Dual inhibition of HCV and HIV by ring-expanded nucleosides containing the 5:7-fused imidazo[4,5-e][1,3]diazepine ring system. In vitro results and implications

Examples of ring-expanded nucleosides (RENs), represented by general structures 1 and 2, exhibited dual anti-HCV and anti-HIV activities in both cell culture systems and the respective target enzyme assays, including HCV NTPase/helicase and human RNA helicase DDX3. Since HCV is a leading co-infection in late stage HIV AIDS patients, often leading to liver cirrhosis and death, the observed dual inhibition of HCV and HIV by the target nucleoside analogues has potentially beneficial implications in treating HIV patients infected with HCV.     

Synthesis and structure–activity relationship analysis of caffeic acid amides as selective matrix metalloproteinase inhibitors

Four series of acid amides were synthesized, and through measurement using a fluorogenic substrate assay with human recombinant MMP-1, MMP-2 and MMP-9, compound 3f showed considerable inhibitory activities against MMP-2, MMP-9 and the best selectivity over MMP-1. Preliminary structure–activity relationship analysis indicated that caffeic acid amides with electron-donating groups at para-position of amino phenyl group showed better inhibitory activities and selectivity than those with electron-withdrawing groups, and the presence of adjacent dihydroxy in the caffeoyl group was very important for the MMP-2 and MMP-9 inhibitory activities.     

Asymmetric synthesis of cyclopropyl-fused 2'-C-methylcarbanucleosides as potential anti-HCV agents

Novel 2'-C-methyl-cyclopropyl-fused carbocyclic nucleosides as potential anti-HCV agents were stereoselectively synthesized, utilizing regioselective cleavage of the isopropylidene group and cyclic sulfate chemistry as key steps.     

Synthesis and biological evaluation of 4,5-dihydro-1H-pyrazole derivatives as potential nNOS/iNOS selective inhibitors. Part 2: Influence of diverse substituents in both the phenyl moiety and the acyl group

In a preliminary article, we reported a series of 4,5-dihydro-1H-pyrazole derivatives as neuronal nitric oxide synthase (nNOS) inhibitors. Here we present the data about the inhibition of inducible nitric oxide synthase (iNOS) of these compounds. In general, we can confirm that these pyrazoles are nNOS selective inhibitors. In addition, taking these compounds as a reference, we have designed and synthesized a series of new derivatives by modification of the heterocycle in 1-position, and by introduction of electron-donating or electron-withdrawing substituents in the aromatic ring. These derivatives have been evaluated as nNOS and iNOS inhibitors in order to identify new compounds with improved activity and selectivity. Compound 3r, with three methoxy electron-donating groups in the phenyl moiety, is the most potent nNOS inhibitor, showing good selectivity nNOS/iNOS.     

Design,synthesis, and anti-HCV activity of thiourea compounds

A series of thiourea derivatives were synthesized and their antiviral activity was evaluated in a cell-based HCV subgenomic replicon assay. SAR studies revealed that the chain length and the position of the alkyl linker largely influenced the in vitro anti-HCV activity of this class of potent antiviral agents. Among this series of compounds synthesized, the thiourea derivative with a six-carbon alkyl linker at the meta-position of the central phenyl ring (10) was identified as the most potent anti-HCV inhibitor (EC₅₀ = 0.047 μM) with a selectivity index of 596.     

Propynyl groups in duplex DNA: stability of base pairs incorporating 7-substituted 8-aza-7-deazapurines or 5-substituted pyrimidines

