Topological descriptors in drug design and modeling studies

Molecular Diversity -     

Synthesis,spectral characterization,docking studies and biological activity of urea,thiourea, sulfonamide and carbamate derivatives of imatinib intermediate

Molecular Diversity - A series of new urea/thiourea derivatives 3a–j were synthesized by simple addition reaction of functionalized phenyl isocyanates/isothiocyanates 2a–j with...     

Eco-friendly methods of synthesis and preliminary biological evaluation of sulfonamide derivatives of cyclic arylguanidines

The chemotype of arylsulfonamide derivatives of cyclic arylguanidines is a source of molecules with valuable biological activities, including antimicrobial and antitumor properties. The methods of the synthesis presented in the literature are characterized with low selectivity and high environmental nuisance. In this publication, we present a developed alternative and earlier undescribed pathway C, for the synthesis of arylsulfonamide derivatives of cyclic arylguanidines (N-(1H-arylimidazol-2-yl)arylsulfonamides and N-(1,4-dihydroquinazolin-2-yl)arylsulfonamides), including reaction between 2-(methylsulfanyl)-benzimidazole or 2-(methylsulfanyl)-3,4-dihydroquinazoline with arylsulfonamides. We also optimized previously reported methods; A (reaction of 2-aminobenzimidazole or 2-amino-3,4-dihydroquinazoline with arylsulfonyl chlorides) and B (reaction of dimethyl-(arylsulfonyl)carbonodithioimidate with aryldiamines). The conducted research allowed achieving two independent ecological and quick methods of obtaining the desired products. We used ecological methods of ultrasound-assisted or microwave synthesis, solvent-free reactions and a “green” reaction environment. In both pathways, it has proven advantageous to use H₂O as the solvent and K₂CO₃ (1 or 3 equivalent) as the basic agent. In the sonochemical variant, the efficiency reached B: 37–89 %, C: 90 % in 60 min (P = 80 W and f = 40 kHz), while in the microwave synthesis it was B: 38–74 %, C: 63–85 % in 0.5–4 min (P = 50 W). Path A led to a complementary substitution product (i.e. 1-(arylsulfonyl)-1H-benzimidazol-2-amine or 1-(arylsulfonyl)-1,4-dihydroquinazolin-2-amine). We obtained a small group of compounds that were tested for cytotoxicity. The 10f (N-(1,4-dihydroquinazolin-2-yl)naphthalene-1-sulfonamide) showed cytotoxic activity towards human astrocytoma cell line 1321 N1. The calculated IC₅₀ value was 8.22 µM at 24 h timepoint (doxorubicin suppressed 1321 N1 cell viability with IC₅₀ of 1.1 µM). The viability of the cells exposed to 10f for 24 h dropped to 48.0 % compared to vehicle control, while the cells treated with doxorubicin experienced decline to 47.5 %. We assessed its potential usefulness in pharmacotherapy in the ADMET study, confirming its ability to cross the blood–brain barrier (Pe = 5.0 ± 1.5 × 10^-6 cm/s) and the safety of its potential use in terms of DDI and hepatotoxicity.     

Predictive QSAR modeling for the antioxidant activity of natural compounds derivatives based on Monte Carlo method

Molecular Diversity - In this research, QSAR modeling was carried out through SMILES of compounds and on the basis of the Monte Carlo method to predict the antioxidant activity of 79 derivatives of...     

Mathematical modeling of the chemical inhibition of the detonation of hydrogen-air mixtures

A mathematical modeling of the chemical inhibition of the detonation of hydrogen-air mixtures is performed. It is demonstrated that a one-dimensional model of detonation based on a chain-branching mechanism of hydrogen combustion makes it possible to describe the main regularities of the effect of inhibitors on detonation. The calculation results, which are in good agreement with the available experimental data, show that inhibition causes a narrowing of the concentration limits of detonation and an increase in the critical diameter of detonation.     

Corrosion inhibition of steel in sulphuric acid by pyrrolidine derivatives

Novel corrosion inhibitors, namely 1-{2-[(2-hydroxyethyl)thio]ethyl}pyrrolidin-2-one (P5) and {[2-(2-oxopyrrolidin-1-yl)ethyl]thio}acetic acid (P4), were synthesised and tested as corrosion inhibitors for steel in 0.5 M H₂SO₄. The effects of P4 and P5 are also compared to their initial reactants 1-vinylpyrrolidin-2-one (P1), 2-mercaptoethanol (P2) and mercaptoacetic acid (P3). The study was carried out by weight loss measurements, potentiodynamic polarisation, linear polarisation resistance (R_p) and electrochemical impedance spectroscopy (EIS) methods. The inhibition efficiency increases with the concentration of P5 to attain 89% at 5 × 10⁻³ M. We note good agreement between the various methods explored. Polarisation measurements show also that the pyrrolidones act essentially as cathodic inhibitors. The cathodic curves indicate that the reduction of proton at the steel surface is an activating mechanism. P4 and P5 adsorb on the steel surface according to Langmuir adsorption model. Effect of temperature is also studied in the 298-353 K range. Efficiency is explained by the theoretical studies.     

