Letters in Drug Design & Discovery - Volume 16, Issue 7, 2019

Background: Pyrazole is an important class of heterocyclic compound, has been shown to exhibit diverse biological and pharmacological activities such as anti-inflammatory, anti-cancer, antioxidant, etc. Methods: In this study, a series of novel 3,5-dimethyl-1H-pyrazole derivatives containing hydrazine 4a-l have been synthesized via the reaction of the 2-(3,5-dimethyl-1H-pyrazol-1-yl)acetohydrazide. All synthesized compounds have been tested for their in vitro antioxidant activities via utilization of 1,1-biphenyl-2-picrylhydrazyl (DPPH) as a free radical scavenging reagent. Results: The data reported herein indicates that compound 4k showed potential radical scavenging capacity and compounds 4f and 4g exhibited best activity for the iron binding while comparing with positive controls. Conclusion: Good activity was noted for some compounds. In particular, compound 4k showed the highest antioxidant activity with IC50 values of 22.79 ± 3.64 and 1.35 ± 0.66 μg/mL in the DPPH and ABTS tests, respectively.

Background: A concatenation of bioactive diethyl(2-hydroxyphenylsubstituted) benzopyrano pyrimidinyl phosphonates were synthesized under eco-friendly green conditions in the presence of palladium doped graphitic carbon nitride (Pd@g-C3N4) as catalyst. Methods: The title compounds were evaluated for cytotoxic activity against MCF-7, SW-480, HeLa and HL-7702 cell lines and in-vitro antioxidant activity by DPPH, NO and H2O2 methods. Results: The synthesized compounds manifested robust cytotoxic and antioxidant activities. Conclusion: Some of them showed much higher bioactivity than the standards.

Background: In the present study synthesis and biological assessment of nine new ethyl [(4,5-disubstituted- 4H-1,2,4-triazol-3-yl)sulfanyl]acetate derivatives 2(a-i) is performed. Methods: The title compounds were characterized by their analytical and spectral data. All the synthesized compounds were screened for their in vivo anti-inflammatory activity using carrageenaninduced rat paw oedema method and in vitro antimicrobial activity. All the compounds exhibited good anti-inflammatory activity; especially compound 2h produced the maximum effect i.e., 62.5 % comparable to that of standard, diclofenac. The antimicrobial screening results indicated that some of the newly synthesized compounds showed good antibacterial activity, especially against Escherichia coli. Results: All the synthesized thioacetate derivatives of triazoles were also studied for their interactions with the enzymes COX-I and COX-II, two important targets of inflammation pathway, through docking analysis. All the compounds showed good binding affinities with both the enzymes with a maximum value of -8.1 for 2e kcal/mol against COX-I. Conclusion: Docking analysis predicted that our compounds reduce inflammation nonselectively by inhibiting both COX-I and COX-II of inflammatory pathway just like other nonselactive NSAIDS.

Background: β-Site amyloidal precursor protein (APP) cleavage enzyme (BACE-1) is reported as prime cause for progession of Alzheimer’s disease (AD). It is a form of dementia characterized by degeneration of neurones in brain. Therefore, attempts have been made to find potent inhibitors of this enzyme. Methods: The paper presents an division-based 2D quantitative structure-activity relationship (QSAR) study on a series of BACE-1 inhibitors to analyse the structural features that may be important to increase the potency of the compounds. Results: The study led to predict some potential leads for the development of potent inhibitors of BACE-1. One of the molecule with pyrrolidine and pyrrolidinone substitutions exhibited drugreceptor interactions comparable with reference drug. Conclusion: The hydrogen-bond interactions between the molecules and the receptor basically control the BACE-1 inhibition activity of the compounds.