Oligonucleotides incorporating the 7-propynyl derivatives of 8-aza-7-deaza-2′-deoxyguanosine (3b) and 8-aza-7-deaza-2′-deoxyadenosine (4b) were synthesized and their duplex stability was compared with those containing the 5-propynyl derivatives of 2′-deoxycytidine (1) and 2′-deoxyuridine (2). For this purpose phosphoramidites of the 8-aza- 7-deazapurine (pyrazolo[3,4-d]pyrimidine) nucleosides were prepared and employed in solid-phase synthesis. All propynyl nucleosides exert a positive effect on the DNA duplex stability because of the increased polarizability of the nucleobase and the hydrophobic character of the propynyl group. The propynyl residues introduced into the 7-position of the 8-aza-7-deazapurines are generally more stabilizing than those at the 5-position of the pyrimidine bases. The duplex stabilization of the propynyl derivative 4b was higher than for the bromo nucleoside 4c. The extraordinary stability of duplexes containing the 7-propynyl derivative of 8-aza-7- deazapurin-2,6-diamine (5b) is attributed to the formation of a third hydrogen bond, which is apparently not present in the base pair of the purin-2,6-diamine 2′-deoxyribonucleoside with dT.     

Synthesis and biological evaluation of novel T-type Ca2+ channel blockers

A small molecule library of piperazinylalkylisoxazole derivatives containing about 600 compounds was designed, synthesized and evaluated for blocking effects on T-type Ca(2+) channel. Several ligands were identified to possess high inhibitory activity against the T-type Ca(2+) channel. The compound 21 with trifluoromethyl substituents at C(3)-position of phenyl group (R(1)) and C(2)-position of phenyl group (R(2)) showed the highest inhibitory activity with IC(50) value of 1.02 microM, which is comparable to that of mibefradil.     

3-Substituted-(5-arylfuran-2-ylcarbonyl)guanidines as NHE-1 inhibitors

The C-3 substituents effect on NHE-1 inhibitory activity of (5-arylfuran-2-ylcarbonyl)guanidines, previously identified as potent NHE-1 inhibitors, was investigated. The introduction of amine or alkyl groups at the 3-position of the furan ring, next to the acylguanidine moiety, remarkably improves NHE-1 inhibitory potency. Especially the important finding is that 5-(2,5-dichloro)phenyl and 5-(2-methoxy-5-chloro)phenyl derivatives exhibit high NHE-1 inhibitory activities (IC50 < 0.02 microM) that match those of 3-unsubstituted derivatives.     

The new generation dihydropyridine type calcium blockers, bearing 4-phenyl oxypropanolamine, display alpha-/beta-adrenoceptor antagonist and long-acting antihypertensive activities

A new series of dihydropyridine derivatives, bearing oxypropanolamine moiety on phenyl ring at the 4-position of the dihydropyridine base, were prepared. Oxypropanolamine was synthesized by replacing the phenolic OH of vanillin or other compounds, having a phenyl aldehyde group, with epichlorohydrin, followed by cleavaging the obtained epoxide compounds with tert-butylamine, n-butylamine or 2-methoxy-1-oxyethylamino benzene (guaiacoxyethylamine), respectively. Obtained various oxypropanolamine compounds, still remaining a phenyl aldehyde moiety, were then performed by Hantzsch condensation reaction with methylacetoacetate or ethylacetoacetate, respectively, to give our new series of dihydropyridine linked with the 4-phenyl ring. These compounds were evaluated for inotropic, chronotropic, and aorta contractility that associated with calcium channel and adrenoceptor antagonist activities. Dihydropyridine derivatives that with oxypropanolamine side chain on their 4-phenyl ring associated alpha-/beta-adrenoceptor blocking activities created a new family of calcium entry and the third generation beta-adrenoceptor blockers. Optimizing this research to obtain more potent alpha-/beta-adrenoceptor blocking and long-acting antihypertensive oxypropanolamine on the 4-phenyl ring of dihydropyridine series compounds was thus accomplished and classified as third generation dihydropyridine type calcium channel blockers, in comparison with previous short-acting type nifedipine and long-acting type amlodipine. We concluded that compounds 1a, 1b and 1g showed not only markedly high calcium-antagonistic activity but also the highest antihypertensive effect; compounds 1b, 1c, 1f, 1g, 1i and 1j induced sustained antihypertensive effects are major and attributed to their calcium entry and alpha-adrenoceptor blocking activities in the blood vessel due to their introduction of 2-methoxy, 1-oxyethylamino benzene moiety in the side chain on the 4-phenyl ring of dihydropyridine. Bradycardiac effects of all the compounds 1a-1j resulted from calcium entry and beta-adrenoceptor blocking, which attenuate the sympathetic activation-associated reflex tachycardia in the heart. We selected compound 1b as candidate compound for further pharmacological and pre-clinical evaluation studies.     