Hydrogen bonds and antiviral activity of benzaldehyde derivatives

We have obtained the Fourier transform IR spectra of solutions of benzaldehyde derivatives having different antiviral activities against a herpes virus. We observe a correlation between the presence of hydrogen bonds in the benzaldehyde molecules and the appearance of antiviral properties in the compounds. For compounds having antiviral activity, we have obtained spectral data suggesting the existence of hydrogen bonds of the type C=O⋅⋅⋅H–O and O–H⋅⋅⋅O in the molecules. When the hydrogen atom in the hydroxyl groups are replaced by a methyl group, no intramolecular hydrogen bonds are formed and the compounds lose their antiviral activity.     

苯乙基噻唑硫脲衍生物抗艾滋病药物3D-QSAR研究

采用三维全息原子场作用矢量（3D-HoVAIF）对61个苯乙基噻唑硫脲衍生物类抗艾滋病药物进行定量构效关系（QSAR）研究.运用偏最小二乘回归（partial 1east square regression,PLS）建模,同时采用内部及外部双重验证的办法对所得模型稳定性能进行了深入分析和检验.PLS建模的复相关系数(R_cum)、留一法交互校验复相关系数(Q_CV)和外部样本校验复相关系数(Q_ext)分别为0.907、0.878、0.913.结果表明,3D-HoVAIF能较好表征苯乙基噻唑硫脲衍生物抗艾滋病药物分子结构信息,因而能建立具有良好稳定性和预测能力的QSAR模型,为抗艾滋病药物的研发提供一定的理论基础.     

苯乙基噻唑硫脲衍生物类抗艾滋病药物3D-QSAR研究

摘要：采用三维全息原子场作用矢量（3D-HoVAIF）对61个苯乙基噻唑硫脲衍生物类抗艾滋病药物进行定量构效关系(QSAR)研究.运用偏最小二乘回归（partial least square regression, PLS）建模,同时采用内部及外部双重验证的办法对所得模型稳定性能进行了深入分析和检验.PLS建模的复相关系数（Rcum）、留一法（leave-one-out, LOO）交互校验（cross-validation, CV）复相关系数（QCV）和外部样本校验复相关系数（Qext）分别为0.907、0.878、0.913.结果表明,3D-HoVAIF能较好表征苯乙基噻唑硫脲衍生物抗艾滋病药物分子结构信息,因而能建立具有良好稳定性和预测能力的QSAR模型,为抗艾滋病药物的研发提供一定的理论基础.     

Synthesis and rational design of anti‐inflammatory compounds: N‐phenyl‐cyclohexenyl sulfonamide derivatives

The synthesis of (±)‐ethyl 6‐[N‐(2‐chloro‐4‐fluorophenyl)sulfamoyl]cyclohex‐1‐ene‐1‐carboxylate ( 5n ) has been reproduced from a method previously described and served as the background for the preparation of a nitro derivative, potentially useful as an anti‐inflammatory agent. Furthermore, a structure‐based QSAR analysis of a series of N‐arylsulfamoyl congeners derived a highly predictive model for the activities of novel small‐molecule inhibitors of NO and cytokine production, whose preparation may be successfully achieved according to a similar procedure as above. Copyright © 2009 John Wiley & Sons, Ltd.     

Atomic resolution of bond descriptors in the two-orbital model

The probability-resolution scheme for partitioning the molecular bond-multiplicities into atomic contributions, suggested by the ‘partial’ atomic channels of the Communication Theory of the chemical bond, is applied to the simplest two-orbital model of a diatomic molecule. It offers a unique perspective upon a degree of the atom involvement in the covalent and ionic interactions with its molecular environment. The row channels generate the atomic contributions to the molecular bond-multiplicity and its covalent/ionic composition, while the atomic column channels give rise to the valence indices of bonded atoms, which reflect their promoted states in a molecule. Plots of the entropy/information bond indicators of atomic partial communication channels are generated over the whole range of the probability of finding an electron on the specified atom, 0?≤?P?≤?1, which measures a degree of polarization of the bonding molecular orbital (MO). They are compared with the MO predictions obtained from the same probability-division rule of the molecular bond-order measures from the MO theory. The atomic bond indices from the communication-theory approach are shown to agree semi-quantitatively with predictions from the MO theory.     

