Synthesis, antiviral and antitumor activity of 2-substituted-5-amidino-benzimidazoles

We have prepared a set of heterocyclic benzimidazole derivatives bearing amidino substituents at C-5 of benzimidazole ring, by introducing various heterocyclic nuclei (pyridine, N-methyl-pyrrole or imidazole) at C-2, and evaluated their antitumor and antiviral activities. The most pronounced antiproliferative activity was shown with compounds 6 and 9, having imidazolinylamidino-substituent. Interestingly, all compounds show noticeable selectivity toward breast cancer cell line MCF-7. The most distinct and selective antiviral activity toward coxsackieviruses and echoviruses was observed with compounds having pyridine ring at C-2. Especially interesting was fairly strong activity of 4 and 8 toward adenoviruses, which could be considered as leads against adenoviral replication.     

Combining the tail and the ring approaches for obtaining potent and isoform-selective carbonic anhydrase inhibitors: Solution and X-ray crystallographic studies

5-(3-Tosylureido)pyridine-2-sulfonamide and 4-tosylureido-benzenesulfonamide (ts-SA) only differ by the substitution of a CH by a nitrogen atom, but they have very different inhibitory properties against the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1). By means of X-ray crystallography on the human CA II adducts of the two compounds these differences have been rationalized. As all sulfonamides, the two compounds bind in deprotonated form to the Zn(II) ion from the enzyme active site and their organic scaffolds extend throughout the cavity, participating in many interactions with amino acid residues and water molecules. However the pyridine derivative undergoes a tilt of the heterocyclic ring compared to the benzene analog, which leads to a very different orientation of the two scaffolds when bound to the enzyme. This tilt also leads to a clash between a carbon atom from the pyridine ring of the first inhibitor and the OH moiety of Thr200, leading to less effective inhibitory properties of the pyridine versus the benzene sulfonamide derivative. Indeed, ts-SA is a promiscuous, low nanomolar inhibitor of 7 out of 10 human (h) CA isoforms, whereas the pyridine sulfonamide is a low nanomolar inhibitor only of the tumor-associated hCA IX and XII, being less effective against other 9 isoforms. Thus, a difference of one atom (N vs CH) in two isostructural sulfonamides leads to drastic differences of activity, phenomenon understood at the atomic level through the high resolution crystallographic structure and kinetic measurements reported in the paper. Combining the tail and the ring approaches in the same chemotype leads to isoform-selective, highly effective sulfonamide CA inhibitors.     

Synthesis and inhibitory activity of benzoic acid and pyridine derivatives on influenza neuraminidase

Based upon the activity and X-ray crystallographic studies of tri-substituted benzene derivatives containing carboxylic acid, acetamido and guanidine groups, we investigated the effect of the fourth substituent to fulfill the fourth pocket of neuraminidase enzyme. The groups selected as fourth substituents were hydroxymethyl, hydroxyethyl, oxime and amino. These tetra-substituted benzene derivatives were synthesized and evaluated for neuraminidase inhibitory activity. All these compounds were found to have poorer IC(50) values than the tri-substituted compounds. Further, benzene ring was replaced by pyridine ring and di, tri and tetra-substituted pyridine derivatives were synthesized. The activity of the pyridine derivatives was comparable to benzene derivatives. The fourth substituent seems to disturb the binding of the other three substituents, so the activity is reduced as compared to tri-substituted benzene and pyridine derivatives.     