Arylethynyltriazole acyclonucleosides inhibit hepatitis C virus replication

Novel acyclic triazole nucleosides with various ethynyl moieties appended on the triazole nucleobase were synthesized efficiently using a convenient one-step Sonogashira reaction in aqueous solution and under microwave irradiation. One of the compounds, 1f, inhibited HCV subgenomic replication with a 50% effective concentration (EC(50)) of 22 microg/ml and did not inhibit proliferation of the host cell at a concentration of 50 microg/ml. A preliminary SAR study suggests that the appended phenyl ring as well as the rigid triple bond linker contributes importantly to the anti-HCV activity.     

Antagonists of human CCR5 receptor containing 4-(pyrazolyl)piperidine side chains. Part 1: Discovery and SAR study of 4-pyrazolylpiperidine side chains

Replacement of the flexible connecting chains between the piperidine moiety and an aromatic group in previous CCR5 antagonists with heterocycles, such as pyrazole and isoxazole, provided potent CCR5 antagonists with excellent anti-HIV-1 activity in vitro. SAR studies revealed optimal placement of an unsubstituted nitrogen atom in the heterocycle to be meta to the bond connected to the 4-position of piperidine. Truncation of a benzyl group to a phenyl group afforded compounds with dramatically improved oral bioavailability, albeit with reduced activity.     

Species variations in the sensitivity of the endoplasmic reticulum to the herbicide 1.1.1. trifluoro-N-(2-methyl-4-phenyl sulfonyl phenyl) methane sulfonamide

1. The effects of the herbicide 1.1.1. trifluoro-N-(2-methyl-4-phenyl sulfonyl phenyl) methane sulfonamide on the drug metabolising enzyme activities in livers of rat, mouse and guinea pig have been compared. 2. In all three animal models, the herbicide increased the activities of both aniline hydroxylase and p-aminopyrine demethylase. The greatest inductive effect was seen in the rat, while the least effect was evident in the guinea pig. 3. In mouse and guinea pig, 1.1.1. trifluoro-N-(2-methyl-4-phenyl sulfonyl phenyl) methane sulfonamide had no effect on the soluble or microsomal epoxide hydratases or the glutathione S-transferases. In the rat, however, the herbicide significantly decreased the microsomal epoxide hydratase activity, as well as the soluble and microsomal glutathione S-transferase activities. 4. These results are discussed in relation to factors responsible for species differences in the response to foreign compounds.     

Synthesis of D-altritol nucleosides with a 3'-O-tert-butyldimethylsilyl protecting group

Four D-altritol nucleosides with a 3'-O-tert-butyldimethylsilyl protecting group are synthesized (base moieties are adenine, guanine, thymine and 5-methylcytosine). The nucleosides are obtained by ring opening reaction of 1,5:2,3-dianhydro-4,6-O-benzylidene-D-allitol. Optimal reaction circumstances (NaH, LiH, DBU, phase transfer, microwave irridation) for the introduction of the heterocycles are base-specific. For the introduction of the 3'-O-silyl protecting group, long reaction times and several equivalents of tert-butyldimethylsilyl chloride are needed.     

Synthesis and Herbicidal Activity of 6-Phenyl-5-Propylamino-2-Pyrazinecarbonitriles and Related Compounds

6-Phenyl- and 5-phenyl-2-pyrazinecarbonitriles with or without a propylamino group at the 3-, 5- or 6-position of the pyrazine ring were prepared together with some related compounds from the corresponding 2,3-pyrazinedicarbonitriles. Their herbicidal activities against barnyardgrass and broadleaf weeds were examined in pot tests. The 6-phenyl-2-pyrazinecarbonitriles were relatively potent compared with the 5-phenyl derivatives. Moreover, the presence of a propylamino group at the 5-position of the 6-phenyl-2-pyrazinecarbonitriles was closely related to an increase in activity.     

