Synthesis, optimization and structure-activity relationships of 3,5-disubstituted isoxazolines as new anti-tuberculosis agents

In the course of the development of a potent series of nitrofuranylamide anti-tuberculosis agents, we investigated if the exceptional activity resulted in part from the isoxazoline core and if it possessed any intrinsic anti-tuberculosis activity. This led to the discovery of an isoxazoline ester with appreciable anti-tuberculosis activity. In this study we explored the anti-tuberculosis structure-activity relationship of the isoxazoline ester compound through systematic modification of the 3,5-di-substituted isoxazoline core. Two approaches were used: (i) modification of the potentially metabolically labile ester functionality at the 3 position with acids, amines, amides, reverse amides, alcohols, hydrazides, and 1,3,4-oxadiazoles; (ii) substitution of the distal benzyl piperazine ring in the 5 position of the isoxazoline ring with piperazyl-ureas, piperazyl-carbamates, biaryl systems, piperidines and morpholine. Attempts to replace the ester group at C-3 position of isoxazoline with a variety of bioisosteric head groups led to significant loss of the tuberculosis inhibition indicating that an ester is required for anti-tuberculosis activity. Optimization of the isoxazoline C-5 position produced compounds with improved anti-tuberculosis activity, most notably the piperazyl-urea and piperazyl-carbamate analogs.     

Synthesis and pharmacology of site specific cocaine abuse treatment agents: a new synthetic methodology for methylphenidate analogs based on the Blaise reaction.

In order to make new analogs of the dopamine (DA) uptake inhibitor methylphenidate, a synthetic methodology based on the Blaise reaction was developed. The reaction between alpha-bromophenylacetic acid esters, zinc and alpha-cyano-omega-mesylates gave stable primary enamines. After reduction of the enamines with cyanoborohydride, the amines could be cyclized to methylphenidate analogs in which the amine ring size and aromatic ring were varied. These compounds were tested for inhibitory potency against [(3)H]WIN 35,428 binding to the cocaine recognition site and [(3)H]DA uptake using rat striatal tissue. When the heterocyclic ring size was varied, the six-membered ring of methylphenidate appeared to be the optimum ring size. When the aryl ring was varied the 4-trifluoromethylphenyl analog was less potent than methylphenidate, the beta-naphthyl congener was considerably more potent, whereas the alpha-naphthyl congener was less potent. Most of the compounds tested had ratios of uptake to binding inhibition (discrimination ratio) that were similar to cocaine and were therefore not lead compounds for the development of cocaine antagonists.     

Exploring QSAR on 3-aminopyrazoles as antitumor agents for their inhibitory activity of CDK2/cyclin A

Chemical inhibitors of cyclin-dependent kinases have great therapeutic potential against various proliferative and neurodegenerative disorders. The pharmacophoric requirement of 3-aminopyrazole, inhibitors of CDK2/cyclin A as antitumor agents was explored. QSAR study was performed using ETSA index, RTSA index, indicator parameters and atomic charges to consider quantitatively the effect of the structural variation on the antitumor activity of 3-aminopyrazole. Result showed that atom number 5 is important for the activity. It plays some electronic roles in the interaction of these compounds with enzymes as well as assumed to be involved through the dispersive/van der Waals interactions with enzyme. Presence of meta substitutions on the phenyl ring indicate the detrimental effects towards the activity. The presence of substituted biphenyl/2-thenyl phenyl at R1 are favorable towards the activity. QSAR study also indicates that with increasing the electronegativity of oxygen at position 8, the activity increases.     

