Exploring the hydrophobic channel of NNIBP leads to the discovery of novel piperidine-substituted thiophene3,2-pyrimidine derivatives as potent HIV-1 NNRTIs

In this report, a series of novel piperidine-substituted thiophene[3,2-]pyrimidine derivatives were designed to explore the hydrophobic channel of the non-nucleoside reverse transcriptase inhibitors binding pocket (NNIBP) by incorporating an aromatic moiety to the left wing of the lead . The newly synthesized compounds were evaluated for anti-HIV potency in MT-4 cells and inhibitory activity to HIV-1 reverse transcriptase (RT). Most of the synthesized compounds exhibited broad-spectrum activity toward wild-type and a wide range of HIV-1 strains carrying single non-nucleoside reverse transcriptase inhibitors (NNRTI)-resistant mutations. Especially, compound exhibited the most potent activity against wild-type and a panel of single mutations (L100I, K103N, Y181C, Y188L and E138K) with an EC ranging from 6.02 to 23.9 nmol/L, which were comparable to those of etravirine (ETR). Moreover, the RT inhibition activity, preliminary structure-activity relationship and molecular docking were also investigated. Furthermore, exhibited favorable pharmacokinetics (PK) profiles and with a bioavailability of 33.8%. Taken together, the results could provide valuable insights for further optimization and compound holds great promise as a potential drug candidate for the treatment of HIV-1 infection.

Synthesis and Bioactivity of Novel Phosphonate Derivatives Containing Thiophene and Sulfonamide Group / 中国药学杂志

OBJECTIVE: To design and synthsize a series of novel phosphonate derivatives. METHODS: First, the intermediates of aminophosphonate was prepared by solvent-free one-pot method using aromatic aldehyde, ammonium acetate, diethyl phosphite and Al(OTf)3 as raw materials. Then, using basic ionic liquid OH as catalyst, the target compounds were synthesized by the reaction of intermediate with sulfonyl chloride. And the antibacterial activities of the products were evaluated by the agar dilution method. RESULTS: Twelve title compounds were synthesized, and their structures were clearly established by 1H-NMR, 13C-NMR and MS. The results showed that the derivatives have different inhibitory activities against Gram-positive bacteria and Gram-negative bacteria, especially the compounds Ⅱe and Ⅱk showed better activity, the MIC of the former for S.aureus, E. coli, MRSA and MREC was 32, 64, 32, and 128 μg•mL-1, respectively, and the MIC of the latter was 16, 64, 32, and 64 μg•mL-1, respectively. Its antibacterial activities were significantly better than that of the control drug sulfadiazine, and close to that of gatifloxacin. CONCLUSION: These derivatives have potential antibacterial activity, which is worth for further structural optimization and study.

Preclinical screening of a novel compound, 2-chlorothiophene for analgesic activity in swiss albino mice

Background: Pain is often the first indication of disease or injury. Analgesics are the drugs used clinically for controlling pain. They relieve pain as a symptom, without affecting its cause. Currently available options are nonsteroidal anti-inflammatory drugs (NSAIDs) and opioid analgesics for the management of pain. Long term use of existing analgesics causes significant disturbances in the body system. A search for new, safe and cost effective analgesic compound is in progress. Hence a study on 2-chlorothiophene, a novel compound has been carried out in different experimental animal models.Methods: The central analgesic activity of 2-chlorothiophene was evaluated by eddy’s hot plate method and compared to standard central analgesic, morphine. Both central and peripheral analgesic activities of 2-chlorothiophene were evaluated by formalin induced paw licking in mice and compared to a standard drug, aspirin.Results: There were 40mg/kg dose of 2-chlorothiophene has shown maximum Pain Inhibition Percentage (PIP) of 46.15% at 60 min compared to 128% by morphine in eddy’s hot plate method. Under Formalin test, 20mg/kg dose of 2-chlorothiophene has shown maximum PIP of 22.91% in early phase and 52.63% in late phase compared to 12.5% and 47.37% by aspirin. The results were statistically significant with p<0.05.Conclusions: 2-chlorothiophene found to have minimal central analgesic activity and significant peripheral analgesic activity as evident in eddy’s hot plate and formalin tests.

Chemcial constituents of Eclipta prostrata / 中国中药杂志

A total of twenty-two compounds were isolated from the 95% EtOH extract of Eclipta prostrata by various purification steps, and their structures were established as ecliptalignin A (1)，ecliptasaponin Ⅰ (2), ecliptasaponin Ⅱ (3), echinocystic acid (4), 3-oxo-16α-hydroxy-olean-12-en-28-oic acid (5), acacetin-7--rutinoside (6), luteoloside (7), apigenin (8), luteolin (9), acacetin (10), skullcapflavone Ⅱ (11), kaempferol (12), kaempferide (13), quercetin (14), 4',7-dihydroxyl-3',6'-dimethoxylisoflavone-7--glucoside (15), ecliptal (16), 5-hydroxymethyl-(2,2',5',2″)-terthienyl tiglate (17), psoralen (18), isopsoralen (19), wedelolactone (20), crinumaquine (21), and 2,3,9,12-tetramethoxyprotoberberine (22) mainly based on the spectroscopic techniques, of which 1 was a new lignin analogue, and 5, 6, 10-13, 15, 18, 19, 21 and 22 were isolated form this plant for the first time.