Inhibition of copper amine oxidases by pyridine-derived aldoximes and ketoximes

The reactions of pea diamine oxidase (PSAO) and 2-phenylethylamine oxidase from Arthrobacter globiformis (AGAO) with pyridine-derived oximes were studied. Pyridine carbaldoximes and alkyl pyridyl ketoximes act as strong non-competitive inhibitors of the enzymes. The inhibition constants K(i) of these compounds vary between 10(-4) and 10(-5) M, for AGAO and some of the studied oximes were found even micromolar K(i) values. The presence of pyridine moiety in the studied compounds has remarkable influence on the inhibition potency. Elementary oximes lacking the heterocyclic ring, i.e., aliphatic (acetone oxime), alicyclic (cyclohexanone oxime) and aromatic (benzaldoxime), are considerably weaker non-competitive inhibitors (K(i) similar to 10(-3) or 10(-2) M). The position of the pyridine ring substitution by -C(R)=NOH group does not play a significant role for the inhibition potency of the studied oxime compounds. If the pyridine nitrogen is quaternised (in hydroxyiminomethyl-1-methylpyridinium iodides), the compound looses its inhibitory properties. Extended length of alkyl substituents on the ketoxime group of alkyl pyridyl ketoximes increases the K(i) value. The enzyme-bound copper represents one of possible target sites for pyridine-derived oxime inhibitors. The addition of an alkyl pyridyl ketoxime or a pyridine carbaldoxime to a native PSAO sample perturbs the absorption spectrum of the enzyme (by an absorption increase in the region 300-400 nm) that is not observed in the spectrum of reacted PSAO apoenzyme. However, an additional formation of hydrogen bonds with amino acid side-chains at the active site should be considered, namely for 3- and 4-substituted pyridine derivatives.     

Synthesis and biological evaluation of aroylguanidines related to amiloride as inhibitors of the human platelet Na(+)/H(+) exchanger

Pyridine and benzene bioisosteres of amiloride were synthesized and evaluated for their inhibitory potency against the sodium-hydrogen exchanger (NHE) involved in intracellular pH regulation. The inhibition of NHE was determined by using the platelet swelling assay (PSA) in which the swelling of human platelets was induced by their incubation in an acid buffer (pH 6.7). Additionally, the inhibitory potency of the most active compounds was assessed by measuring the inhibition of the EIPA-sensitive (22)Na(+) uptake (UIA) by human platelets after intracellular acidosis. The results indicated that several benzene derivatives and compounds bearing an carbonylguanidine moiety in the meta position of the pyridine nitrogen were much more potent than amiloride (PSA:IC(50)=43.5 microM; UIA:IC(50)=100.1 microM), but less than EIPA, a pyrazine NHE inhibitor (PSA:IC(50)=0.08 microM; UIA:IC(50)=0.5 microM). In both biological assays (2-amino-5-bromo-pyridine-3-carbonyl)guanidine (32) was the most active molecule (PSA: IC(50)=0.8 microM, UIA : IC(50)=0.8 microM). Our investigations demonstrated that the replacement of the pyrazine ring of amiloride by a pyridine or a phenyl ring improved the NHE inhibitory potency (phenyl >pyridine >pyrazine).     

2,6-diaminopyridine derivatives as models of molecular sensor for nucleic acid base detection: ab initio calculations of electronic effects induced by hydrogen bonds formation

The performance of a molecular sensor for detecting nucleic acid base was studied by molecular orbital calculations of model compounds. The model compounds consist of a detecting unit (pyridine derivative), a conducting unit (benzene) and a connection between them. The changes of the HOMO, LUMO energy levels and charge distributions of the conducting unit by the hydrogen bonds formation between the detecting unit and thymine were studied. The calculations show that the choice of the connection and its position are significantly important to efficiently transmit the electronic effects to the conducting unit. The comparison with aminopyridine, where the pyridine ring plays both detecting and conducting units, shows that the electronic effects are transmitted quite efficiently, if the connection is properly selected. The size of the electronic effects by the formation of the hydrogen bonds were also compared with those induced by the change of the torsional angle between the pyridine and benzene rings and by substitution of the benzene ring.     

QSARs of some novel isosteric heterocyclics with antifungal activity

QSAR analysis of a set of previously synthesized 2,5,6-trisubstituted benzoxazole, benzimidazole and 2-substituted oxazolo(4,5-b)pyridine derivatives tested for growth inhibitory activity against Candida albicans, was performed by using the computer-assisted multiple regression procedure. The activity contributions for either heterocyclic ring systems or substituent effects of these compounds were determined from the correlation equation and the predictions for the lead optimization were described. The resulting QSAR revealed that the oxazolo(4,5-b)pyridine ring system with the substitution of a benzyl moiety at position 2 was the most favourable structure among the heterocyclic nuclei. Moreover, the fifth position in the fused ring system is found more significant than the other positions in improving the activity.     