Phenyl phosphoramidate derivatives of stavudine as anti-HIV agents with potent and selective in-vitro antiviral activity against adenovirus

Adenoviruses are responsible for a broad range of clinical diseases that may be associated with high mortality, including pneumonia, hepatitis, encephalitis, hemorrhagic cystitis, nephritis, and gastroenteritis in immunocompromised patients, including HIV-infected individuals. Here we report the identification of halo-substituted stavudine phenyl phosphoramidate derivatives as a new class of dual-function anti-HIV agents with potent and selective anti-adenovirus (ADV) activity. We examined the investigational stavudine phenyl phosphoramidate derivative stampidine and 12 structurally similar stavudine derivatives for anti-ADV activity. All 13 derivatives of stavudine, including stampidine, were substantially more potent than stavudine and inhibited ADV-induced plaque formation at nanomolar IC(50) values. Compounds with halo substitutions in the phenyl ring as well as the unsubstituted compound 607 were more potent than compounds with methoxy, methyl, or cyano substitutions. Compound 113 (stampidine) with a 4-Br substitution and compound 609 with a 4-Cl substitution were identified as the most potent lead anti-ADV agents. Compound 113/Stampidine inhibited ADV-induced plaque formation in skin fibroblasts in a concentration-dependent fashion with a mean (+/-S.E.M.) IC(50) value of 17 +/- 2 nM without any evidence of cytotoxicity even at 100 microM. Similarly, compound 609 inhibited ADV-induced plaque formation with an IC(50) value of 27 +/- 3 nM. We next sought to determine if the lead compounds 113 and 609 can also inhibit other viruses. Both compounds exhibited potent anti-HIV activity at nanomolar concentrations. However, neither compound exhibited any antiviral activity against non-HIV viruses, including Cytomegalovirus (CMV), Type I or Type II herpes simplex viruses (HSV-1, HSV-2), enterovirus ECHO 30, or respiratory syncytial virus (RSV) (IC(50) > 100 microM). The remarkable anti-ADV potency of the lead compounds stampidine and compound 609 warrants the further development of these promising new antiviral agents for possible clinical use in ADV infected patients.     

A quantitative structure-activity relationship study on a novel class of calcium-entry blockers: 1-[(4-(aminoalkoxy)phenyl)sulphonyl]indolizines

A quantitative structure-activity relationship (QSAR) study has been made on two different series of 1-[(4-(aminoalkoxy)phenyl)sulphonyl]indolizines acting as calcium entry blockers, using some physicochemical and structural parameters. Two different assays were reported for both the series: (IC(50))(A), referring to the molar concentration of the compound required to reduce [3H] nitrendipine binding by 50%, and (IC(50))(B), referring to that required to block Ca(2+) induced concentration of K(+) depolarised rat aorta by 50%. For series 1, where the 2-position substituents of indolizine ring were varied along with the aminoalkoxy moieties of the phenyl ring, the QSAR analysis shows that the 2-position substituents can equally affect both the activities through their hydrophobic and electronic properties and the aminoalkoxy moiety through some steric effects. For series 2, where the indolizine ring has been replaced by varying heterocyclic rings, along with the changes in aminoalkoxy moiety of the phenyl ring, the QSAR exhibits that these different heterocyclic rings affect both the activities through some steric roles, altering the conformations of the receptors from system A to system B. Among the different heterocyclic rings, the N-substituted indole ring is shown to be more conducive to both the activities than any other ring. However, a 5-membered ring is indicated to be less effective than a 9- or 10-membered ring for activity B. Additionally, the amino moieties having phenyl ring with methoxy groups at 3,4,and 5-positions are shown to favour both A and B activities.     

Affinity of 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives to the ion channel binding site of the NMDA receptor complex

A series of 1-aryl-1,2,3,4-tetrahydroisoquinoline and 8-methyl-1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives was evaluated for affinity to the PCP binding site of the NMDA receptor complex. The (S)-configured tetrahydroisoquinoline derivative (S)-4 e x HCl bearing a 2-methylphenyl substituent in position 1 of the heterocyclic ring system and a methyl group in position 8 was found to exhibit the highest affinity among the derivatives with a K(i)-value of 0.0374 microM. In addition, this compound shows a remarkable enantioselectivity of binding by being almost 90 times more potent than the corresponding (R)-enantiomer (R)-4 e x HCl. Additionally, a convenient and efficient synthetic approach to racemic 1-aryl-1,2,3,4-tetrahydroisoquinoline derivatives is described.     

