Letters in Drug Design & Discovery - Volume 14, Issue 5, 2017

Background: The positional effects of the methoxy- and hydroxyl substituents in the phenyl ring were examined in vivo for distinct receptor classes in order to gain an insight into the mechanism by which isomeric compounds (2S,4R,4aR,8R,8aR)-2-(3(4)-hydroxy-4(3)-methoxyphenyl)-4,7-dimethyl- 3,4,4a,5,8, 8a-hexahydro-2H-chromene-4,8-diols 1 and 2 exhibit their pharmacological activity. Conclusion: Our findings suggest a strong structure-function relationship between the substitution pattern and the mechanism of biological activity of compound. The methoxy substituent at C4 and the hydroxyl substituent at C3 (compound 1) seem to employ the cannabinoid and adrenergic systems, whereas compound 2 with the methoxy substituent at C3 and the hydroxyl substituent at C4 possibly targets the opioid and dopaminergic mechanisms.

Background: There has been a growing interest of pharmacophore hybridization in anticancer drug discovery that may be utilized for designing new potential lead candidates against multiple targets that may exhibit synergetic activity. Pyrazole and 1,2,3-triazole nucleus are amongst the most important ones. Method: Statistically validated 3D-QSAR models of the pyrazolo-triazole hybrids on 4 different types of human cancer cell lines (U87MG, PC-3, HT-29 and A549) are constructed through simulated annealing k-Nearest neighbor molecular field analysis (SA-kNN-MFA) method followed by robust molecular docking study, druggability assessment and in silico ADMET analysis. Results: 3D-QSAR study reveales the importance of electronegative group at R1 position and 3, 4- OCH3 substituent at R2 position that may enhance biological potency against these cancer cell lines. The docking analysis suggests that the pyrazolo-triazole hybrids may have better binding affinities compared to the redocked co-crystallized ligand for targets namely CDK-2, CDK-5, FTase, HSP-90, TGF-β, topoisomerase-I and tubulin. Moreover, these compounds show better ADMET profile than the standard drug 5-fluorouracil. Conclusion: The results of molecular docking, druggability and ADMET analysis may focus the utility of targeting these possible potential enzymes for developing newer pyrazolo-triazoles as multi-targeted anticancer agents.

Background: Carbamate compounds have attracted a great deal of interest in medicinal chemistry due to their inhibition potential against cholinesterase enzymes. Method: Hence, this study was undertaken to synthesize new piperazine derivatives including dithiocarbamate moiety, which is the bioisoster of carbamate. Twenty eight 4-(dimethylaminoalkyl) piperazine-1-carbodithioate derivatives (3a-3n, 4a-4n) were synthesized. Chemical structures of these compounds were confirmed by spectral data. Ellman’s assay was applied in order to investigate inhibitory potency of the compounds against Acetylcholinesterase (AChE) and Butyrylcholinesterase (BChE) enzymes. Results and Conclusion: It was determined that some of the compounds have remarkable activity on AChE. ADME (Absorption, distribution, metabolism, elimination) predictions were theoretically performed for all compounds in the series. Enzyme kinetics and molecular docking studies were carried out for the most active compound (3n) and nature of inhibition and interactions between enzyme and ligand were described.

Background: Glucokinase activators (GKAs) are the new class of candidate drugs which act on glucokinase (GK) enzyme and show their hypoglycaemic activity. Objective: The present work was planned to synthesize and evaluate the antidiabetic activity of a series of newer benzamide derivatives as potential GKAs. Method: This work involved synthesis of newer benzamide derivatives from benzoic acid and their evaluation by docking studies to determine the binding interactions for the best fit conformations in the binding site of GK enzyme. Based on the results of docking studies, the selected molecules were tested for their antidiabetic activity in the animal model. Results: Amongst the synthesized molecules, compounds 14 and 20 with phenyl-substituted thiazole moiety on amide nitrogen, exhibited highest activity in vivo. The results of the in vivo antidiabetic studies were found to be consistent with those of docking studies. Conclusion: These newly synthesized molecules thus can be treated as the initial hits for the development of new, safe, effective and orally bioavailable GKAs as therapeutic agents for the treatment of diabetic disorders.

