Synthesis and antinociceptive properties of a series of exo- and endo-6-hydroxy-2-aminobenzonorbornenes

A series of 6-hydroxy endo- and exo-derivatives of 2-aminobenzonorbornene has been synthesized and evaluated for antinociceptive activity in the mouse. The results indicated a stereospecific effect in the antinociceptive responses exhibited by the two isomeric groups of compounds. The exo-amines 10a-10c were inactive in both the tail immersion and tail clip tests. The corresponding endo-isomers exhibited antinociceptive properties; 4a was the most active compound tested but was toxic at the dose administered.     

In vitro-in vivo antifungal evaluation and structure-activity relationships of 3H-1,2-dithiole-3-thione derivatives

As part of our project devoted to the search of new antifungal agents, we report here the in vitro-in vivo antifungal evaluations and a structure-activity relationship (SAR) study of 17 thione derivatives. Some compounds of this series exhibited remarkable antifungal activity against a broad spectrum of pathogenic opportunistic fungi. SAR studies provide a useful information for the determination of the minimum structural requirements for producing the biological response.     

A field‐based disparity analysis of new 1,2,5‐oxadiazole derivatives endowed with antiproliferative activity

A series of 1,2,5‐oxadiazoles were synthesized as new potential antiproliferative agents. The in vitro cytotoxic activity evaluation of title compounds through MTT assay revealed that some of them showed significant activity against the HCT‐116 cancer cell line. The field‐based disparity analysis provided indications about the electrostatic, hydrophobic, and shape features underlying the cytotoxicity, suggesting that increasing the negative electrostatic field on the heterocyclic core of the structure has positive effects on the activity. The structure–activity relationships (SAR) around a particular compound can be explained allowing for a structural rationale for the differences in activity. The SAR provided by this series of compounds can be exploited to carry out further lead optimization.     

Piperazine amides with desirable solubility,physicochemical and drug-like properties: Synthesis and evaluation of the anti-Trypanosoma cruzi activity

The absence of effective chronic treatment, expansion to non-endemic countries and the significant burden in public health have stimulated the search for novel therapeutic options to treat Chagas disease, a protozoan disease caused by Trypanosoma cruzi. Despite current efforts, no new drug candidates were approved in clinical trials in the past five decades. Considering this, our group has focused on the expansion of a series (LINS03) with low micromolar activity against amastigotes, considering the optimization of pharmacokinetic properties through increasing drug-likeness and solubility. In this work, we report a new set of 13 compounds with modifications in both the arylpiperazine and the aromatic region linked by an amide group. Five analogues showed activity against intracellular amastigotes (IC₅₀ 17.8 to 35.9 µM) and no relevant cytotoxicity to mammalian cells (CC₅₀ > 200 µM). Principal component analysis (PCA) was performed to identify structural features associated to improved activity. The data revealed that polarity, hydrogen bonding ability and flexibility were key properties that influenced the antiparasitic activity. In silico drug-likeness assessments indicated that compounds with the 4-methoxycinammyl (especially compound 2b) had the most prominent balance between properties and activity in the series, as confirmed by SAR analysis.     

2-aryl-3-phenylamino-4,5-dihydro-2h-benz[g]indazoles with analgesic activity

A series of 2-aryl-3-phenylamino-4,5-dihydro-2H-benz[g]indazoles was synthesized and tested for antiarrhythmic, local anaesthetic and analgesic activity. The title compounds showed a good antinociceptive activity.     

R,S-1-(取代苯基)-4-[3-(萘-1-氧基)-2-羟基丙基]哌嗪类化合物的设计、合成及血管舒张活性

设计合成具有血管舒张活性的苯基哌嗪类系列化合物。以naftopidil活性代谢产物为先导化合物，根据已报道的苯基哌嗪类α₁-受体拮抗剂构效关系研究结论对先导化合物进行结构优化，设计并合成一系列新的苯基哌嗪类化合物，确定其结构，并通过测定其对苯肾上腺素引起家兔胸主动脉条收缩的抑制作用评价其血管舒张活性。发现其中5个化合物显示出不同程度的活性，其中化合物16的血管舒张活性较强，其在0.01和1 μmol·L^-1条件下血管收缩抑制率分别达到7.03%和22.72%，化合物16拟采用自发性高血压大鼠降压试验等进行进一步抗高血压活性研究。以上研究提示已报道苯基哌嗪类化合物的构效关系研究结论可适合于naftopidil的结构修饰。     

Some 9-hydroxycannabinoid-like compounds. Synthesis and evaluation of analgesic and behavioral properties.