Design, synthesis and pharmacological screening of novel nitric oxide donors containing 1,5-diarylpyrazolin-3-one as nontoxic NSAIDs

Various substituted 1,5-diarylpyrazol-3-one derivatives were synthesized and screened for analgesic, anti-inflammatory activities, ulcerogenic potential and for their ability to release nitric oxide. Most compounds exhibited significant analgesic and anti-inflammatory activities. It was interesting to note that out of ten compounds, 7j (59.64%) was found to have anti-inflammatory activity greater than the standard drug Indomethacin (57.89%), whereas compound 7b (57.89%) was found to be equipotent to that of standard, Indomethacin. The pharmacological studies suggested that the presence of 4-nitro and 2-methoxy on phenyl ring at C₅ of pyrazole has a significant anti-inflammatory activity and 4-chloro substitution on same phenyl ring was found to have decreased activity. However only a phenyl substituted derivative was found to have most potent activity. Compound 7j containing plane phenyl at C₅ of pyrazole was found to have significant analgesic activity (56.86%) in acetic acid induced writhing model. Compounds 7d and 7i having 4-chloro substituted phenyl ring showed least analgesic activity (10.78%) and (6.86%) respectively. The compounds also showed significantly reduced GI-ulcerogenicity and gastroprotective results in histopathological studies i.e. they were found to be causing no mucosal injury. All the synthesized compounds were found to exhibit significant nitric oxide releasing activity, in both in vitro and in vivo models. Molecular docking studies served to be an important tool for the study of binding of compounds with that of a COX-2 enzyme. The results of the docking studies were found to endorse the result of experimental work. Thus, the rationale used to design the NCEs was found to produce the promising results as anticipated. Therefore it can be said that the strategy employed can serve as an important tool in future for the design and development of novel therapeutic agents of various categories too.     

Novel Genistein Derivatives Induce Cell Death and Cell Cycle Arrest Through Different Mechanisms

Genistein is a natural compound belonging to isoflavone family of secondary plant metabolites, characterized by pleiotropic biological activity. Here we present the results of a study on new analogs and polysaccharide complexes of genistein as potent antiproliferative and cell death-inducing agents. Most potent were 2 analogs (i.e., IFG-027 and IFG-043) and 2 complexes (i.e., SPG-G and XG-G), which had higher or similar antiproliferative activity in comparison to genistein. However, these 2 analogs decreased the number of cells in G2/M phase in contrast to genistein and SPG-G complex. Genistein analogs, IFG-027 and IFG-043, and also SPG-G complex decreased mitochondrial membrane potential and induced the externalization of phosphatidylserine to the extracellular membrane site, which indicates the induction of apoptosis. Interestingly, genistein and its analogs induced caspase 3-activation supporting apoptotic mechanism of cell death but SPG-G supported caspase 3-independent apoptosis. XG-G complex probably did not induce cell death through the apoptotic pathway, as we did not find the externalization of phosphatidylserine and activation of caspase-3. After the treatment of HL-60 cells with genistein, SPG-G and XG-G formation of acidic vesicular organelle (AVO) was detected. In contrast, in the cells that were treated with genistein analogs IFG-027 and IFG-043, AVO formation was not observed.     

Synthesis and diuretic activity of imidazo[2,1-b]thiazole acetohydrazones

The synthesis of dimethylaminoacetohydrazones of 5-formylimidazo[2,1-b]thiazoles and thiazolines is reported. A potent diuretic activity was confirmed for the 2-methyl derivative bearing a phenyl ring at position 6 (4₁).     

