Letters in Drug Design & Discovery - Volume 16, Issue 11, 2019

Background: Pigment melanin has primarily a photo defensive role in human skin, its unnecessary production and irregular distribution can cause uneven skin tone ultimately results in hyper pigmentation. Melanin biosynthesis is initiated by tyrosine oxidation through tyrosinase, the key enzyme for melanogenesis. Not only in humans, tyrosinase is also widely distributed in plants and liable for browning of vegetables and fruits. Search for the inhibitors of tyrosinase have been an important target to facilitate development of therapies for the prevention of hyperpigmentary disorders and an undesired browning of vegetables and fruits. Methods: Different natural and synthetic chemical compounds have been tested as potential tyrosinase inhibitors, but the mechanism of inhibition is not known, and the quest for information regarding interaction between tyrosinase and its inhibitors is one of the recent areas of research. Computer based methods hence are useful to overcome such issues. Successful utilization of in silico tools like molecular docking simulations make it possible to interpret the tyrosinase and its inhibitor’s intermolecular interactions and helps in identification and development of new and potent tyrosinase inhibitors. Results: The present review has pointed out the prominent role of computer aided approaches for the explication of promising tyrosinase inhibitors with a focus on molecular docking approach. Highlighting certain examples of natural compounds whose antityrosinase effects has been evaluated using computational simulations. Conclusion: The investigation of new and potent inhibitors of tyrosinase using computational chemistry and bioinformatics will ultimately help millions of peoples to get rid of hyperpigmentary disorders as well as browning of fruits and vegetables.

Background: The role of microtubules in cell division and signaling, intercellular transport, and mitosis has been well known. Hence, they have been targeted for several anti-cancer drugs. Methods: A series of 3-(alkylthio)-5,6-diphenyl-1,2,4-triazines were prepared and evaluated for their cytotoxic activities in vitro against three human cancer cell lines; human colon carcinoma cells HT-29, human breast adenocarcinoma cell line MCF-7, human Caucasian gastric adenocarcinoma cell line AGS as well as fibroblast cell line NIH-3T3 by MTT assay. Docking simulation was performed to insert these compounds into the crystal structure of tubulin at the colchicine binding site to determine a probable binding model. Compound 5d as the most active compound was selected for studying of microtubule disruption. Results: Compound 5d showed potent cytotoxic activity against all cell lines. The molecular modeling study revealed that some derivatives of triazine strongly bind to colchicine binding site. The tubulin polymerization assay kit showed that the cytotoxic activity of 5d may be related to inhibition of tubulin polymerization. Conclusion: The cytotoxicity and molecular modeling study of the synthesized compounds with their inhibition activity in tubulin polymerization demonstrate the potential of triazine derivatives for development of new anti-cancer agents.

Background: With approximately one-third of the world’s population infected, tuberculosis continues to be a global public health crisis. The rise of strains that are unusually virulent or highly resistant to current drugs is a cause of special concern, prompting research into new classes of compounds, as well as the re-evaluation of known chemotherapeutic agents. Objectives: The antimycobacterial activities associated with some recently-reported thiocarbonyl compounds kindled our interest in the synthesis of substituted hydrazinecarbothioamides (3) and carbonothioic dihydrazides (4), with the aim of investigating their potential in antitubercular drug design and discovery. Methods: In the present study, the title compounds 3 and 4 were prepared by the condensation of hydrazines with isothiocyanates in reactions readily controlled by stoichiometry, temperature and solvent. The compounds were assessed against Mycobacterium bovis BCG in Kirby-Bauer disc diffusion, and minimum inhibitory concentrations were determined against the virulent strain M. tuberculosis Erdman. Results: The chemical structures of these thermally stable compounds were determined by IR, 1HNMR, 13C-NMR, high-resolution mass spectrometry and elemental analysis. In the Kirby-Bauer disc diffusion assay, some of the compounds showed substantial diameters of inhibition against BCG. In some cases, the zones of inhibition were so large that no growth at all was observed on the assay plates. Against M. tuberculosis Erdman, several of the compounds showed significant activities. Compound 3h was the most active, demonstrating a minimum inhibitory concentration of 0.5 μg/mL. Conclusion: We found that the title compounds may be prepared conveniently in excellent purity and good yields. They are readily identified on the basis of their characteristic spectra. Some members of this class showed significant activities against mycobacteria. We conclude that further work will be warranted in exploring the antitubercular properties of these compounds.