Background: Cancer is one of the leading causes of morbidity and mortality worldwide and extensive efforts have been devoted to the discovery of new anticancer agents. In the last few decades, the clinical efficacy of tiazofurin and its analogues, dasatinib and bleomycins has pointed out the importance of thiazole moiety in the field of cancer treatment. Methods: In the present paper, some thiazolyl hydrazone derivatives were synthesized and evaluated for their cytotoxic effects on A549 human lung adenocarcinoma, C6 rat glioma and NIH/3T3 mouse embryonic fibroblast cell lines using MTT assay. The most effective compounds were also investigated for their effects on DNA synthesis, apoptosis and mitochondrial membrane potential. In order to investigate the relationship between anticancer activity and cholinesterases, all compounds were evaluated for their ability to inhibit AChE and BuChE using a modification of Ellman’s spectrophotometric method. Results: Generally, the compounds showed more potent inhibitory effects on C6 cells than A549 cells. 2- [2-(4-(1H-1,2,4-Triazol-1-yl)benzylidene)hydrazinyl]-4-(4-nitrophenyl)thiazole (2) was the most promising agent due to its notable inhibitory effect on C6 cells with an IC50 value of 13.00±1.00 μg/mL when compared with cisplatin (IC50= 12.67±3.06 μg/mL) and low cytotoxicity against NIH/3T3 cell line (IC50= 733.33±256.58 μg/mL). DNA synthesis inhibition percent of compound 2 was 62.2%, whereas the inhibition percent of cisplatin was 53.95%. Compound 2 increased early and late apoptotic cell population (18.3%) more than cisplatin (16.3%). This compound also caused disturbance on mitochondrial membrane potential (40.2%) in C6 cells, which was similar to cisplatin (42.3%). Conclusion: Compound 2, the most promising antitumor agent against C6 cells in this series, did not show any inhibitory activity against AChE and BuChE. This outcome pointed out that there is no relationship between the anticancer activity of compound 2 and cholinesterases.

Introduction: The demand for new antiviral agents is creating all possible approaches towards the development of newantiviral drugs. One of the possible methodologies that can be used for the discovery of such drugs is the screening of novel organophosphorus compounds for antiviral activity. Objectives: The primary objective of the study was to discover potential new anti-viral agents by phosphorylating ribosyl moiety at 5′ positionof 2′, 3′-O-isopropylidene adenosine nucleoside and evaluation of their in ovo antiviral activity against New castle disease virus and Blue tongue virus. Methods: The synthesis of phosphorylated derivatives of 2′, 3′-O-isopropylidene adenosine was carried out by reacting 2′, 3′-O-isopropylidene adenosine (I) with 4-nitrophenylphosphorodichloridate (II) to get intermediate (III). Further, it was reacted with various bioactive secondary and primary amines IV(a-k) to obtain the title compounds V(a-k).All the newly synthesized compounds were screened in ovo for their antiviral activity on New Castle Disease Virus, Blue Tongue Virus by Heamagglutination test and Embryonated chicken Egg Method. Results: All eggs inoculated with the virus control, 1 mg/mL of the title compounds V(a-k) with New Castle Disease Virus. The Survivability of virus cultured eggs were examined by haemagglutination test upto 96 hr. Piperazine ring containing amine compounds exhibited good antiviral activity, remaining compounds exhibited moderate activity. Compounds V(a-k) exhibited 40-100% embryo survivability basing on bioactive amine attached to phosphorus atom. Compounds Ve and Vi showed inhibition of virus up to 96 hr of which is more than standard Isopropylidene adenosine (I). Based on the lesions on the embryo and the percentage of live cells in Blue tongue virus infected BHK 21 cells, compounds Ve and Vi exhibited more antiviral activity than that of the standard nucleoside isopropylidene adenosine (I) whereas, compounds Va, Vb, Vd, Vg and Vh exhibited moderate activity. Conclusion: The antiviral activity was mainly influenced by fragments attached to phosphorus atom. Compounds Ve and Vi exhibited good antiviral activity towards New Castle disease virus as well as Blue Tongue Virus whereas remaining compounds exhibited moderate activity. The in ovo antiviral activity results of the synthesized compounds provided an additional direction for the structural optimization of the compounds for the development of antiviral drugs with improved selectivity and reduced side effects.