Background: The re-emerging Zika virus has posed a serious threat to human health due to its association with the neurological disorders. The NS3 protein of Zika virus plays a pivotal role in the genome replication and thus may prove to be a critical target for the drug designing studies. Objective: The present study was conceptualized to analyze the crystal structure of NS3 protein of Zika virus followed by the identification of it’s potential inhibitors. Methods: Crystal structure of the NS3 protein was evaluated in detail. Docking of the NS3 protein was done with 130 different ligands including dengue virus inhibitors and their similar compounds along with some approved drugs. The drug likeliness properties were checked for non drug compounds. Results: Structural analysis of the NS3 protein revealed three important sites namely ATP- and RNAbinding sites as well as a central cavity. The selected ten ligands (ZINC05487635, ZINC0092398, ZINC13345444, 4-methoxyphenyl 4-chloro-3-nitrobenzoate, Luteolin, Ivermectin, Suramin, Dasatinib, Panduratin A, and ARDP0009) showed a higher binding affinity for the NS3 protein and good drug likeliness properties. Conclusion: These inhibitors could possibly act as potential lead molecules for future drug designing studies. Our present computational data is envisaged to be useful for gathering experimental evidences towards the development of potential therapeutic molecules against this arthropod mediated pathogen.

Background: Alzheimer’s disease is a medical condition with detrimental brain health. It is majorly diagnosed in aging individuals plaque in β) characterized by accumulated Amyloidal beta (A 1 BACE) 1 secretase APP cleavage enzyme βneurological areas. The ) is the target of choice that can be exploited to find drugs against Alzheimer’s disease. Methods: A series of BACE-1 inhibitors with reported binding constant were considered for the development of a feature based pharmacophore model. Results: The good correlation coefficient (r=0.91) and RMSD of 0.93 was observed with 30 compounds in training set. The model was validated internally (r2test=0.76) as well as externally by Fischer validation. The pharmacophore based virtual screening retrieved compounds that were docked and biologically evaluated. Conclusion: The three structurally diverse molecules were tested by in-vitro method. The pyridine derivative with highest fit value (6.9) exhibited IC50 value of 2.70 μM and thus was found to be the most promising lead molecule as BACE-1 inhibitor.

Background: In recent years, pyrazole carboxamide derivatives possessed excellent fungicidal activity. In the process of designing new fungicides, the carboxamide group was modified in order to find novel structure pyrazole carboxamide derivatives. Methods: Ten novel trifluoromethyl pyrazole acyl thiourea derivatives were designed and synthesized. In vivo fungicidal activities of these compounds were tested against Fusarium oxysporum, Corynespora mazei and Botrytis cinerea, respectively. Results: Particularly compounds exhibited significant control effective at 100 mg/L. More importantly, some compounds showed the good control effective at 10 mg/L. Furthermore, docking was established to study the structure-activity relationship of the title compounds. Conclusion: It is possible that trifluoromethylpyrazole acyl thiurea derivatives, which possess good control effective against Botrytis cinerea, may become novel lead compounds for the development of fungicides with further structure modification.

Background: The term vitamin B6 refers to a set of six compounds, pyridoxine,pyridoxal ,and pyridoxamine and their phosphorylated forms, among which pyridoxal 5´-phosphate (PLP) is the most important and active form acting as a critical cofactor. These compounds are very useful in medicinal chemistry because of their structure and functionalities and are also used in bioinorganic chemistry as ligands for complexation with metals. Methods: In this study, a series of hydrazones 1a-g and N-acylhydrazones 2a-f containing vitamin B6 have been synthesized from commercial pyridoxal hydrochloride and the appropriate aromatic or heteroaromatic hydrazine or N-acylhydrazine. All synthesized compounds have been fully characterized and tested against Mycobacterium tuberculosis. Results: Among the N-acylhydrazones derivatives 2a-f, 2d (para- pyridine substituted Nacylhydrazone; MIC = 10.90 μM) exhibited the best activity. The ortho-pyridine derivative 2b exhibited intermediate activity (MIC = 87.32 μM), and the meta-pyridine derivative 2c was inactive. In case of the hydrazone series 1a-g, 7-chloroquinoxaline derivative 1f (MIC = 72.72 μM) showed the best result, indicating that the number of nitrogen and chlorine atoms in the radical moiety play an important role in the anti-tuberculosis activity of the quinoxaline derivatives (1f and 1g). Conclusion: The data reported herein indicates that the isoniazid derivative 2d (MIC = 10.90 μM) exhibited the best activity in the N-acylhydrazone series and; the quinoxaline nucleus derivative 1f (MIC = 72.72 μM) was the most active compound in the hydrazone series.

