Synthesis, antitubercular evaluation and 3D-QSAR study of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazole derivatives

As a part of our ongoing research to develop novel antitubercular agents, a series of N-phenyl-3-(4-fluorophenyl)-4-substituted pyrazoles have been synthesized and tested for antimycobacterial activity in vitro against Mycobacterium tuberculosis H37Rv strain using the BACTEC 460 radiometric system. A 3D-QSAR study based on CoMFA and CoMSIA was performed on these pyrazole derivatives to correlate their chemical structures with the observed activity against M. tuberculosis. The CoMFA model provided a significant correlation of steric and electrostatic fields with the biological activity while the CoMSIA model could additionally shed light on the role of hydrogen bonding and hydrophobic features. The important features identified in the 3D-QSAR models have been used to propose new molecules whose activities are predicted higher than the existing systems. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antitubercular agents.     

Synthesis,characterization, antifungal evaluation and 3D-QSAR study of phenylhydrazine substituted tetronic acid derivatives

A series of 3-(1-(2-(substituted phenyl)hydrazinyl)alkylidene)furan-2,4(3H,5H)-diones were designed and prepared using two synthetic routes. Their structures were confirmed by FT-IR, ¹H NMR, ¹³C NMR, MS, elemental analysis and single-crystal X-ray diffraction. Their bioactivity was evaluated against Botrytis cinerea in vitro. Most target compounds exhibited remarkable antifungal activity. Two compounds 7f and 7h were highly effective and their EC₅₀ values were 0.241 μg/mL and 0.167 μg/mL, respectively, close to that of the control drug procymidone. 3D-QSAR studies of CoMFA and CoMSIA were carried out. Models with good predictive ability were generated with the cross validated q² values for CoMFA and CoMSIA being 0.565 and 0.823. Conventional r² values were 0.983 and 0.945, respectively. The results provided a practical tool for guiding the design and synthesis of novel and more potent tetronic acid derivatives containing substituted phenylhydrazine moiety.     

Synthesis, anti-tuberculosis activity, and 3D-QSAR study of ring-substituted-2/4-quinolinecarbaldehyde derivatives

We have previously identified ring-substituted quinolines as a new structural class of anti-tuberculosis agents. In our ongoing efforts at structural optimization of this class, four series of ring-substituted-2/4-quinolinecarbaldehyde derivatives were synthesized. All twenty-four compounds were synthesized using short and convenient one to two high yielding steps. The newly synthesized compounds were tested in vitro against drug-sensitive Mycobacterium tuberculosis H37Hv strain. Several derivatives were found to be promising inhibitors of M. tuberculosis. For example, derivatives 4a-c (Series 2), 7a-d (Series 3), and 8a-b (Series 4) displayed >90% inhibition at 6.25 microg/mL in the primary assay. The most active compounds, N-(2-fluorophenyl)-N'-quinolin-2-ylmethylene-hydrazine (4a), N-(2-adamantan-1-yl-quinolin-4-ylmethylene)-N'-(4-fluorophenyl)hydrazine (7c), and N-(2-cyclohexyl-quinolin-4-ylmethylene)-N'-(2-fluorophenyl)hydrazine (8a), exhibited 99% inhibition at the lowest tested concentration of 3.125 microg/mL against drug-sensitive M. tuberculosis H37Rv strain. The similarity index based on steric and electrostatic features of the molecules was used, in conjunction with principal component analysis and linear discriminant analysis, successively to classify the molecules based on their activity into two classes. This classification method gives us confidence in predicting the activity class of any new unsynthesized molecule belonging to these series.     

Antimycobacterial activity of ionic fullerene derivatives

Positively charged fullerene derivatives, moderately soluble in water:DMSO 9:1, have been tested using three strains of Mycobacterium spp. Some compounds inhibit the growth of Mycobacterium tuberculosis, a human clinical isolate, particularly virulent and resistant, at doses as low as 5 microg/mL.     

