Predicting anti-cancer activity of quinoline derivatives: CoMFA and CoMSIA approach

The 3D quantitative structure-activity relationships of 31 quinoline nuclei containing compounds and their biological activity have been investigated to establish various models. The comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) studies resulted in reliable and significant computational models. The obtained CoMFA model showed high predictive ability with q(2) = 0.592, r(2) = 0.966 and standard error of estimation (SEE) = 0.167, explaining majority of the variance in the data with two principal components. Predictions obtained with CoMSIA steric, electrostatic, hydrophobic, hydrogen-bond acceptor and donor fields (q(2) = 0.533, r(2) = 0.985) showed high prediction ability with minimum SEE (0.111) and four principal components. The information obtained from the CoMFA and CoMSIA contour maps can be utilized for the design and development of topoisomerase-II inhibitors for synthesis.     

Predicting anti-HIV activity of 2,3-diaryl-1,3-thiazolidin-4-ones: computational approach using reformed eccentric connectivity index

The eccentric connectivity index, which has recently been employed successfully for the development of numerous mathematical models for the prediction of biological activities of diverse nature, has been reformed to overcome its limitations caused by degeneracy and insensitivity towards heteroatoms. The reformed eccentric connectivity index, termed the eccentric connectivity topochemical index, overcomes the limitations of the eccentric connectivity index by exhibiting very low degeneracy and displaying sensitivity to both the presence and relative position of heteroatoms without compromizing the discriminating power of the eccentric connectivity index. The relationship of the eccentric connectivity topochemical index, eccentric connectivity index and Wieners index with regard to the anti-HIV activity of 2, 3-diaryl-1, 3-thiazolidin-4-one derivatives was subsequently investigated. The values of the eccentric connectivity topochemical index, the eccentric connectivity index and Wieners index of each of 31 analogues comprizing the data set were computed using in-house computer program. Resultant data was analyzed and suitable models developed after identification of active ranges. Subsequently, each derivative was assigned a biological activity using these models, which was then compared with the reported anti-HIV activity. The accuracy of prediction using these models was found to vary from 81 to 90%. The proposed index offers a vast potential for virtual screening of combinatorial libraries, structure property/activity studies and drug design.Figure Basic structure of 2,3-diaryl-1, 3-thiazoidin-4-ones.     

Synthesis and anti-HIV activity of oleanolic acid derivatives

Thirteen oleanolic acid derivatives were prepared and evaluated for anti-HIV activity in H9 lymphocytes. Saturating the C₁₂–C₁₃ double bond and converting the C₁₇-carboxyl group to an aminomethyl group led to compounds 13– 15 and 19– 20, respectively, which showed improved anti-HIV activity. Compound 15 was the most potent derivative with EC₅₀=0.0039 μg/mL and TI=3570.     

Synthesis and anti-HIV activity of bi-functional betulinic acid derivatives

Betulinic acid (BA) derivatives with a side chain at C-3 can inhibit HIV-1 maturation. On the other hand, BA derivatives with a side chain at C-28 can block HIV-1 entry. In order to combine the anti-maturation and anti-entry activities in a single molecule, new bi-functional BA derivatives containing side chains at C-3 and C-28 have been synthesized. The most potent compound ([[N-[3beta-O-(3',3'-dimethylsuccinyl)-lup-20(29)-en-28-oyl]-7-aminoheptyl]-carbamoyl]methane) inhibited HIV-1 at an EC50 of 0.0026 microM and was at least 20 times more potent than either the anti-maturation lead compound DSB or the anti-entry lead compound IC9564. This bi-functional BA derivative was active against both HIV entry and maturation. These results suggest that bi-functional BA derivatives with dual mechanisms of action have the potential to become clinically useful for AIDS therapy.     

Synthesis of sulfated derivatives of curdlan and their anti-HIV activity

Sulfopropyl curdlan was synthesized, its structure was determined, and the anti-HIV activity was compared with that of standard curdlan sulfates obtained with piperidine N-sulfonic acid in dimethyl sulfoxide. It was shown that sulfopropyl curdlan exhibits weaker anti-HIV activity than curdlan sulfate. Curdlan sulfates were synthesized with a SO₃-pyridine complex in a heterogeneous phase. It was shown from ¹³C-NMR spectra of acetylated curdlan sulfates that they had a different substituent distribution from standard curdlan sulfate. The cytotoxicity of the curdlan sulfates was attributed to their heterogeneous structure.     