Background: Mannich bases are an important compounds in medicinal chemistry. They have wide range of biological activities including carbonic anhydrase (CA) inhibitory and acetylcholine esterase inhibitory (AChE) activities. Objective: It was aimed to synthesize Mannich bases, 1-aryl-3-(morpholin-4-yl/piperidin-1-yl)-1- propanone hydrochloride, by microwave irradiation and conventional heating methods to compare the methods in terms of reaction times and yields and to investigate their inhibitory effects on AChE enzyme and CA isoenzymes. Method: Mannich bases were synthesized using conventional heating and microwave irradiation methods under different reaction conditions. Inhibitory effects of the compounds on CA isoenzymes and AChE were evaluated according to literature procedure. Results: IC50 and Ki values of the compounds were evaluated against hCA I, II and AChE. The compounds had more potent or equal Ki values with the references used. Conclusion: This study makes an important contribution to the Mannich base library in terms of synthetic strategy. According to IC50 or Ki values the compounds 6 in Series A with morpholine and and 15 in Series B with piperidine towards both hCA I and/or II isoenzymes and the compounds 4 in Series A and 11, 13, 14, 15, 16, and 18 in Series B towards AChE seemed the leader compounds of the study.

Background: Polo like kinase 2 (PLK2) has been reported as a new target for developing novel anticancer drugs. Here, three-dimensional quantitative structure-activity relationship (3D-QSAR), docking and molecular dynamics (MD) simulation studies were carried out on 70 pyridopyrimidine derivatives to focus on the structural necessities of potent PLK2 inhibitors. Method: An optimal CoMFA model with cross-validated correlation coefficient (q2) of 0.588 and non-cross-validated correlation coefficient (r2) of 0.812 was obtained through 3D-QSAR modeling. The predicted correlation coefficients (r2 pred) of 0.534 and validation result from bootstrapping analysis and progressive scrambling indicated the predictability and reliability of the model. Results and Conslusion: 3D-QSAR analysis demonstrated that inhibitory activities of these compounds are highly influenced by steric and electrostatic properties. Docking and MD simulations were used for inspecting interactions of PLK2 with inhibitors. Ligand-binding residues such as Leu88, Val143, Leu159, Cys162, Arg165 and Phe212 were identified at the binding site of PLK2. The binding interaction pattern observed during MD simulation was in accordance with the docking study. Present work offers insights about the structural requirements for PLK2 inhibition which can be exploited for the development of novel PLK2 inhibitors.

Background: Quinoline-containing compounds have displayed an impressive array of pharmacological actions over the years, including antiprotozoal activities. Methods: In this work we evaluate antimalarial and antileishmanial activities of some aminoquinoline (AMQ) derivatives hybridized to sulfa or isoniazid or hydrazine groups. Results and Conclusion: In murine model of infection occasioned by P. berghei, compounds AMQa, AMQ-d and AMQ-e have shown promising antiplasmodial activity inhibiting the multiplication of parasites in a manner similar to chloroquine in some cases. For leishmaniasis, the majority of the compounds exhibited a strong in vitro activity against amastigotes of L. braziliensis (IC50 values below 10 μg/mL). Furthermore, AMQ-f, -g and -h (IC50 of 2.1, 1.4 and 1.8 μg/mL against amastigotes of L. braziliensis, respectively) showed IC50 values very close to miltefosine (IC50 1.6 mg/mL), the reference drug. None of the compounds showed cytotoxicity in vitro against uninfected human erythrocytes (HC50 > 500.0 μg/mL). These results provide evidence that the AMQ compounds are promising candidates as antimalarial and leishmanicidal drugs, which are extremely important considering that these are endemic parasitic diseases in tropical countries and sometimes occur concurrently.