Synthesis and antibacterial activity of 2-(4-substituted phenyl)-3(2H)-isothiazolones

Several new and known 2-(4-substituted phenyl)-3(2H)-isothiazolone derivatives with or without chloro substituent at C-5 position were synthesized and their in vitro antibacterial activity against selected Gram-negative and Gram-positive bacteria were evaluated using agar dilution method. Most of compounds exhibited moderate to high activities against tested microorganisms, and in comparison with the reference drugs some compounds showed comparable or higher activities. In contrast to results of the previous studies, some 5-chloro derivatives showed lower or comparable activities against some tested microorganism, in comparison with analogues without C-5 substitution. In general, most of the compounds bearing electron withdrawing group at 4-position of the phenyl ring were more active against Gram-positive and most of those having piperazine derivatives were more active against Gram-negative bacteria.     

Synthesis and structure-activity relationships of new arylpiperazines: para substitution with electron-withdrawing groups decrease binding to 5-HT(1A) and D(2A) receptors

Compounds in which N-phenylpiperazines were linked by a propyloxy chain to position 6 or 7 of a coumarin ring were designed and synthesised, and their affinities for 5-HT(1A) and D(2A) receptors were determined by radioligand binding assays. The influence of para substitution in the phenyl ring, substitution at position 4 of the coumarin system, and the coumarin position at which the piperazinylalkyl chain is linked was explored. Electron-withdrawing phenyl ring substituents para to the piperazine strongly reduced activity at both receptors. Binding at 5HT(1A) was influenced by the bulk of substituents at position 4 of the coumarin system, and binding at D(2A) by their electronic properties. Neither binding affinity was significantly affected by whether the piperazinylalkyl chain was inserted at position 6 or 7 of the coumarin system.     

Synthesis and SAR/3D-QSAR studies on the COX-2 inhibitory activity of 1,5-diarylpyrazoles to validate the modified pharmacophore

Diverse analogs of 1,5-diarylpyrazoles having 3-hydroxymethyl-4-sulfamoyl (SO2NH2)/methyl sulfonyl (SO2Me)-pheny group at N1 were synthesized and evaluated for their in vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The SAR study mainly involved the variations at positions C-3, C-5 and N1 of the pyrazole ring. Several small hydrophobic groups at/around position-4 of C-5 phenyl, viz. 3,4-dimethylphenyl analog 9, 3-methyl-4-methylsulfanylphenyl analog 14 and 2,3-dihydrobenzo[b]thiophenyl analog 17, exhibited impressive COX-2 inhibitory potency. In general, the sulfonamide analogues with a CHF2 at C-3 were found to be more potent than those having a CF3 group. The three dimensional quantitative structure activity relationship comprising comparative molecular field analysis (3D-QSAR-CoMFA) afforded the models with high predictivity which further validated the acceptance of hydroxymethyl (CH2OH) group in the hydrophilic pocket of the COX-2 enzyme.     

Tetrahydrobenzo- and benzofurobenzopyrones as a new class of potential photoreagents toward DNA

The synthesis and the photobiological activity of new tetrahydrobenzo- and benzofurobenzopyrone derivatives carrying at position 4 of benzopyrone ring of furobenzopyrone moiety a phenyl, or a methyl group with a linear structure or with various angular arrangements, are reported. The new compounds are characterized by having an additional cyclohexene or phenyl ring condensed at the 2, 3 double bond of the furan ring of furobenzopyrone nucleus. The syntheses were performed starting from the appropriate hydroxybenzopyrones on which the tetrahydrobenzofuran or benzofuran moiety was built, which look most promising for enhancement of photoreactivity of compounds toward DNA. All the synthesized compounds were screened for photosensitizing activity and some of them exhibited good activity also a certain effect was observed in the dark.     

Synthesis and cytotoxic activity of new alkyl[3-(2-chloroethyl)ureido]benzene derivatives

Several alkyl[3-(2-chloroethyl)ureido] (CEU) benzene derivatives were prepared as potential anticancer agents. These new compounds were readily prepared in good yields by addition of anilines to 2-chloroethylisocyanate. Their cytotoxic activity was evaluated on human breast cancer (MDA-MB-231), human colon adenocarcinoma (LoVo) and mouse lymphocytic leukemia (P388D₁) tumor cell lines. Several new CEUs were significantly more cytotoxic than the nitrogen mustard chlorambucil. The biological activity of these aromatic urea derivatives seems to be related to the nature and position of the alkyl substituents on the aromatic ring. Substitution by branched alkyl groups on position 4 of the aromatic ring led to cytotoxic molecules which are up to 5 times more potent than the standard chlorambucil.     

