β unsaturated ketones with nitrogen based nucleophiles like hydrazine and its derivatives. The synthetic manipulations of pyrazoline derivatives offer a high degree of varied medicinal properties with improved potency and good pharmacological actions. Results: The present review compiles the different synthetic methods to arrive at diversely substituted pyrazoline derivatives. It presents the biological evaluations such as, antimicrobial, antioxidant, antidepressant, antimalarial, analgesic, anti-inflammatory, antiviral, antidiabetic, antitubercular, anticancer and anticonvulsant properties and also documents the utility of these compounds based on their potency. Conclusion: This review presents that the synthetic pyrazolines are excellent scaffolds which possess multiple biological and medicinal properties.