Antimycobacterial activity of 3,4-dichlorophenyl-ureas, N,N-diphenyl-ureas and related derivatives

Substituted urea derivatives were prepared by reacting 3,4-dichlorophenyl isocyanate with amino acids, dipeptides, histamine or dicyandiamide among others, or from N,N-diphenyl-carbamoyl chloride and amino acids, dipeptides, or histamine. Other derivatives were obtained by reaction of PABA or PAS with arylsulfonyl halides. Some of the new compounds showed appreciable activity as antimycobacterial agents against Mycobacterium tuberculosis H37Rv, producing an inhibition of growth in the range of 80-89%, at a concentration of 6.25 microM. Some derivatives of this series might constitute interesting lead molecules for designing novel types of drugs effective against M. tuberculosis, a re-emerging pathogen both in the developed and under-developed countries.     

Antimycobacterial activity of new 3,5-disubstituted 1,3,4-oxadiazol-2(3H)-one derivatives. Molecular modeling investigations

3H-1,3,4-Oxadiazol-2-one derivatives were synthesized and tested for their in vitro antimycobacterial activity. Oxadiazolone derivatives showed an interesting antimycobacterial activity against the reference strain of Mycobacterium tuberculosis H₃₇Rv. Molecular modeling investigations were performed and showed that the active compounds possess all necessary features to target the protein active site of the mycobacterial cytochrome P450-dependent sterol 14α-demethylase in the sterol biosynthesis pathway as the calculated free energy of binding were in agreement with the corresponding MIC values.     

Synthesis,structure analysis,antitumor evaluation and 3D-QSAR studies of 3,6-disubstituted-dihydro-1,2,4,5-tetrazine derivatives

3,6-Diaryl-dihydro-1,2,4,5-tetrazine derivatives were synthesized and their structures were confirmed by single-crystal X-ray diffraction. Monosubstituted dihydrotetrazines are the 1,4-dihydro structure, but disubstituted dihydrotetrazines are the 1,2-dihydro structure. The results of further research indicated there may be a rearrangement during the synthesis process of disubstituted dihydrotetrazines. Their antitumor activities were evaluated against A-549 and P388 cells in vitro. The results showed several compounds to be endowed with cytotoxicity in the low micromolar range. Two compounds were highly effective against A-549 cell and IC₅₀ values were 0.575 and 2.08 μM, respectively. Three-dimensional quantitative structure–activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were carried out on 37 1,2,4,5-tetrazine derivatives with antitumor activity against A-549 cell. Models with good predictive abilities were generated with the cross validated q² values for CoMFA and CoMSIA being 0.744 and 0.757, respectively. Conventional r² values were 0.978 and 0.988, respectively, the predicted R² values were 0.916 and 0.898, respectively. The results provide the tool for guiding the design and synthesis of novel and more potent tetrazine derivatives.     

Synthesis, anti-tuberculosis activity, and 3D-QSAR study of 4-(adamantan-1-yl)-2-substituted quinolines

Structural optimization of the previously identified 4-(adamantan-1-yl)-2-quinolinecarbohydrazide (AQCH, MIC=6.25 microg/mL, 99% inhibition, Mycobacterium tuberculosis H37Rv) has led to two series of 4-(adamantan-1-yl)-2-substituted quinolines (Series 1-2). All new derivatives were evaluated in vitro for antimycobacterial activities against drug-sensitive M. tuberculosis H37Rv strain. Several 4-adamantan-1-yl-quinoline-2-carboxylic acid N'-alkylhydrazides (Series 1) described herein showed promising inhibitory activity. In particular, analogs 7, 9, 20, and 21 displayed MIC of 3.125 microg/mL. Further investigation of AQCH by its reaction with various aliphatic, aromatic, and heteroaromatic aldehydes led to the synthesis of 4-adamantan-1-yl-quinoline-2-carboxylic acid alkylidene hydrazides (Series 2). Analogs 42-44 and 48 have produced promising antimycobacterial activities (99% inhibition) at 3.125 microg/mL against drug-sensitive M. tuberculosis H37Rv strain. The most potent analog 35 of the series produced 99% inhibition at 1.00 microg/mL against drug-sensitive strain, and MIC of 3.125 microg/mL against isoniazid-resistant TB strain. To understand the relationship between structure and activity, a 3D-QSAR analysis has been carried out by three methods-comparative molecular field analysis (CoMFA), CoMFA with inclusion of a hydropathy field (HINT), and comparative molecular similarity indices analysis (CoMSIA). Several statistically significant CoMFA, CoMFA with HINT, and CoMSIA models were generated. Prediction of the activity of a test set of molecules was the best for the CoMFA model generated with database alignment. Based on the CoMFA contours, we have tried to explain the structure-activity relationships of the compounds reported herein.     

