Letters in Drug Design & Discovery - Volume 13, Issue 5, 2016

Background: Hypertension is a complex and multifactorial disorder that is an important cause of morbidity and mortality in all around the world; and the rationalized structural modification of drugs represents an important strategy for to develop new antihypertensive drugs. Objective: To determine the vasorelaxant effect of 4H-pyranes and 2-pyridones derivatives designed from nifedipine and milrinone as pharmacophoric scaffolds. Methods: The vasorelaxant effect of all designed and synthesized compounds were carried out on the contraction induced by noradrenaline 0.1 μM in isolated rat aorta rings. Results: Compounds 4a—j, 6a-c and 8a-c showed a concentration– dependent and endothelium-independent relaxation on contraction induced by noradrenaline in isolated rat aorta rings. Compounds 6a, 8a, 8b, and 8c were the most potent compounds of entire series evaluated; however, were less potent than nifedipine and carbachol used as positive controls. Conclusions: Some compounds were designed and synthesized with significant vasorelaxant effect which can be used for the development of new antihypertensive drugs.

Neurotoxic organophosphate compounds (OP) are toxic and acetylcholinesterase (AChE) inhibitors widely used as insecticides and pesticides in agriculture. This is a key enzyme in the search for new strategies for poisoning treatment by means of pesticides and insecticides. The standard OP intoxication treatment involves the administration of an anticholinergic to reduce spasms and convulsion as well as a cationic oxime capable of removing the OP compounds inside the AChE active site to reactivate the enzyme. In this paper, a theoretical strategy combining docking(MM), chemometric analysis and QM calculations was employed to check out the association and kinetic reactivation coefficients associated to oximes, confronting in vitro the data found in the literature before. The docking results were selected by means of the principal components analysis and submitted to QM calculations. The calculated thermodynamics and kinetics parameters revealed a good correspondence between the calculated intermolecular energy values of the oximes and experimental results, reinforcing the theoretical findings and confirming the theoretical strategy used as a suitable tool for the prediction of kinetic and thermodynamics parameters, which would be able to collaborate with the design of new oximes more effective.

Structure of acetylcholinesterase (AChE) reactivators influences their reactivation activity. Monoquaternary or bisquaternary reactivators are generally used for this purpose. In this work, there is discussed in vitro activity of trisquaternary AChE reactivator – Trisoxime (K388). Its reactivation activity is tested on the AChE inhibited by selected nerve agents – tabun, sarin, cyclosarin, soman, VX, Russian VX and diisopropyl fluorophosphates (DFP). As a result, only AChE inhibited by three nerve agents (VX, Russian VX and DFP) was satisfactorily reactivated at tested oxime concentrations (10-5 M and 10-3 M). This relatively poor reactivation potency was probably caused by the bulky spherical structure of tested oxime. Although results obtained in this study are not favorable, they are showing that the addition of one more quaternary ring to the reactivator´s molecule is not the right way to improve its reactivation potency.

Our previous studies showed that L-tyrosine derivatives possessed potential inhibitory activities against matrix metalloproteinase-2 (MMP-2), a target greatly embodied in tumor invasion and metastasis process. The CoMFA/CoMSIA and molecular docking analyses were performed to study the structure-activity relationships of these molecules. A data set of 21 L-tyrosine derivatives was used as the training set to derive the 3D-QSAR models, and 9 L-tyrosine derivatives was used as the test set to validate the models. Based on the molecular alignment, highly predictive CoMFA model was obtained with a crossvalidated q2 value of 0.542 and a conventional r2 of 0.998 in the non-cross-validated partial least-squares (PLS) analysis, while the CoMSIA model with a better predictive ability was shown with q2 and r2 values of 0.793 and 0.948, respectively. Contour maps derived from the 3D-QSAR models provided information on main factors towards the activity. In the docking studies, the docking scores and binding poses represented the detailed information about intermolecular interactions between the compound and the target protein. Therefore, combination of the CoMFA/CoMSIA and molecular docking results could be used in designing more potent MMP-2 inhibitors.