Synthesis and evaluation of anti-HIV activity of isatin beta-thiosemicarbazone derivatives

On the basis of pharmacophoric modelling studies of existing NNRTIs, a series of isatin beta-thiosemicarbazone derivatives was synthesized and evaluated for their anti-HIV activity in HTLV-III(B) strain in the CEM cell line. Three compounds showed significant anti-HIV activity, whereupon compound 6 was found to be the most active compound with an EC(50) value of 2.62 microM and a selectivity index of 17.41, while not being cytotoxic to the cell line at a CC(50) value of 44.90 microM. Other tested compounds exhibited marked activity below their toxicity threshold.     

Synthesis and anti-HIV activity of unusual nucleoside oxanosine derivatives.

A series of the oxanosine and carbocyclic oxanosine derivatives were synthesized to evaluate for their anti-HIV activity. Compound 1, 7 and 9 showed weak anti-HIV activities.     

Design, synthesis and anti-HIV activity of homologous PMEA derivatives

This article describes an efficient route for synthesizing novel cyclopropyl homologous PMEA analogues. The condensation of the bromide 8 with nucleosidic bases (A, U, T, C, 5-FU, G) under standard nucleophilic substitution and deprotection conditions, afforded the target phosphonic acid analogues 14 approximately 18 and 21. These compounds were evaluated for their potential antiviral properties against various viruses. Guanine derivative 21 showed significant antiviral activity.     

New anti-HIV derivatives: synthesis and antiviral evaluation

A small focused library of 18 compounds incorporating the motif 1,3-(N,N'-dibenzyl)diamino-2-propanol has been synthesized, using adapted synthetic methodologies. These series of compounds were evaluated for their in vitro anti-HIV activity on infected MT4 cells (syncytium formation observation). Some of the new synthesized compounds show potent anti-HIV activities. EC50 values for compounds (31, 40, 34, 37 and 46) range from 0.1 to 1 microM. In order to determine at which level these new derivatives interfere with the HIV replicative cycle, inhibition assays on recombinant HIV protease and HIV integrase have been performed. None of the compounds were found active on these two enzymatic targets. Experiments are in progress in order to identify their biological target within the HIV replicative cycle.     

Synthesis, anti-HIV activity, and stability studies of 5'-phosphorofluoridate derivatives of AZT

The synthesis, in vitro anti-HIV activity and stability studies of the 5'-fluorophosphate derivative of 3'-azido-3'-deoxythymidine (AZT) are reported. The results support the hypothesis that this phosphorylated entity exerts its biological effect via the delivery of the corresponding 5'-mononucleotide through an enzymatic process. However, the antiviral evaluation in thymidine kinase-deficient CEM cells as well as the stability studies in culture medium and cell extract showed that this bioconversion is not specific to the intracellular medium. Attempts to improve the biological activity of mononucleoside 5'-fluorophosphates by the use of the S-pivaloyl-2-thioethyl (tBuSATE) group as biolabile phosphate protection are reported.     

CoMFA and CoMSIA studies on fluorinated hexahydropyrimidine derivatives

3D-QSAR models of a series of fluorinated hexahydropyrimidine derivatives with cytotoxic activities have been developed using CoMFA and CoMSIA. These models provide a better understanding of the mechanism of action and structure–activity relationship of these compounds. By applying leave-one-out (LOO) cross validation study, the best predictive CoMFA model was achieved with 3 as the optimum number of components, which gave rise to a non-cross-validated r² value of 0.978, and standard error of estimate of 0.059, and F value of 144.492. Similarly, the best predictive CoMSIA model was derived with 4 as the number of components, r² value of 0.999, F value of 4381.143, and standard error of estimate, 0.011. The above models will inspire the design and synthesis of novel hexahydropyrimidines with enhanced potency and selectivity.     

Synthesis and anti-HIV activity of arylpiperazinyl fluoroquinolones: a new class of anti-HIV agents

Synthesis and anti-HIV activity of a series of novel arylpiperazinyl fluoroquinolones are reported. In the SAR study, the aryl substituents on the piperazine nitrogen were found to play an important role for the anti-HIV-1 activity. A few of the compounds exhibited potent anti-HIV activity: IC50=0.06 microM in chronically infected cells.     

New acyclonucleosides: synthesis and anti-HIV activity

The synthesis of new acyclic nucleosides is described. These syntheses were accomplished by various methods: glycosylation, selective or total deprotection, oxidation/reduction, chlorination or azidation of hydroxyl groups. The compounds were characterized with NMR, mass and IR spectroscopy. Antiviral properties of these compounds were evaluated on HIV-1 infected cell lines.     