Tumor invasion inhibition of thiophene substituted long chain chalcones / 中国药理学通报

Aim To elucidate the structure-activity re-lationship between a new class of long chain chalcone compounds and tumor invasion. Methods The basic idea of the research was to enhance the specificity by prolonging the molecular structure. Based on the lead compound TSAHC, the thiophene was used as the main derivative at the carbonyl groups to obtain six new chalcones. Then we evaluated the anti-tumor activities of the compounds and the expression of key protein MMP-2 of the tumor invasion. Finally, six new com-pounds were docked to the protein by the SYBYL soft-ware. Results The structures of the six compounds were confirmed by H-NMR and MS. Among them, compound 2,3 showed fine capability to inhibit tumor invasion. The docking results also showed that the sul-fonamide and thiophene groups of the compounds had positive contribution to the target binding of the com-pounds. Conclusion Cell experiments and molecular docking show that the long chain modification of chal-cone by using thiophene as a derivative group can sig-nificantly enhance the anti-tumor invasion.

Synthesis of some novel pyrimidine, thiophene, coumarin, pyridine and pyrrole derivatives and their biological evaluation as analgesic, antipyretic and anti-inflammatory agents

Pyrimidine derivative 3 was afforded through the reaction of compound (1) with 5-ureidohydantion (2). Product 3 underwent a cyclization to produce fused pyrimidine derivative 7, although the latter product 7 was synthesized through one step via the reaction of compound (1) with 5-ureidohydantion (2) using another catalyst. Compound 3 was oriented to react with cyclic ketones 8a,b in the presence of elemental sulfur, salicylaldehyde (10), aryldiazonium chlorides 12a,b and ω-bromo-4-methoxy- acetophenone (14), which afforded, fused thiophene derivatives 9a,b, coumarin derivative 11, arylhdrazono derivatives 13a,b and 4-methoxyphenyl butenyl derivative 15, respectively. The latter product 15 was reacted with either potassium cyanide (16a) or potassium thiocyanide (16b) to form cyano and thiocyano derivatives 17a,b, respectively. Compound 17a underwent further cyclization to afford pyridopyrimidine derivative 19. Compound 15 was reacted with either hydrazine (20a) or phenylhydrazine (20b) to produce hydrazo derivatives 21a,b and these products were cyclize to produce pyrrole derivatives 23a,b. Finally, 5-ureidohydantion (2) was reacted with compounds 24a,b,c to afford pyrimidine derivatives 25a,b,c. The structures of the synthesized compounds were confirmed using IR, 1H NMR, 13C NMR and mass spectrometry techniques. Compounds 11 and 19 have promising as analgesic and antipyretic activities

Design and synthesis of novel antifungal compounds bearing quinoline and thiophene moieties / 药学实践杂志

Objective Based on the structure-activity relationships on the reported antifungal agents bearing quinoline or thiophene moieties ,novel compounds bearing both quinoline and thiophene were designed ,synthesized ,and evaluated for in vitro antifungal activity against Candida albicans .Methods With 5-cyanothiophene-2-carbaldehyde or 5-cyanothiophene-3-car-baldehyde as starting materials ,13 compounds were synthesized via reductive amination ,reduction of cyano group and amida-tion of quinoline-or isoquinoline-carboxylic acid .Their chemical structures were characterized by 1 H NMR and MS . In vitro antifungal screening against Candida albicans SC5314 was performed with the microbroth dilution method .Results All the compounds exhibited potent antifungal activities against Candida albicans .Among them ,compound 6k showed the highest an-tifungal activity with MIC80 value of 0 .5 μg/ml ,which is same potent as fluconazole .Conclusion The designed compounds bearing both quinoline and thiophene exhibited potent antifungal activities ,and deserve further research .

Unraveling the Role of Π - Conjugation in Thiophene Oligomers for Optoelectronic Properties by DFT/TDDFT Approach

ABSTRACT Thiophene oligomer has been investigated using DFT/TDDFT calculations with an aim to check its suitability for opto electronic applications and also to analyse the influence of π-bridge. Our results revealed that thiophene oligomers have excellent π-conjugation throughout. FMO analysis give an estimate of band gap of thiophene oligomer and further revealed HOMO are localized on π - bridge, donor group and LUMO are localized on π - bridge and acceptor group. A TDDFT calculation has been performed to understand the absorption properties of them in gas phase and solvent phase. PCM calculations convey that absorption maxima show positive solvatochromism. Among the designed candidates, the one with more π - bridge show higher wavelength of absorption maxima and would be a choice for better optoelectronic materials. NBO analysis provides support for complete delocalization in these systems. It is interesting to note that oligomer with more π-bridge display an enhanced optoelectronic properties than with less π - bridge.