QSAR studies to predict acridinones’ ability to interstrand DNA crosslinks formation were performed. The study is based on experimental, as well as predicted retention data (log k) and was conducted by connected QSRR and QSAR strategy. For this purpose, chromatography analysis of acridinone derivatives was utilized. Moreover, computer modeling of the above-mentioned compounds was performed. Afterwards, statistical analysis of the obtained results was performed by two different HPLC stationary phases: phosphatidylcholine (IAM) and α1-glycoprotein (AGP). This approach allowed determining retention parameter log k, which characterizes binding affinity of acridinones to phospholipids or proteins. Moreover, molecular modeling was performed based on the chemical structure of considered acridinones using HyperChem 8.0 program (HyperCube Inc., Gainesville, FL, USA). Structural descriptors were obtained from Dragon 6.0 software (Talete, Italy). Those data were used to create general QSAR equations. Derived QSAR models described acridinones’ ability to interstrand DNA crosslinks formation (C0) depending on HPLC retention parameters, whereas log k parameter obtained by HPLC analysis was mostly dependent on molecular descriptors calculated. Additionally, the predictive performance of obtained QSARs and QSRRs models allowed us to predict the ability to interstrand DNA crosslinks formation by acridinones derivatives. It also enabled us to predict their chromatographic retention parameters. Proposed connected QSRR and QSAR approach could be a useful tool for in silico experiments, which verifies acridinones’ activity, without any in vivo biological test.

The study of isatin, as well as its kind of derivatives, has become a hot topic for a long time. To explore the new compounds and bioactivities, in this work, a series of simple isatin Mannich and Schiff bases was synthesized through the condensation reaction. The structures of these synthesized compounds were characterized using NMR and MS. Furthermore, structure of one of these compounds (IMS-4) was studied by using single crystal X-ray diffraction. Then the anti-tumor and neuro-protection activities of these compounds were evaluated. The results showed that several compounds show protection activity on the PC12 cells apoptosis induced by H2O2, which are more effective than that of (±) α-Tocophreol (VE). Besides, some compounds also show anti-tumor activity against A549 and P388 cell lines more potent than that of isatin.

The anti-hyperlipidemic effect of nicotinic acid and its ability to overexpress PPARγ combined with the recently elucidated role of carbonic anhydrase III (CAIII) in of PPARγ expression, suggested the possibility that nicotinic acid inhibits CAIII. To validate this hypothesis we docked nicotinic acid into the binding pocket of CAIII. Apparently, nicotinic acid shared at least four critical binding interactions with potent CAIII inhibitor. Subsequent experimental validation using Hummel– Dreyer method indicated that nicotinic acid indeed inhibited the enzymatic activity of CAIII with an Ki value of 203 μM. Additional eighteen nicotinic acid analogues were tested and seven compounds were more active than nicotinic acid with ki values ranging 69.7- 115.2 μM. Docking studies and QSAR analysis were applied to explore the structural requirements for inhibiting CAIII and to build self-consistent and predictive model. Our findings strongly suggest that CAIII inhibition is at least one of the mechanisms for the reported anti-hyperlipidemic properties of nicotinic acid.

This study was planned to investigate possible antinociceptive activity of 1,5-diaryl-3-[4- (methylsulfonyl)phenyl]-4,5-dihydro-1H-pyrazole derivatives (2a-s), based on the analgesia-inducing potential of 4,5-dihydro-1H-pyrazole moiety carrying compounds. Tail-clip and hot-plate tests, measuring centrally organized responses to a noxious stimulus, were performed in order to examine antinociceptive potential of the test compounds (100 mg/kg, i.p). In addition, peripherally mediated antinociceptive effect was evaluated by acetic acid-induced writhing tests. Motor coordination of the animals was tested in a Rota-rod apparatus. Among the tested compounds 2c, 2e, 2g, 2h, 2j, 2l, 2m, 2o and 2r prolonged the reaction time, measured in the tail-clip and hot-plate tests, with respect to the control values. The same compounds also decreased the quantity of acetic acidinduced writhing behaviours. In the Rota-rod tests, compound 2r was the only derivative decreasing the falling latency of mice. The obtained results indicated that some of the tested 4,5-dihydro-1H-pyrazole derivatives induce notable antinociceptive activity by effecting both of the central and peripheral nociceptive pathways. In addition, this study provided some information about structure-activity relationship for the compounds carrying similar chemical scaffold. Nevertheless, it should be noted that mechanism of action for these agents should be clarified with further detailed investigations.