Synthesis and anti-HIV activity of some non-nucleoside 2,3-disubstituted quinazoline derivatives (Part-V)

Several [2-phenyl-4(3H)-oxo-3-quinazolinylamino]-N-substituted- arylacetamides (1a-j) have been synthesized and tested at the National Cancer Institute, Bethesda, Maryland, USA, for their anti-HIV activity against susceptible human host cells (CEM cell line) over a wide range of concentrations (6.35 x 10(-8) to 2.00 x 10(-4) M). The highest protection observed is 45.67%. The structures of these compounds have been established on the basis of elemental analysis and spectral data.     

Synthesis of new phorbol derivatives having ethereal side chain and evaluation of their anti-HIV activity

Several new phorbol derivatives having ethereal substituents at the 12-position were synthesized and subjected to biological evaluation to find new candidates of an anti-HIV agent. Among them, 12-O-(methoxymethyl)phorbol 13-decanoate showed potent inhibitory activity against infection of HIV-1 in MT-4 cells (EC50: 1.3 ng/mL) and relatively low cytotoxicity (CC50: 8.3 microg/mL). This compound was also found to have sufficient stability in mouse plasma compared with the corresponding 12-acetate derivative, which was an equipotent HIV-1 inhibitor, but with an activity that decreased considerably after plasma treatment.     

CoMFA of artemisinin derivatives: effect of location and size of lattice.

A CoMFA study of artemisinin derivatives with changes of the location and the number of lattice points was performed. The location of probe atoms in a large lattice has practically no effect on the cross-validated r(2) value (r(2)(cv)). The selection of only 18 probe atoms around the peroxide bond, considering the action mechanism of artemisinin, provided a less time-demanding and more reliable CoMFA model, which forecasts better than the large lattice model despite the lower r(2)(cv) value. Only 1 A displacement of the small lattice caused a reduction of cross-validated r(2) value of more than 50%, which indicates the lattice location played an important role in this small lattice model.     

Synthesis of novel hetero ring fused pyridine derivatives; Their anticancer activity,CoMFA and CoMSIA studies

A series of novel furo[2,3-b]pyridine-2-carboxamide 4a–h/pyrido[3′,2′:4,5]furo[3,2-d] pyrimidin-4(3H)-one derivatives 5a–p were prepared from pyridin 2(1H) one 1 via selective O-alkylation with α-bromoethylester followed by cyclization, then reaction with different aliphatic primary amines to obtain 4 and further reaction with triethyl orthoacetate/triethyl orthoformate. Also prepared novel furo[2,3-b]pyridine-2-carbohydrazide Schiff’s bases 7a–h and pyrido [3′,2′:4,5]furo[3,2-d]pyrimidin-4(3H)-one derivatives 8a–h starting from furo[2,3-b]pyridine carboxylate derivatives 3 by reaction with hydrazine hydrate to form 6 and reaction with diverse substituted aldehydes and cyclization. Products 4a–h, 5a–p, 7a–h and 8a–h were screened against four human cancer cell lines (HeLa, COLO205, Hep G2 and MCF 7) and one normal cell line (HEK 293). Compounds 4e, 4f, 4g, 5h, 7c, 7d, 7e and 7f showed significant anticancer activity against all the cell lines at micro molar concentration and found to be non-toxic to normal cell line. Studies for HeLa, COLO205 and MCF-7 using CoMFA and CoMSIA. Models from 3D-QSAR provided a strong basis for future rational design of more active and selective HeLa, COLO205 and MCF-7 cell line inhibitors.     

Anthranilate derivatives as TACE inhibitors: Docking based CoMFA and CoMSIA analyses

Anthranilic acid based derivatives (ANTs) have been identified as a novel class of potent tumor necrosis factor-α converting enzyme (TACE) inhibitors. A computational strategy based on molecular docking studies, followed by CoMFA and CoMSIA analyses has been performed to elucidate the atomic details of the TACE/ANT interactions and also to identify the most important features impacting TACE inhibitory activity of ANTs. The CoMSIA model resulted to be slightly more predictive than CoMFA model, and gave conventional r² 0.991, r_cv² 0.793, q² 0.777, SEE 0.050, F-value 655.610, and r_test² 0.871. The 3D-QSAR field contributions and the structural features of the TACE binding site showed a good correlation. These studies will be useful to design new TACE inhibitors with improved potency.