A series of 9-hydroxylated cannabinoid-like compounds was prepared and tested for analgesic properties in mice and behavioral properties in dogs. Although the prototype compound, 9-nor-9-hydroxyhexahydrocannabinol, has potent antinociceptive activity in laboratory animals, the new analogues were relatively inactive. All of the compounds produced an alteration of behavior in unanesthetized dogs. Two of the compounds produced cannabinoid-like effects and the other two produced general CNS depression.     

Comprehensive analysis of single- and multi-target activity cliffs formed by currently available bioactive compounds

Activity cliffs are formed by structurally similar compounds having large potency differences. Their study is a focal point of SAR analysis. We present a first systematic survey of single- and multitarget activity cliffs contained in currently available bioactive compounds. Approximately 12% of all active compounds were involved in the formation of activity cliffs. Perhaps unexpectedly, activity cliffs were found to be similarly distributed over different protein target families. Moreover, only approximately 5% of all activity cliffs were multitarget cliffs. Importantly, we also found that only very few multitarget cliffs were formed by compounds having different target selectivity. In addition, 'polypharmacological cliffs', i.e., multitarget activity cliffs involving targets from different protein families, were also only rarely found. Taken together, our findings reveal that only approximately 2% of all pairs of structurally similar compounds sharing the same biological activity form activity cliffs but that, on average, approximately one of 10 active compounds is involved in the formation of one or two single-target cliffs of large magnitude (with at least 100-fold difference in potency). These compounds provide a rich source of SAR information and can be identified across many different target families.     

(1S)-1-(aminomethyl)-2-(arylacetyl)-1,2,3,4-tetrahydroisoquinoline and heterocycle-condensed tetrahydropyridine derivatives: members of a novel class of very potent kappa opioid analgesics.

The synthesis and structure-activity relationship (SAR) of a novel class of kappa opioid analgesics, 1-(aminomethyl)-2-(arylacetyl)-1,2,3,4- tetrahydroisoquinolines and (aminomethyl)-N-(arylacetyl)-4,5,6,7-tetrahydrothienopyridines+ ++, are described. These compounds, formally derived by the condensation of a benzene or thiophene ring on the piperidine nucleus of the recently described compounds 1, are from 3 to 7 times more potent as antinociceptive agents and with a longer duration of action than the original lead compounds. A similar N2-C1-C9-N10 pharmacophore torsional angle of approximately 60 degrees was also found for this class of compounds by using X-ray and 1H NMR analyses. The same absolute configuration (S) at the chiral center of the active (-) enantiomers was determined by X-ray crystallographic analysis. A varied degree of kappa receptor selectivity was a feature of this novel class of antinociceptive agents (mu/kappa ratio from 44 to 950 according to the nature of the basic moiety). SAR analysis indicated that the presence of electron-withdrawing and lipophilic substituents in para and/or meta positions in the arylacetic moiety and the pyrrolidino or dimethylamino basic groups are required to optimize biological activity. The lead compounds 28, 30, and 48 are among the most potent antinociceptive agents (ED50 ca. 0.020 microM/kg sc) and kappa ligands (Ki(kappa) ca. 0.20 nM) identified so far.     

Biological Evaluation of Isoniazid Derivatives as an Anticancer Class

A series of thirty-two isoniazid derivatives have been evaluated for their activity against four human cancer cell lines with potent cytotoxicity (IC50 ranging from 0.61 to 3.36 μg/mL). The structure-activity relationship (SAR) analysis indicated the number, the positions, and the types of substituents attached to the aromatic ring as being critical factors for the biological activity. Briefly, we observed that the presence of a hydroxyl group on the benzene ring plays an important role in the anticancer activity of this series, especially when it is located in ortho-position. Among the thirty-two compounds, three displayed good cytotoxic activity when compared to the reference drug doxorubicin and are thus being considered leading compounds of this new class.     

Synthesis, antibacterial and antifungal activities of bifonazole derivatives

Two series of chlorinated benzhydryl imidazole and triazole derivatives were synthesized and tested in vitro against representative strains of potent pathogenic bacteria (Staphylococcus aureus CIP 4.83, Escherichia hirae CIP 5855, Pseudomonas aeruginosa CIP 82118, Escherichia coli CIP 53126) and fungi (Aspergillus niger IP 1431.83, Candida albicans IP 48.72, Candida krusei IP 208.52, Trichophython rubrum IP 1657.86). Most of these compounds were devoid of any antimicrobial activity, but several of them inhibited T. rubrum with MIC values in the range of 0.125 to 32 μg/mL, similar or superior to those of bifonazole and clotrimazole, used as standard controls. The replacement of the imidazole ring with a triazole moiety in these compounds led to derivatives with less antifungal activity. A preliminary SAR was undertaken on the effect of the number and the position of chlorine atoms on the distribution of negative charge on the surface of some compounds on antifungal activity.     