Background: Trypanosomiasis is one of the neglected tropical diseases and continues to cause serious morbidity, mortality and economic loss. Current anti-trypanosomal drugs are antiquated and suffer from a number of serious setbacks, thereby necessitating the search for new drugs. Stigmasterol has previously demonstrated in vitro and in vivo anti-trypanosomal activity. Methods: Herein, stigmasterol was docked into three validated anti-trypanosomal drug targets; uridylyl transferase, farnesyl diphosphate synthase and sterol 14α-demethylase, in order to elucidate the possible biochemical targets for the observed anti-trypanosomal activity. Results: The binding free energy between stigmasterol and the enzymes was in the order; sterol 14α-demethylase (-8.9 kcal/mol) < uridylyl transferase (-7.9 kcal/mol) < farnesyl diphosphate synthase (-5.7 kcal/mol). At the lowest energy docked pose, stigmasterol interacts with the active site of the three trypanosomal enzymes via non-covalent interactions (apart from hydrogen bond) while highly hydrophobic stigmasterol carbon atoms (21 and 27) were crucial in the interaction with varying residues of the three anti-trypanosomal targets. Conclusion: Therefore, results from this study might suggest that stigmasterol mediated the antitrypanosomal activity through interaction with the three anti-trypanosomal targets but with more preference towards sterol 14α-demethylase.

Background: In spite of the availability of various treatment approaches including surgery, radiotherapy, and hormonal therapy, the steroidal aromatase inhibitors (SAIs) play a significant role as chemotherapeutic agents for the treatment of estrogen-dependent breast cancer with the benefit of reduced risk of recurrence. However, due to greater toxicity and side effects associated with currently available anti-breast cancer agents, there is emergent requirement to develop target-specific AIs with safer anti-breast cancer profile. Methods: It is challenging task to design target-specific and less toxic SAIs, though the molecular modeling tools viz. molecular docking simulations and QSAR have been continuing for more than two decades for the fast and efficient designing of novel, selective, potent and safe molecules against various biological targets to fight the number of dreaded diseases/disorders. In order to design novel and selective SAIs, structure guided molecular docking assisted alignment dependent 3D-QSAR studies was performed on a data set comprises of 22 molecules bearing steroidal scaffold with wide range of aromatase inhibitory activity. Results: 3D-QSAR model developed using molecular weighted (MW) extent alignment approach showed good statistical quality and predictive ability when compared to model developed using moments of inertia (MI) alignment approach. Conclusion: The explored binding interactions and generated pharmacophoric features (steric and electrostatic) of steroidal molecules could be exploited for further design, direct synthesis and development of new potential safer SAIs, that can be effective to reduce the mortality and morbidity associated with breast cancer.

Background: This work reports design, synthesis, and in vitro cytotoxicity of novel coumarin-1,2,3-triazole-1,2,4-oxadiazole hybrids against three breast cancer cell lines MCF-7, MDA-MB-231, and T-47D. Methods: Synthetic procedure for the preparation of desired compounds was started from the reaction of coumarins or with propargyl bromide to give O-propargylated coumarins or 5. Then, click reaction between the later compounds and 3-aryl-5-(chloromethyl)-1,2,4-oxadiazoles afforded the desired products in good yields. Results: Among the synthesized compounds, 4-((1-((3-(4-chlorophenyl)-1,2,4-oxadiazol-5- yl)methyl)-1H-1,2,3-triazol-4-yl)methoxy)-2H-chromen-2-one (9a) showed the best cytotoxicity against breast cancer cell lines. Conclusion: Compound 9a depicted the most activity toward MDA-MB-231 and T-47D cells while compounds 8a and 8c were the most potent compounds against MCF-7.