The 3D-QSAR study of antitumor arylsulfonylimidazolidinone derivatives by CoMFA and CoMSIA

Three-dimensional quantitative structure-activity relationship (3D-QSAR) studies for a series of arylsulfonylimidazolidinone derivatives having antitumor activity were conducted using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). The in vitro cytotoxicity against human lung carcinoma (A549) exhibited a strong correlation with steric and electrostatic factors of the molecules. Four different types of models have been built using CoMFA and CoMSIA method with AM1 charge or Gasteiger-Huckel charge. By comparison of the statistical results of these models, model I obtained by CoMFA study with AM1 showed the best predictability of the antitumor activities based on the cross-validated value (0.642), conventional r2 (0.981), standard error of estimate (0.106) and PRESS value (0.170).     

Pharmacokinetic evaluation of C-3 modified 1,8-naphthyridine-3-carboxamide derivatives with potent anticancer activity: lead finding

Abstract

To develop naphthyridine derivatives as anticancer candidates, pharmacokinetic (PK) evaluations of 10 novel derivatives of 1,4-dihydro-4-oxo-1-proparagyl-1,8-naphthyridine-3-carboxamide, with potent anticancer activity were done using in vitro ADME (absorption, distribution, metabolism, excretion) and pharmacokinetic--pharmcodynamic (PK/PD) assays. Only derivatives 5, 6, 9 and 10 showed better metabolic stability, solubility, permeability, partition coefficient and cytochrome P450 (CYP) inhibition values. PK of derivatives 5, 6, 9 and 10 in rat showed comparable PK profile for derivative 5 (C₀?=?6.98?µg/mL) and 6 (C₀?=?6.61?µg/mL) with no detectable plasma levels for derivatives 9 and 10 at 5.0?mg/kg i.v. dose. PK/PD assay of derivatives 5 and 6 in tumor-bearing mice (TBM) showed comparable PK but tumor plasma index (TPI) of derivative 6 (4.02) was better than derivative 5 (2.50), suggesting better tumor uptake of derivative 6. Derivative 6, as lead compound, showed highest tumor growth inhibition (TGI) value of 33.6% in human ovary cancer xenograft model.     

Docking-based 3D-QSAR (CoMFA,CoMFA-RG,CoMSIA) study on hydroquinoline and thiazinan-4-one derivatives as selective COX-2 inhibitors

A series of 26 selective COX-2 inhibitors which reported previously by our laboratory was selected to generate three-dimensional quantitative structure activity relationship (3D-QSAR) model. Active conformation of each molecule was predicted by docking studies and used for molecular alignment. Activity of 20 molecules as a train set was predicted using three methods including comparative molecular field analysis (CoMFA), CoMFA region focusing (CoMFA-RG) and comparative molecular similarity index analysis (CoMSIA). The best models of CoMFA-RG and CoMSIA revealed correlation coefficients r² of 0.955 and 0.947, the leave one out cross-validation coefficients q² of 0.573 and 0.574, respectively. In addition, CoMFA-RG and CoMSIA models were validated by a test set of six molecules with predicted coefficients r²_pred of 0.644 and 0.799, respectively. Contour maps of generated models provided fruitful information about structural aspect of molecules that affected their COX-2 inhibitory activity. Based on three models results, steric and electrostatic properties are the most important factors in controlling the activity of the molecules. Results of CoMFA-RG and CoMSIA models were utilized to design new molecules. Comparison of experimental and predicted pIC₅₀ values of designed molecules indicated that CoMFA-RG had the more predictive ability.