Background: The quest for new drug entities and novel structural fragments with applications in therapeutic areas is always at the core of medicinal chemistry. Methods: As part of our efforts to develop novel selective cyclooxygenase-2 (COX-2) inhibitors containing tyrosine scaffold. The objective of this study was to identify potent COX-2 inhibitors by dynamic simulation, pharmacophore and 3D-QSAR methodologies. Dynamics simulation was performed for COX-2/tyrosine derivatives complex to characterise structure validation and binding stability. Certainly, Arg120 and Tyr355 residue of COX-2 protein formed a constant interaction with tyrosine inhibitor throughout the dynamic simulation phase. A four-point pharmacophore with one hydrogen bond acceptor, two hydrophobic and one aromatic ring was developed using the HypoGen algorithm. The generated, statistically significant pharmacophore model, Hypo 1 with a correlation coefficient of r2, 0.941, root mean square deviation, 1.15 and total cost value of 96.85. Results: The QSAR results exhibited good internal (r2, 0.992) and external predictions (r2pred, 0.814). The results of this study concluded the COX-2 docked complex was stable and interactive like experimental protein structure. Also, it offered vital chemical features with geometric constraints responsible for the inhibition of the selective COX-2 enzyme by tyrosine derivatives. Conclusion: In principle, this work offers significant structural understandings to design and develop novel COX-2 inhibitors.

Background: A new class of 5-(styrylsulfonylmethyl)-1,3,4-oxadiazol-2-amine and 5- (styrylsulfonylmethyl)-1,3,4-thiadiazol-2-amine derivatives were prepared by derivatization of amino function. Methods: All the synthesized compounds were tested for antioxidant and anti-inflammatory activities. Results: The 2-amino-3-chloro-N-(5-(4-methylstyrylsulfonylmethyl)-1,3,4-oxadiazol-2-yl)-propanamide (12b) and 3-chloro-N-(5-(4-methylstyrylsulfonylmethyl)-1,3,4-oxadiazol-2-yl)-butanamide (14b) displayed significant antioxidant activity, greater than the standard Ascorbic acid. Conclusion: Moreover, 12b and 14b also exhibited promising anti-inflammatory activity.

Background: Aryl-methoxybenzaldehydes substituted in various positions may serve as valuable starting materials for the synthesis of biologically active compounds. Methods: Biaryl-methoxybenzaldehydes and pyridyl-aryl-methoxybenzaldehydes were synthesized by the Suzuki-Miyaura cross-coupling reactions as intermediates of potential drug substances. Three different catalytic approaches were compared. The classical Suzuki method utilising tetrakis(triphenylphosphine)palladium and sodium ethoxide, the protocol applying palladium acetate and tri(o-tolyl)phosphine, and the method using tetrakis(triphenylphosphine)palladium and cesium carbonate, were studied. Results: The selected boronic acids were the classical phenylboronic acid, as well as 4-pyridineand 3-pyridineboronic acids. 26 New biaryl-methoxybenzaldehydes or pyridyl-phenylmethoxybenzaldehydes have been synthesized, which may be intermediates for pharmaceutically active compounds. Conclusion: The method of Anderson et al. was preferred, because it provides satisfactory results in all cases.

Background: Potency is the broadest available biological activity data type. In turn, Ligand Efficiency (LE) is a molecular descriptor that probes the ratio of potency vs Heavy Atom Count (HAC), which emphasizes low HAC more than potency and thus has drawbacks as an estimator of drug candidates. The objective was to design a novel transform to probe potency and HAC interaction in which potency and HAC would be balanced more evenly. Methods: In this study, potency data of ChEMBL, PubChem, FDA approvals and drug (fragments) were analysed. A novel descriptor, a product of the pAC50 value with HAC, multiplicative or Product Ligand Efficiency (PLE) was designed and tested. Results: In particular PLE was compared with pAC50 and LE vs the HAC statistics for different series of ligands. This indicated that PLE is an informative estimator that can be used to recognize the potential of drugs. PLE has a maximum value in the range around 30-50 HAC. Conclusion: Drug design is a complex problem. Similarly, to drug-likeness, LE prefers small molecules. This makes LE a tool serendipitously improving drug likeness. In this context, LE performs unexpectedly well even despite the uncertainty of its physical meaning. PLE is a more evenly balanced estimator whose physical meaning is the Minimum Inhibitory Concentration (MIC).

Background: Treating tuberculosis is a challenge due to the development of drug resistance. Hence, it is imperative to develop novel leads having high potency and efficacy to curb drug resistance. Methods: The present research work is focused on microwave-assisted synthesis of novel twenty-six 3-amino-N’-benzylidenepyrazine-2-carbohydrazide derivatives (3a-z), where, lyophilization technique was used for isolation of the major intermediate, 3-aminopyrazin-2-carbohydrazide. All synthesized compounds were subjected for anti-tubercular screening against Mycobacterium tuberculosis H37Ra by using XTT Reduction Menadione Assay (XRMA) protocol. Results: Out of 26 synthesized compounds, four N’-substitutedbenzaldehyde-3-amino-pyrazine-2- carbohydrazide derivatives viz. 3i, 3j 3v and 3z showed significant activity against M. tuberculosis H37Ra. The compounds 3i, 3j, 3v and 3z showed 99, 98, 92 and 87 % inhibition respectively as compared to 94% inhibition shown by the standard drug rifampicin. The MIC and IC50 values were in the range of 24.3-110 and 5.9-20.8 μg/ml respectively. Conclusion: A classification model called Recursive Partitioning (RP) based on binary Quantitative Structure-Activity Relationship (QSAR) was derived for the establishment of structure-activity relationship (SAR). The predictions derived on the basis of RP model were found to be in agreement with anti-tubercular screening data.