Copper complexes with heterocyclic sulfonamides: synthesis, spectroscopic characterization, microbiological and SOD-like activities: crystal structure of [Cu(sulfisoxazole)2(H2O)4] . 2H2O

The synthesis, characterization and comparative biological study of a series of antibacterial copper complexes with heterocyclic sulfonamides were reported. Two kinds of complexes were obtained with the stoichiometries [Cu(L)2] . H2O and [Cu(L)2(H2O)4] . nH2O. They were characterized by infrared and electronic spectroscopies and the crystal structure of [Cu(sulfisoxazole)2(H2O)4] . 2H2O was determined by single crystal X-ray diffraction. It crystallized in the C2/c with Z = 8 monoclinic space group C2/c with Z = 8. The Cu(II) is in a slightly tetragonal distorted octahedron formed by four oxygen atoms from water molecules and two nitrogen atoms from two isoxazole rings. The antimicrobial activity was evaluated for all the synthesized complexes and ligands using the agar dilution test. The results showed that the complexes with five-membered heterocyclic rings were more active than the free sulfonamides while the pyrimidine, pyridine and pyridazine complexes had similar or less activity than the free ligands. In order to find an explanation for this behavior lipophilicity and superoxide dismutase-like activity were tested, showing that the [Cu(sulfamethoxazol)2(H2O)4] . 3H2O presented the highest antimicrobial potency and a superoxide dismutase-like activity comparable with pharmacological active compounds.     

天然产物中五元杂环生物合成过程的研究进展

五元杂环是指一类含有除碳以外的杂原子的五元环有机化合物,可分为含有一个杂原子的杂环和含有两个杂原子的五元杂环。杂原子通常为氮原子、氧原子或硫原子,在成环时符合休克尔(Hückel)规则,具有芳香性。五元杂环以独特的生物学特性和参与氢键相互作用的能力,成为天然化合物发挥活性功能的重要基团。五元杂环在不同的生物合成途径中有多种环化过程,其前体可以是天然氨基酸、乙酸及乙酰辅酶A等多种形式。将从吡咯、恶唑和噻唑三种五元杂环入手,以代表性化合物为例,对其在生命体中生物合成过程的成环过程进行探讨,为组合生物合成和未知化合物中五元杂环成环过程的研究提供参考。     

Synthesis of hybrid molecules of caffeine and eudistomin D and its effects on adenosine receptors

Four hybrid molecules (1 and 12-14) of caffeine and eudistomin D, a beta-carboline alkaloid from a marine tunicate, were synthesized, and their affinity and selectivity for adenosine receptors A(1), A(2A), and A(3) were examined. It was found that all the compounds showed better potency as adenosine receptor ligands as compared with caffeine. Among them, a compound (13) possessing a nitrogen at the delta-position of the pyridine ring (delta-N type) showed the most potent affinity for adenosine receptor A(3) subtype, while N-methylation (14) of a pyrrole ring in 13 significantly lowered the potency as adenosine receptor ligands. Compounds (1 and 12) having a nitrogen at the beta-position of the pyridine ring (beta-N type) showed lower affinity than the corresponding delta-N type compounds (13 and 14), while compounds (10, 11, and 17) lacking a pyrrole ring between the pyridine and pyrimidine rings exhibited almost no affinity to the adenosine receptor subtypes examined.     

Factors involved in the maintenance of luteal function in the pseudopregnant rat

Some data on a new antispermatogenic and antifertility compound, DL-6-(N-alpha-pipecolinomethyl)-5-hydroxy-indane maleate (PMHI) are presented. It was found that PMHI depressed testicular weight and interfered with spermatogenesis and fertility in the male rat. At equal doses, by weight, PMHI caused a greater reduction in testicular weight than WIN 18446, nitrofurazone, methallibure, and diethylstilbestrol, but lesser reductions in seminal vesicle and ventral prostate weights than were obtained with the 2 antigonadotropic compounds, methallibure and diethylstilbestrol. The data obtained in the experiments indicate that administration of PMHI causes sterility in male rats as a consequence of antispermatogenic activity. At low dosage levels (3 mg/kg), the action was reversible, but animals given 6.25 mg/kg/day or more remained sterile for 19 weeks following the treatment period. Doses of the compound which were effective in the male rat did not interfere with normal estrous cycles or fertility when administered to female rats.     