Communicated by Ramaswamy H. Sarma     

Synthesis,biological evaluation and 3D-QSAR studies of new chalcone derivatives as inhibitors of human P-glycoprotein

P-glycoprotein (P-gp) is an ATP-dependent multidrug resistance efflux transporter that plays an important role in anticancer drug resistance and in pharmacokinetics of medicines. Despite a large number of structurally and functionally diverse compounds, also flavonoids and chalcones have been reported as inhibitors of P-gp. The latter share some similarity with the well studied class of propafenones, but do not contain a basic nitrogen atom. Furthermore, due to their rigidity, they are suitable candidates for 3D-QSAR studies. In this study, a set of 22 new chalcone derivatives were synthesized and evaluated in a daunomycin efflux inhibition assay using the CCRF.CEM.VCR1000 cell line. The compound 10 showed the highest activity (IC₅₀ = 42 nM), which is one order of magnitude higher than the activity for an equilipohillic propafenone analogue. 2D- and 3D-QSAR studies indicate the importance of H-bond acceptors, methoxy groups, hydrophobic groups as well as the number of rotatable bonds as pharmacophoric features influencing P-gp inhibitory activity.     

Synthesis and antiviral evaluation of C-4-hydrazide derivatives of 2',3'-dideoxycytidine

Syntheses of three hitherto unknown derivatives of 2',3'-dideoxycytidine, namely C-4-(salicylic hydrazide)-ddC, C-4-(N-butyloxycarbonyl-isoleucine hydrazide)-ddC and its N-unprotected chlorhydrate salt have been carried out. These compounds do not induce inhibition of HIV-1 replication in cell culture experiments. Nevertheless, the modifications on the base moiety increased in all cases the lipophilicity of the parent molecule with an acceptable water solubility compared to ddC.     

Synthesis,biological evaluation, 3D-QSAR studies of novel aryl-2H-pyrazole derivatives as telomerase inhibitors

A series of novel aryl-2H-pyrazole derivatives bearing 1,4-benzodioxan or 1,3-benzodioxole moiety were designed as potential telomerase inhibitors to enhance the ability of aryl-2H-pyrazole derivatives to inhibit telomerase, a target of anticancer. The telomerase inhibition tests showed that compound 16A displayed the most potent inhibitory activity with IC₅₀ value of 0.9 μM for telomerase. The antiproliferative tests showed that compound 16A exhibited high activity against human gastric cancer cell SGC-7901 and human melanoma cell B16-F10 with IC₅₀ values of 18.07 and 5.34 μM, respectively. Docking simulation showed that compound 16A could bind well with the telomerase active site and act as telomerase inhibitor. 3D-QSAR model was also built to provide more pharmacophore understanding that could be used to design new agents with more potent telomerase inhibitory activity.     

Antimycobacterial and H1-antihistaminic activity of 2-substituted piperidine derivatives

2-Substituted derivatives of the antihistaminic agents Bamipine, Diphenylpyraline and of their 1-phenyl analogues were tested for their antimycobacterial and H(1)-antagonistic activities. They are strong H1-receptor antagonists and also inhibit the growth of mycobacterials with a maximum MIC of 6.25 microg/mL against Mycobacterium tuberculosis H(37)Rv. H1-receptor antagonistic potency was slightly decreased by substitution in ring position 2 and distinctly diminished by N-aryl substitution. The antimycobacterial potency of Diphenylpyraline was in general increased by substitution in ring position 2, whereas only a few Bamipine derivatives showed markedly improved activity. A correlation between the two activities was not detected for those compounds.     

Synthesis,semipreparative HPLC separation,biological evaluation,and 3D-QSAR of hydrazothiazole derivatives as human monoamine oxidase B inhibitors

The present study reports on synthesis in high yields (70–99%), HPLC enantioseparation, inhibitory activity against human monoamino oxidases, and molecular modeling including 3D-QSAR studies, of a large series of (4-aryl-thiazol-2-yl)hydrazones (1–45). Most of the synthesized compounds proved to be potent and selective inhibitors of hMAO-B isoform in the micromolar or nanomolar range, thus demonstrating that hydrazothiazole could be considered a good pharmacophore to design new hMAO-B inhibitors. Due to the presence in some derivatives of a chiral center, we also performed a semipreparative chromatographic enantioseparation of these compounds obtained by a stereoconservative pattern. The separated enantiomers were submitted to in vitro biological evaluation to point out the stereorecognition of the active site of the enzyme towards these structures. Finally, a 3D-QSAR study was carried out using Comparative Molecular Field Analysis (CoMFA), aiming to deduce rational guidelines for the further structural modification of these lead compounds.