A series of 6- and 7-piperazinyl- and -piperidinylmethylbenzoxazinones with dopamine D4 antagonist activity: discovery of a potential atypical antipsychotic agent

As part of a program to develop dopamine D4 antagonists for the treatment of schizophrenia, we discovered a series of 6- and 7-(phenylpiperazinyl)- and -(phenylpiperidinyl)methylbenzoxazinones through mass screening of our compound library. A structure-activity relationship SAR study was carried out involving substituents on the phenyl ring, and several selective D4 antagonists were identified. The 7-substituted benzoxazinones showed more activity in neurochemical and behavioral tests than the 6-substituted series. One of the most potent and selective compounds (26) was found to have potent activity in animal tests predictive of antipsychotic activity in humans after oral administration. This paper describes the SAR of the benzoxazinone series and the preclinical characterization of 26.     

Synthesis and antinociceptive activity of 6-substituted-3-pyridazinone derivatives.

A series of 3-pyridazinones carrying morpholino, arylpiperidino and arylpiperazino moiety in the position 6 IIa-g were synthesized and evaluated for antinociceptive activity. In the modified Koster test in mice 4-(4-fluorophenyl) piperazine, IIf, was found the most active compound. All the compounds except IId were more active than aspirin in the antinociceptive activity test.     

Progress in 5H[1]benzopyrano[4,3-d]pyrimidin-5-amine series: 2-methoxy derivatives effective as antiplatelet agents with analgesic activity

A series of 2-methoxy-5H[1]benzopyrano[4,3-d]pyrimidin-5-amines were prepared and screened for their in vitro antiplatelet activity inducing the aggregation by ADP, arachidonic acid (AA) and collagen. In vivo experiments were performed in order to evaluate their antiphlogistic, analgesic and antipyretic activities. Title compounds showed antiplatelet activity in aggregation AA or collagen-induced, and a good analgesic activity without any gastric toxicity. Comparison with a number of analogue benzopyrano[4,3-d]pyrimidine derivatives and some SAR consideration were reported.     

Discovery of potent, orally bioavailable phthalazinone bradykinin B1 receptor antagonists

The bradykinin B1 receptor is rapidly induced upon tissue injury and inflammation, stimulating the production of inflammatory mediators resulting in plasma extravasation, leukocyte trafficking, edema, and pain. We have previously reported on sulfonamide and sulfone-based B1 antagonists containing a privileged bicyclic amine moiety leading to potent series of 2-oxopiperazines. The suboptimal pharmacokinetics and physicochemical properties of the oxopiperazine sulfonamides led us to seek B1 antagonists with improved druglike properties. Using a pharmacophore model containing a bicyclic amine as anchor, we designed a series of amide antagonists with targeted physicochemical properties. This approach led to a novel series of potent phthalazinone B1 antagonists, where we successfully replaced a sulfonamide acceptor with a cyclic carbonyl unit. SAR studies revealed compounds with subnanomolar B1 binding affinity. These compounds demonstrate excellent cross-species PK properties with high oral bioavailability and potent activity in a rabbit biochemical challenge pharmacodynamic study.     

α-苯基取代肉桂酰胺类化合物的合成及其钾通道开放活性

目的　寻找新的降压药物。方法和结果　以N-(4-甲氧基苯甲酰基)-N′-肉桂基哌嗪为先导物,用混合酸酐法和酰氯法合成了22个α-苯基取代的肉桂酰胺类衍生物,这些化合物均为新化合物。用MS和¹HNMR确证了其结构。结论　生物活性筛选结果表明,大部分化合物对去甲肾上腺素引起的大鼠主动脉条收缩有较好的抑制作用,一些化合物(3,9,11)对去甲肾上腺素和高钾收缩的抑制作用优于先导物,其中化合物11有一定的钾通道开放活性     

依布硒啉衍生物对白三烯B4生物合成抑制作用及其构效关系

目的：研究一系列依布硒啉衍生物对白三烯B₄生物合成的影响,并探讨其构效关系。方法：高效液相色谱法测定白三烯B₄。结果：依布硒啉的磺酰胺类似物以及N-芳香环取代的磺酰胺衍生物对白三烯B4生物合成具有抑制作用,其IC₅₀在10^-5～10^-6 mol.L^-1之间,并存在一定的构效关系。结论：磺酰胺基团上的酸性氢原子是关键因素,它的存在可以形成分子内氢键,从而使化合物具有活性。