Furazano[3,4-b]quinoxaline 1-oxides indicate significant chemical reactivity and release NO fragments in their electron impact mass spectra. A series of fused furazan N-oxide derivatives were synthesized and tested in vitro as potential NO releasing agents in the presence of L- cysteine used as a thiol cofactor. The synthesized compounds were determined using cysteine as cofactor and Griess reagent. The yield in nitrite for each compound was expressed as % NO2- (mol/mol). Compound 4c showed the higher NO releasing ability among the tested furazan N-oxide derivatives. A new class of NO-donors, Furazano[3,4-b]quinoxaline 1-Oxides hybrids was developed by joining NOdonor furoxan moiety to substituted quinoxaline 1-Oxides. It seems that lipophilicity and stereochemistry of the X substitution influences the NO donating behavior.

Carbapenems are β- lactam antibiotics used to fight infections caused by organisms characterized by multidrug resistance. The use of β-lactams for over 60 years has led to a dramatic increase in resistance, which resulted in a decrease in the effectiveness of many antibiotics in this group. European Centre for Disease Prevention and Control successively informs about the emerging resistance to carbapenems. Aim of the present study was to determine the relationship between physicochemical parameters and the MIC50 values of meropenem, imipenem, doripenem, tebipenem, and ertapenem designated for Streptococcus spp., Klebsiella spp., Haemophilus spp., Pseudomonas spp., Staphylococcus spp., and Proteus mirabilis. Quick- Prop 3.1 software from Schrödinger package v 31207 was used for calculations. The leave-one-out method was used for model cross-validation. Squared cross-validated correlation coefficient (Q2) parameter and differences between Q2 and R2 were calculated as measure of the internal performance and model predictive ability. Difference of ability between fitting and predictive ability was analyzed using difference between asymptotic squared cross-validated correlation coefficient (Q2 asym) and Q2. In the presented work, it has been shown that it is possible to correlate physicochemical parameters groups (in the form of arithmetic expressions) with MIC50 values. The results of the analysis lead to a hypothesis that, depending on the differences between strains of bacteria various physicochemical parameters of arithmetic expressions reflect the diversity of interactions at the molecular level, despite the common mechanism of action. The presented models illustrate the correlations of sum of interactions between drug molecule and bacteria, expressed by MIC50 value.

Background: The rapid evolution of antibiotic resistance poses a serious threat to public health. The development of heterocyclic benzothiazole derivatives, as efficient and potential agents, has been the focus of antibacterial drug discovery. Objective: Present study attempts to evaluate the antibacterial activity and mechanism of action of novel 2-(4’- aminophenyl) benzothiazole derivatives. Methods: Antibacterial activity of novel benzothiazole derivatives was evaluated by agar disc diffusion method against a panel of susceptible Gram-positive and Gram-negative strains. The mechanism of action was explored by bactericidal kinetics, membrane depolarization, fluorescent assisted cell cytometry and DNA cleavage studies. Results: Our findings revealed that compounds A07a and A07b turned out to be the most potent analogues having minimum inhibitory concentration values in the range of 3.91-31.2 μg/ml against Staphylococcus aureus, Salmonella typhi, Pseudomonas aeruginosa and Escherichia coli. The new benzothiazole derivatives displayed different modes of action as elucidated by the studies on intact bacterial cells and plasmid DNA. The structure activity relationship studies showed prominent activity of compound A07a containing oxime moiety on carbonyl carbon along with less bulky electron releasing and lipophillic group (methoxy and chloro) in phenyl ring at C2 position of 2-(4’-aminophenyl) benzothiazole ring system. Conclusion: The potent antibacterial activity of compounds (A07a and A07b) was mediated by membrane perturbing and intracellular mode of actions. These results further validate the use of these derivatives in the treatment of microbial diseases and provide scope for further research.