(2-Aryl-5-methylimidazol-4-ylcarbonyl)guanidines and (2-aryl-5-methyloxazol-4-ylcarbonyl)guanidines as NHE-1 inhibitors

A series of (2-aryl-5-methylimidazol-4-ylcarbonyl)guanidines and (2-aryl-5-methyloxazol-4-ylcarbonyl)guanidines were synthesized and evaluated as NHE-1 inhibitors. The structure–activity relationships well matched those of furan derivatives, which were previously investigated. The (2,5-disubstituted)phenyl compounds showed better activities than the other analogues in both imidazole and oxazole compounds. Especially, 2-(2,5-dichlorophenyl)imidazole 52, and 2-(2-methoxy-5-chlorophenyl)imidazole 54 compounds exhibited potent cardioprotective efficacy both in vitro and in vivo as well as high NHE-1 inhibitory activities.     

Synthesis of Nucleosides with Additional Nucleobases

The syntheses of two nucleosides with additional nucleobases in the 2′-position are presented. The nucleosides have two- and one-carbon linkers to the additional nucleobase, respectively. The two nucleosides are synthesized from different strategies. The nucleoside with two carbons in the linker has been incorporated into oligonucleotides and showed stabilization of a tree-way junction.     

Parallel DNA containing pyrazolo[3,4-D]pyrimidine analogues of isoguanine

The phosphoramidites of 8-aza-7-deaza-2'-deoxyisoguanosine (1a) and its bromo derivative 1b as well as of 6-aza-2'-deoxyisocytidine and its 5-methyl derivative (3a,b) were synthesized. Parallel-stranded duplexes containing the nucleosides 1a,b show a significantly enhanced duplex stability compared to those containing 2'-deoxyisoguanosine.     

Synthesis and Biological Evaluation of 4′-C-Methyl Nucleosides

Abstract

A series of 2′-deoxy, 2′,3′-unsaturdted and 2′,3′-dideoxynucleoside analogues, which have an additional methyl group at the 4′-position, have been synthesized. When evaluated for their inhibitory activity against HIV in MT-4 cell, 2′-deoxy-4′-C-methyl nucleosides exhibited potent activity.

     

Triaryl (Z)-olefins suitable for radiolabeling with iodine-124 or fluorine-18 radionuclides for positron emission tomography imaging of estrogen positive breast tumors

A group of (Z)-1,2-diphenyl-1-[4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl]but-1-enes were synthesized using methodologies that will allow incorporation of a [¹²⁴I]iodine substituent at the para-position of either the C-1 phenyl ring or the C-2 phenyl ring, or a [¹⁸F]OCH₂CH₂F substituent at the para-position of the C-2 phenyl ring. These [¹²⁴I] and [¹⁸F] radiotracers are designed as potential radiopharmaceuticals to image estrogen positive breast tumors using positron emission tomography (PET).     

Design,synthesis, and biological evaluation of novel triazoloquinazolinone derivatives as SHP2 protein inhibitors

A novel series of triazoloquinazolinone derivatives were designed, synthesised, and evaluated for their in vitro biological activities against the SHP2 protein. Moreover, some compounds were evaluated against A375 cells. The results revealed that target compounds possessed moderate to excellent inhibitory activity against SHP2 protein, whereas compounds 12f, 12l, 12j, 17e, and 17f have strong antiproliferative activity on A375 cells. The compound 12l showed remarkable cytotoxicity against A375 cells and a strong inhibitory effect against SHP2 protein when compared with SHP244. The structure-activity relationships (SARs) indicated that electron-donating groups (EDGs) on phenyl rings are beneficial for improving the antitumor activity; compounds with a hydroxyl substituent at the 2-position of phenyl ring exhibited superior activities than compounds with a substituent at the 4-position. In addition, compound 12l displayed improved physicochemical properties as well as metabolic stability compared to SHP244. Our efforts identified 12l as a promising SHP2 protein inhibitor, warranting its further investigation.