Chiral gossypol derivatives: Evaluation of their anticancer activity and molecular modeling

To better use gossypol to find promising anticancer compounds, a series of new and known bis-Schiff base analogs of chiral gossypol were synthesized, and their anticancer activity on HeLa, U87 and M85 cells was tested. The results showed that through a simple chemical modification, less active (+)-gossypol could be converted into more active derivatives. When compared with (−)-gossypol, many more potent compounds that could be the promising anticancer agents were found, and some of them were more potent than the anticancer drug Cisplatin against all three cancer cell lines. By eliminating target functional groups, we observed that the major contributor to the anticancer activity of chiral gossypol seemed to be the phenolic groups, and not the aldehyde groups. Through comprehensive analysis of chiral gossypol analogs, the structure–activity relationships were elaborated.     

Tuberculosis in Australia: bacteriologically confirmed cases and drug resistance, 2005

The Australian Mycobacterium Reference Laboratory Network (AMRLN) collects and analyses laboratory data on new cases of disease caused by the Mycobacterium tuberculosis complex. In 2005, a total of 810 cases were identified by bacteriology; an annual reporting rate of 4.0 cases per 100,000 population. Isolates were identified as M. tuberculosis (n = 806), Mycobacterium africanum (n = 2) and Mycobacterium bovis (n = 2). Fifteen children aged under 10 years had bacteriologically-confirmed tuberculosis. Results of in vitro drug susceptibility testing were available for all 810 isolates for isoniazid (H), rifampicin (R), ethambutol (E), and pyrazinamide (Z). A total of 74 (9.1%) isolates of M. tuberculosis were resistant to at least one of these anti-tuberculosis agents. Resistance to at least H and R (defined as multi-drug resistance, MDR) was detected in 12 (1.5%) isolates; nine were from the respiratory tract (sputum n = 8, bronchoscopy n = 1). Of the 74 M. tuberculosis isolates resistant to at least one of the standard drugs, 67 (90.5%) were from new cases, 6 from previously treated cases, and no information was available on the remaining case. Eight were Australian-born, 65 were overseas-born, and the country of birth of one was unknown. Of the 65 overseas-born persons with drug resistant disease, 41 (63.1%) were from 4 countries; Vietnam (n = 16), Papua New Guinea (n = 10), the Philippines (n = 9), and India (n = 6). A retrospective review of AMRLN data on isolates collected between 2000 and 2005 found that none of 70 MDR-TB isolates met the new definition for extensively drug resistant TB (XDR-TB, i.e. MDR-TB with additional resistance to quinolones and second-line injectable agents).     

Design, synthesis and structure-activity relationships of antiproliferative 1,3-disubstituted urea derivatives

Twenty-four new 1,3-disubstituted urea derivatives were synthesized and reported for the first time. The antiproliferative activities of these compounds were evaluated against a panel of one human liver cell line (L02) and two human tumor cell lines (KB and K562) by applying the MTT colorimetric assay. The series of 1,3-disubstituted urea derivatives show good antiproliferative activity against human cancer cell lines (KB and K562) and no antiproliferative activity against liver cell line (L02). The potent in vitro antiproliferative activity of these derivatives and their selectivity for L02 are quite important points for an anticancer drug candidate with fewer side effects. Structure-activity relationships were also discussed based on the obtained experimental data. The hydroxyl groups on the phenyl ring reduced the antiproliferative activities of 1,3-disubstituted urea derivatives. The OH groups could be responsible for a reduction in the permeability of the cell membrane. Generally, an aromatic ring on N-3 seems to be in favor of enhancing the inhibitory activity, compounds introduced a nitro group substituent at C-3 position on the aromatic ring approved to generally decrease activity.