Plant growth regulators with the suitable concentrations had obvious effects on the accumulation of indole alkaloids in Catharanthusroseus cells. Four salicylic acid saccharide carboxylate derivatives were designed and synthesized as plant elicitors. The structures were confirmed and the accumulation effect was also evaluated. The results showed that it exhibited obvious effects on the accumulation of indole alkaloids, catharanthine and ajmalicine in Catharanthus roseus cells.

Background: Vasoconstriction is a major pathological feature of cardiovascular diseases involving endothelium dependent and independent mechanisms. Oxadiazole moiety appeared to be effective in various pathologies. Objective: The aim of the study was to synthesize and evaluate the mechanism of vasorelaxation exhibited by synthesized oxadiazole derivatives. Method: The 2,5-disubstituted-1,3,4-oxadiazole derivatives were synthesized by an efficient and simple method. The derivatives were investigated for their ex-vivo vasorelaxant action on intact/denuded endothelium rat aortic rings precontracted with norepinephrine/ phenylephrine/KCl. Results: The contractions induced in the aortic rings by the addition of cumulative concentrations of norepinephrine, phenylephrine, KCl and calcium were significantly antagonized by a derivative, OXD-Z2. In another experiment, verapamil pretreatment inhibited phenylephrine and Ca2+-induced aortic contractions and OXD-Z2 did not alter verapamilinduced inhibition. This indicated the role of L-type Ca2+-channels in the OXD-Z2-induced vasorelaxation via inhibition of calcium influx. Further, atropine (muscarinic receptor antagonist), L-NAME (NO synthase inhibitor) and methylene blue (non-selective cGMP inhibitor) inhibited OXD-Z2-induced relaxation in other sets of experiments. These results indicate that OXD-Z2 also mediates vasorelaxation through NO release by muscarinic receptor activation. In addition, the molecular docking studies showed that OXD-Z2 interacts with L-type Ca2+-channel, muscarinic (M2) receptor and eNOS. Conclusion: Thus, it is deduced from the above findings that the vasorelaxant activity of OXD-Z2 involves muscarinic receptor-mediated nitric oxide release in addition to direct inhibition of L-type Ca2+-channels.

Background: Neisseria gonorrhoeae is a Gram-negative, obligate human specific pathogenic bacteria, predominantly causing a sexually transmitted infection known as gonorrhoea. The frequent emergence of new multiple drug resistant strain needs an extensive study of its genome for the development of new drug/vaccine target. Objective: Here, our aim is to predict the function of all hypothetical proteins (HPs) of Neisseria gonorrhoeae genome using modern bioinformatic-tools. Method: We have analyzed the genome sequence of N. gonorrhoeae and found that ~43% of genes are listed as conserved HP, for which no biochemical evidences are reported. To predict their possible functions using various bioinformatics tools and databases we have annotated amino acid sequences of all HPs from N. gonorrhoeae genome. Results: We found proteins of unknown functions belonging to various classes. Functions of 478 proteins were annotated and we observed that out of these proteins 48% are enzymes, 10% as transporter, 5% proteins as nucleic acid-binding proteins and 11% sequences contain a domain of unknown function. Conclusion: Functional annotation and identification of functionally important regions in the HPs from N. gonorrhoeae may be helpful for better understanding of its virulence mechanism, adaptability in host system, tolerance for host immune system and emergence of novel therapeutic intervention.

Coumarin and its derivatives belong to an important group of natural compounds with diverse biological properties. They are found in vegetables and plants and have been extensively investigated for various applications in pharmacology, medicine and cosmetics. The coumarins are lactones of hydroxycinnamic acids with photoprotective effect, the furanocoumarins (coumarins with furan ring) have photosensitizing properties and are often used for the treatment of skin diseases such as vitiligo and psoriasis. As cosmetic ingredients, coumarin derivatives are well known in fragrances, but have also been identified as UV absorbers, with photo-oxidation, antioxidant and photosensitizing properties also being reported. In this minireview we focused on photoprotective and photosensitizing effects of coumarins.