Ultrastructural, fertility, and spermicidal studies with isomers and derivatives of gossypol in male hamsters

The effects of fourteen new, orally administered synthetic analogs of gossypol on testicular ultrastructure and fertility in hamsters and the spermicidal properties of these compounds, as well as of the optical isomers of gossypol against hamster and human sperm in vitro, are reported in this study. Test compounds were administered to adult male hamsters by daily gavage for 9 weeks at doses ranging from 15 to 50 mg/kg. The results of this study have demonstrated that the fourteen new gossypol analogs evaluated herein are not effective as male antifertility agents and their in vitro activity or lack of activity as spermicides is unrelated to their in vivo contraceptive potential. In addition, the results of the study suggest that (1) the isopropyl moiety of the gossypol molecule, like the aldehyde group, is essential for its mechanism of action and (2) the pathognomonic defect in the mitochondrial sheath induced by gossypol appears to be related to its unique activity as a male antifertility agent. The significance of these findings is discussed.     

Synthesis and antiproliferative activity of benzophenone tagged pyridine analogues towards activation of caspase activated DNase mediated nuclear fragmentation in Dalton’s lymphoma

A series of benzophenones possessing pyridine nucleus 8a–l were synthesized by multistep reaction sequence and evaluated for antiproliferative activity against DLA cells by in vitro and in vivo studies. The results suggested that, compounds 8b with fluoro group and 8e with chloro substituent at the benzoyl ring of benzophenone scaffold as well as pyridine ring with hydroxy group exhibited significant activity. Further investigation in mouse model suggests that compounds 8b and 8e have the potency to activate caspase activated DNase (endonuclease) which is responsible for DNA fragmentation, a primary hallmark of apoptosis and thereby inhibits the Dalton’s lymphoma ascites tumour growth.     

Synthesis and antimicrobial activity of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles

A number of new 3-(1-R-3(5)-methyl-4-nitroso-1H-5(3)-pyrazolyl)-5-methylisoxazoles 6a–g (7b–f) were synthesized and tested for antibacterial and antifungal activity. Some of these compounds displayed antifungal activity at non-cytotoxic concentrations. Derivative 6c was 9 times more potent in vitro than miconazole and 20 times more selective against C. neoformans. 6c was also 8- and 125-fold more potent than amphotericin B and fluconazole, respectively. None of the compounds was active against bacteria. Preliminary structure–activity relationship (SAR) studies showed that the NO group at position 4 of the pyrazole ring is essential for the activity. Lipophilicity of the pyrazole moiety, N-alkyl chain length and planarity of the two heterocyclic rings appear to play a decisive role in modulating cytotoxicity and antifungal activity.     

In vitro TRPV1 activity of piperine derived amides

A series of natural and synthetic piperine amides were evaluated for activity on the human TRPV1 expressed in HEK293 cells. The agonistic effect of piperine amides was mainly dependent on the length of the carbon chain. Structural changes of double bonds and stereochemistry in the aliphatic chain of these compounds did not change their potency or efficacy, indicating that increased rigidity or planarity of the piperine structure does not affect the activity. The opening of the methylenedioxy ring or changes in the heterocyclic ring of the piperine molecule reduced or abolished activity. Furthermore, inactive compounds did not display functional antagonistic activity.     

Effect of structural modulation of polyphenolic compounds on the inhibition of Escherichia coli ATP synthase