Investigations of the inhibition of copper corrosion in nitric acid solutions by ketene dithioacetal derivatives

Ketene dithioacetal derivatives, namely 3-[bis(methylthio)methylene] pentane-2,4-dione (1), 3-(1,3-dithian-2-ylidene) pentane-2,4-dione (2) and 3-(1,3-dithiolan-2-ylidene) pentane-2,4-dione (3) were synthesized and their respective capacity to inhibit copper corrosion in 3 M HNO₃ was investigated by means of weight loss, potentiodynamic polarization, scanning electron microscopy (SEM) and energy dispersive X-ray fluorescence (XRF). The obtained results indicate that the addition of these compounds significantly decreases the corrosion rate. Potentiodynamic polarization studies clearly showed that the inhibition efficiency increases with increasing concentration of the investigated compounds at a fixed temperature, but decreases with increasing temperature. These results on the whole showed that the studied substances are good cathodic inhibitors for copper corrosion in nitric acid medium. SEM and energy dispersive X-ray (EDAX) examination of the copper surface revealed that these compounds prevented copper from corrosion by adsorption on its surface to form a protective film, which acts as a barrier to aggressive agents. The presence of these organic compounds adsorbed on the electrode surface was confirmed by XRF investigations.     

An exploratory study to investigate possible simple descriptors in order to predict relative activity of antiepileptic enaminones

A general structure, substituent and activity relationship of the following type has been fitted to the available ED₅₀ values of cyclic enaminone antiepileptic compounds: . In this relationship ‘structure’ was quantified by d, the distance measured between the carbonyl oxygen and the first atom of the aromatic ring. The ‘substituent’ was quantified by Hammett substituent constant: (σ). With the aid of the above function of two independent variables, a new molecular structure was predicted by extrapolation that has shown about two orders of magnitude greater activity than the most active molecule in the original set with measured ED₅₀ values. Copyright © 2008 John Wiley & Sons, Ltd.     

Spectroscopy properties of the amide group in valpromide and some derivatives with antiepileptic activity

Infrared spectra at 300 and 77 K and Raman spectra at 300 K of the valpromide (Vpd), N‐substituted derivatives, N‐ethylvalpromide (Etvpd), N‐isopropylvalpromide (Ipvpd) and the N,N‐disubstituted derivative, N,N‐dimethylvalpromide (Dmvpd) with antiepileptic activity, have been measured and analyzed with results derived from computational chemistry calculation. In agreement with theoretical predictions, experimental data indicate that while in Etvpd, Dmvpd and Ipvpd there are four different conformational co‐existing components (Etvpd: TTCG⁺, TCCG⁻, TTTC, G⁺G⁺C G⁺; Dmvpd: TTCC, G⁻TTA⁺, G⁺A⁻TC, G⁺A⁻C A⁺; Ipvpd: TTCT, TCCT, TCCC, G⁻ TTT) in the Vpd there are only three distinct stable conformations of C₁ symmetry group: TTC, TCT, G⁺G⁺T. Based on the accuracy of the B3LYP calculation, with the 6‐31 + G** basis set estimated by comparison between the predicted values of the vibrational modes and the available experimental data, we performed a structural and vibrational study of the amide group in the Vpd and their derivatives. We found that small nonplanarity deviations of C(O)N backbone induce significant changes on the structural and spectroscopic properties. These are not compatible with the decreasing of the resonance effect as it is produced when the twisting around the C(O) N increases. From the Natural Bond Orbital (NBO) analysis the existence of stabilizing electrostatic interactions of type C H···O/N and C H···H N/C, which induce significant structural changes and a complex electronic redistribution of charge on the π‐system in those structures becomes evident. We view this as a consequence of the filled electron density change Lewis‐type NBOs type lp_{O1, 2}, lp_N1, σ_{(C H)N acyl} and empty non‐Lewis NBOs type σ*_{(C H)N acyl}, σ*_{N H}. Copyright © 2009 John Wiley & Sons, Ltd.     

Ultrasound-promoted synthesis and immunosuppressive activity of novel quinazoline derivatives

An environmentally friendly and mild Bischler cyclization was developed to access quinazolines with diverse substitution. Based on this method, a library of 53 quinazoline derivatives was prepared and tested in vitro for cytotoxicity and inhibition on T-cell and B-cell proliferation. Compounds 6b, 7b, 17b, 33, and 35 showed higher inhibitory activity on both T-cell and B-cell proliferations, with IC(50) values of 6.16, 6.30, 5.43, 2.54, and 9.80?μM on T-cell, respectively. All the tested compounds showed no obvious cytotoxicity at 10?μM concentration. The preliminary structure-activity relationship was concluded revealing that 4-position is the key modification site for potent quinazoline immunosuppressive agent.     

Adamantyl pyran-4-one derivatives and their in vitro antiproliferative activity

Molecular Diversity - Pyran-4-one (maltol, kojic acid and chlorokojic acid 1) esters of adamantan-1-ylacetic acid were prepared through efficient synthetic routes in good yields and evaluated for...