Background: Tyrosinase enzyme is one of the important targets to reduce melanoma and other skin disorders. Standard inhibitors of tyrosinase enzyme including arbutin and kojic acid are less effective. Some NSAIDs such as acetylsalicylic acid, mefanamic acid, and diclofenac are known to possess inhibitory potential against melanogenesis. The current study deals with the screening of tyrosinase inhibitory potential of S-naproxen derivatives. Methods: Synthetic S-naproxen derivatives 1-33 were evaluated for tyrosinase inhibitory activity in vitro. Results: Six compounds 2, 8, 9, 20, 21, and 29 showed good to moderate activity in the range of (IC50 = 21.05 ± 0.9-53.22 ± 0.7 μM) as compared to the standard kojic acid (IC50 = 16.9 ± 1.3 μM). Compound 9 (IC50 = 21.05 ± 0.9 μM) was found to be significantly active and showed activity close to the standard. Compounds 2 (IC50 = 33.23 ± 1.1 μM), 8 (IC50 = 42.10 ± 1.0 μM), 20 (IC50 = 35.40 ± 0.4 μM), 21 (IC50 = 41.01 ± 0.6 μM), and 29 (IC50 = 53.22 ± 0.7 μM) were found to be moderately active. Structure-activity relationship (SAR) was rationalized on the basis of different substituents and functionalities present on the main scaffold. Conclusion: This study has identified a number of compounds derived from S-naproxen with comparable tyrosinase inhibitory activity.

Objective: To predict and analyze the target of anti-Hepatocellular Carcinoma (HCC) in the active constituents of Safflower by using network pharmacology. Methods: The active compounds of safflower were collected by TCMSP, TCM-PTD database and literature mining methods. The targets of active compounds were predicted by Swiss Target Prediction server, and the target of anti-HCC drugs was collected by DisGeNET database. The target was subjected to an alignment analysis to screen out Carvacrol, a target of safflower against HCC. The mouse HCC model was established and treated with Carvacrol. The anti-HCC target DAPK1 and PPP2R2A were verified by Western blot and co-immunoprecipitation. Results: A total of 21 safflower active ingredients were predicted. Carvacrol was identified as a possible active ingredient according to the five principles of drug-like medicine. According to Carvacrol's possible targets and possible targets of HCC, three co-targets were identified, including cancer- related are DAPK1 and PPP2R2A. After 20 weeks of Carvacrol treated, Carvacrol group significantly increased on DAPK1 levels and decreased PPP2R2A levels in the model mice by Western blot. Immunoprecipitation confirmed the endogenous interaction between DAPK1 and PPP2R2A. Conclusion: Safflower can regulate the development of HCC through its active component Carvacrol, which can affect the expression of DAPK1 and PPP2R2A proteins, and the endogenous interactions of DAPK1 and PPP2R2A proteins.

Background: Considering the limitations of cisplatin in clinical application, there is ongoing research to fabricate new platinum-containing prodrug which are highly effective to tumor cells and have low toxicity to normal cells. Methods: In this study, a cyclodextrin-based supramolecular platinum prodrug that is 6,6’-ophenylenediseleno- bridged bis (β-cyclodextrin)s (CD) and its potassium tetrachloroplatinate(II) complex was reported. The cytotoxicity experiments were performed to evaluate the anticancer activities of supramolecular prodrug in vitro by means of MTT assay. The practical application of supramolecular prodrug in tumor treatment in vivo were evaluated using BALB/c nude mice model bearing Hela cancer cells. Results: Compared with commercial anticancer drug cisplatin, the resultant cyclodextrin-based platinum prodrug exhibited comparative anticancer effect but with much lower toxicity side effects in vitro and in vivo. Conclusion: The cyclodextrin-based supramolecular platinum prodrug displayed antitumor activity comparable to the commercial antitumor drug cisplatin but with lower side effects both in vitro and in vivo, implying that the two adjacent cyclodextrin cavities not merely act as desired solubilizer, but also endowed the prodrug with cell permeability through the interaction of cyclodextrin with phospholipids and cholesterol on cell membrane.