In this paper we present the inhibitory effect of a variety of structurally modulated/modified polyphenolic compounds on purified F(1) or membrane bound F(1)F(o)Escherichia coli ATP synthase. Structural modulation of polyphenols with two phenolic rings inhibited ATP synthase essentially completely; one or three ringed polyphenols individually or fused together inhibited partially. We found that the position of hydroxyl and nitro groups plays critical role in the degree of binding and inhibition of ATPase activity. The extended positioning of hydroxyl groups on imino diphenolic compounds diminished the inhibition and abridged position enhanced the inhibition potency. This was contrary to the effect by simple single ringed phenolic compounds where extended positioning of hydroxyl group was found to be effective for inhibition. Also, introduction of nitro group augmented the inhibition on molar scale in comparison to the inhibition by resveratrol but addition of phosphate group did not. Similarly, aromatic diol or triol with rigid or planar ring structure and no free rotation poorly inhibited the ATPase activity. The inhibition was identical in both F(1)F(o) membrane preparations as well as in isolated purified F(1) and was reversible in all cases. Growth assays suggested that modulated compounds used in this study inhibited F(1)-ATPase as well as ATP synthesis nearly equally.     

Design, synthesis and cytotoxic activities of naphthyl analogues of combretastatin A-4

The 3,4,5-trimethoxyphenyl and 3-hydroxy-4-methoxyphenyl rings of combretastatin A-4 are deemed optimal for its activity as antimitotic agent. The replacement of either one by a naphthalene ring results in compounds with a potency comparable to that of the parent compound. These results show that the naphthalene ring is a good surrogate for the 3,4,5-trimethoxyphenyl or the 3-hydroxy-4-methoxyphenyl rings of combretastatin A-4 and that neither of them is essential for the antitumor activity.     

Novel bis-(arylsulfonamide) hydroxamate-based selective MMP inhibitors

A series of bis-(arylsulfonamide) hydroxamate inhibitors were synthesized. These compounds exhibit good potency against MMP-7 and MMP-9 depending on the nature, steric bulk, and substitution pattern of the substituents in the benzene ring. In general, the preliminary structure-activity relationships (SAR) suggest that among the DAPA hydroxamates (i) electron-rich benzene rings of the sulfonamides may produce better inhibitors than electron-poor analogs. However, potential H-bond acceptors can reverse the trend depending on the isozyme; (ii) isozyme selectivity between MMP-7 and -9 can be conferred through steric bulk and substitution pattern of the substituents in the benzene ring, and (iii) the MMP-10 inhibition pattern of the compounds paralleled that for MMP-9.     

5-(3-Bromophenyl)-7-(6-morpholin-4-ylpyridin-3-yl)pyrido[2,3-d]pyrimidin-4-ylamine: structure-activity relationships of 7-substituted heteroaryl analogs as non-nucleoside adenosine kinase inhibitors

4-Amino-5,7-disubstituted pyridopyrimidines are potent, non-nucleoside inhibitors of adenosine kinase (AK). We recently identified a potent, orally efficacious analog, 4 containing a 7-pyridylmorpholine substituted ring system as the key structural element of this template. In this report, we disclose the pharmacologic effects of five- and six-membered heterocyclic ring replacements for the pyridine ring in 4. These replacements were found to have interesting effects on in vivo efficacy and genotoxicity as well as in vitro potency. We discovered that the nitrogen in the heterocyclic ring at C(7) is important for the modulation of mutagenic side effects (Ames assay).     

The Translocation of Sulphonamides in Higher Plants: I. UPTAKE AND TRANSLOCATION IN BROAD BEANS

The uptake and translocation of sulphanilamide, sulphacetamide,sulphaguani-dine, sulphapyridine, sulphadiazine, sulphathiazole,and 4:4-diaminodiphenyl-sulphone by broad bean plants growingin water culture has been studied. After varying times of exposureto the compounds at 100/µg./ml., total sulphonamide presentin the roots, stems, and leaves was determined in acid-hydrolysedmacerates by diazotization and coupling of the primary aminogroup. These compounds were identified in the leaves of treatedplants by paper chromatography. Accumulation of sulphonamide in the roots appears to be relatedsimply to time, and the concentration of sulphonamide may, eventually,be far higher than that in the treating solution. Movement fromthe roots to the stems and leaves depends on transpiration.Sulphanilamide and the sulphone passed rapidly into the leaves;sulphacetamide, sulphapyridine, sulphadiazine, and sulphathiazolemoved less rapidly. There was, however, a marked accumulationof sulphacetamide, sulphapyridine, sulphadiazine, sulphathiazole,and the sulphone in the roots. Sulphaguanidine was poorly absorbedfrom the treating solution.