Desenvolvimento e validação de metodologias analíticas para quantificação de um derivado tiofênico em sistemas microemulsionados / Development and validation of analytical methodologies for measurement of a tiophene derivative in microemulsion systems

O presente trabalho teve por objetivo validar métodos por espectrofotometria UV-Vis e por CLAE para a análise quantitativa de um derivado do tiofeno, o 2-[(3,4-dicloro-benzilideno)-amino]-5,6-diidro-4H-ciclopen-ta[b]tiofeno-3-carbonitrila (5CN05) e aplicá-los no doseamento da molécula contida em microemulsões, Os métodos propostos foram validados conforme a Resolução 899/2003 da Agência Nacional de Vigilância Sanitária (ANVISA), O comprimento de onda de máxima absorção do fármaco 5CN05 foi detectado em λ max= 387nm, O método espectrofotométrico validado mostrou-se seletivo, apresentando linearidade na faixa de 3 a 16 µg.mL-1, coeficiente de correlação (r) igual a 0,9998 e limites de detecção e quantificação de 0,12 µg.mL-1 e 0,41 µg.mL-1, respectivamente, Para o método CLAE, observou-se linearidade na faixa de 0,1 a 3,0 µg.mL-1, r = 0,99915, limites de detecção e quantificação de 0,07 µg.mL-1 e 0,10 µg.mL-1 respectivamente, Para ambos os métodos, os parâmetros precisão, exatidão e robustez mostraram-se adequados para o uso pretendido, As metodologias propostas podem ser seguramente aplicadas para quantificação do 5CN05 em produtos farmacêuticos como microemulsões...

This study aims to validate methods of Uv-Vis) and HPLC for quantitative determination of a thiophene derivative, 2 - [(3,4-dichloro -benzylidene)-amino] -5,6-dihydro-4H-cyclopentyl-ta [b] thiophene-3- carbonitrile referred in this study as 5CN05, and apply them to quantify the 5CN05 in microemulsions. The proposed methods were validated according to the Resolution RE 899/2003 of the National Health Surveillance Agency (ANVISA). The 5CN05 was detected by UV-Vis at λ max= 387nm. The validated UVVis UVVis method proved to be selective, showing linearity in the range of 3-16 µg.mL-1, correlation coefficient (r) of 0.9998 and limits of detection and quantification of 0.12 µg.mL-1 and 0.41 µg.mL-1 respectively. For the CLAE method the linearity was observed in the range 0.1 to 3.0 µg.mL-1, r = 0.99915, limits of detection and quantification of 0.07 µg.mL-1 and 0.10 µg.mL-1 respectively. For both UV-Vis and CLAE methods, the precision parameters, accuracy and robustness were adequate for the intended use. The proposed methodologies can be safely applied to quantify the 5CN05 in pharmaceutical microemulsions products...

Antifungal activity of topical microemulsion containing a thiophene derivative

Fungal infections have become a major problem of worldwide concern. Yeasts belonging to the Candida genus and the pathogenic fungus Cryptococcus neoformans are responsible for different clinical manifestations, especially in immunocompromised patients. Antifungal therapies are currently based on a few chemotherapeutic agents that have problems related to effectiveness and resistance profiles. Microemulsions are isotropic, thermodynamically stable transparent systems of oil, water and surfactant that can improve the solubilization of lipophilic drugs. Taking into account the need for more effective and less toxic drugs along with the potential of thiophene derivatives as inhibitors of pathogenic fungi growth, this study aimed to evaluate the antifungal activity of a thiophene derivative (5CN05) embedded in a microemulsion (ME). The minimum inhibitory concentration (MIC) was determined using the microdilution method using amphotericin B as a control. The formulations tested (ME- blank and ME-5CN05) showed physico-chemical properties that would allow their use by the topical route. 5CN05 as such exhibited moderate or weak antifungal activity against Candida species (MIC = 270-540 µg.mL-1) and good activity against C. neoformans (MIC = 17 µg.mL-1). Candida species were susceptible to ME-5CN05 (70-140 µg.mL-1), but C. neoformans was much more, presenting a MIC value of 2.2 µg.mL-1. The results of this work proved promising for the pharmaceutical industry, because they suggest an alternative therapy against C. neoformans.

Chemical constituents from the roots of Echinops sphaerocephalus linn / 中国药学杂志

OBJECTIVE: To study the chemical constituents of the roots of Echinops sphaerocephalus. METHODS: The compounds were isolated and purified by silica gel column chromatography and recrystallization. The structures were identified by physicochemical properties and spectral analysis method. RESULTS: Ten compounds were isolated from E. sphaerocephalus and identified as n-hentriacontane(1), α-terthienyl(2), cardopatine(3), lup-20 (29) -en-3-one(4), lupeol acetate (5), 5-acetyl-2,2'-bithiophene(6), arctinal(7), tetracosanoic acid(8), lupeol(9), and β-sitosterol(10), respectively. CONCLUSION: Ten compounds are isolated from E. sphaerocephalus, among which nine are isolated for the first time from this plant.