Background: Hydrogels, due to their unique potentials such as high-water content and hydrophilicity are interest for the controlled release of drug molecules. But most of hydrogels are not biodegradable. Method: To address these issues, we have developed hydrogels that combined sensitive polymers such as poly (acrylic acid) and polymethacrylic acid based on Starch and Chitosan. Owing to their unique potentials through combining the characteristics of a hydrogel system (e.g. hydrophilicity and extremely high water content) with a Starch and Chitosan (e.g. biocompatibility and biodegradability, bioadhesiveness and continued drug release properties that can be easily removed from the body that improve sustained drug release systems). Thus, Chitosan–poly(acrylic acid) (CTS-p(AA)), Starchpoly( acrylic acid) (St-p(AA)), and St-Poly(methacrylic acid) (St-p(MAA)), hydrogels were synthesized by radical polymerization method. The effect of pH on the swelling behavior of the hydrogels was also studied. The swelling ratio was measured for all the hydrogel structures, in different media (pH=1.1, 4, 7.4 and 10) as a function of time. Vitamin B12 was loaded into polymeric matrix. Results and Conclusion: The hydrogels loaded with vitamin B12 demonstrated a decrease of release rate in pH = 1.1 compared to pH = 10. Moreover, we investigated the effect of scaffold materials in hydrogels and monomer in dug release in constant pHs. Our results indicated that the release rate of vitamin B12 is in the following order: St-p(AA) > St-p(MAA) >> CTSp(AA).

Background: A series of novel N-(substituted aryl/alkylcarbamothioyl)-4-[5-(4-methylphenyl)- 3-(trifluoromethyl)-1H-pyrazol-1-yl]benzene sulfonamides [SGK 318, 319, 320, 324, 327] and N-(3- substitutedaryl/alkyl-4-oxo-1,3-thiazolidin-2-ylidene)-4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1- yl]benzenesulfonamides[SGK 328, 329, 330, 334, 337] were synthesized and tested for their quorum sensing inhibitor (QSI) capacity using quorum sensing inhibitor selector 1 (QSIS1) bioassay. Findings: QSIS assay revealed that SGK 324, SGK 327 and SGK 330 have the potentials to interfere with QS system in QS inhibitor selector1 (QSIS1) reporter strain. Moreover, these compounds were found to significantly affect QS regulated elastase and biofilm productions in Pseudomonas aeruginosa PA01 strain without affecting its growth. Molecular modeling experiments suggested that SGK 330 fits within the binding site of LasR protein of P. aeruginosa. SGK 324 and 327 also bind LasR provided that they adopt a s-trans/s-cis conformation with respect to the thiourea function. Results and Conclusion: Results of this study indicated that these compounds could be developed as new QS inhibitors without killing the bacteria but as antivirulence compounds to restrict virulence of clinically important human pathogens.

Overexpression and aberrant activation of NF-ΚB has been extensively documented during the development and progression of head and neck squamous cell carcinoma (HNSCC), the sixth most common cancer worldwide. Accumulating evidence indicates that NF-ΚB plays a central role in HNSCC development via regulation of a multitude of genes involved in cell proliferation, cell survival, apoptosis evasion, inflammation, immune functions, stress response, invasion, metastasis, angiogenesis and resistance to anticancer therapies. Different classes of drugs, chemicals, dietary agents, medicinal plants and phytochemicals have been demonstrated to inhibit NF-ΚB signalling at various levels including upstream of IKK, directly at the IKK complex, phosphorylation of IΚB, ubiquitination or proteasomal degradation of IΚB; nuclear translocation of NF-ΚB and binding of NF- ΚB to DNA. NF-ΚB expression has been suggested as a novel marker of chemo- and radiotherapy resistance. Downregulation or knockdown of NF-ΚB activators, combination chemotherapy, as well as natural products that inhibit NF-ΚB signalling confer chemoradiosensitivity. In particular, inhibition of proteasomal degradation of IΚB has evolved as an important tool for pharmacological intervention. Further investigation to identify NF-ΚB inhibitors with greater specificity, efficacy and safety as well as strategies to intensify chemo-radiosensitivity will aid in the prevention and treatment of HNSCC.