Synthesis of some novel substituted purine derivatives as potential anticancer, anti-HIV-1 and antimicrobial agents

In search of novel purine antimetabolites, a series of 8-substituted methylxanthine derivatives was prepared in order to explore their in vitro anticancer, anti-HIV-1 and antimicrobial activities. The target compounds include: 8-[(3-substituted-4-oxo-thiazolidin-2-ylidene)hydrazino]-1,3-dimethyl (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 5a-e, 8-[(3,4-disubstituted 2,3-dihydrothiazol-2-ylidene)hydrazino]-1,3,7-trimethyl-3,7-dihydropurine-2,6-diones 6a-d and 8-(5-amino-3-arylpyrazol-1-yl)-1,3-dimethyl- (or 1,3,7-trimethyl)-3,7-dihydropurine-2,6-diones 7a-g. The in vitro anticancer results revealed that compound 5d exhibited a super sensitivity profile towards leukemia K-562 with a GI(50) value of <0.01 microM. Compound 7c showed significant activity against colon cancer HCT-15 and renal cancer CAKI-1 (GI(50) values of 0.47 and 0.78 microM, respectively). Compound 7a displayed high activity against colon cancer HCT-15 (GI(50 )= 0.8 microM). The anti-HIV-1 results indicated that compound 6b displayed a good reduction of viral cytopathic effect (56.69%). The antimicrobial results showed that compound 5a was four times more active than ampicillin against P. aerugenosa (MIC =or< 25 microg/mL), compound 5b had twice the activity of ampicillin, while compounds 5d, 7c and 7f were equipotent to ampicillin. On the other hand, compound 7a was equipotent to ampicillin against P. vulgaris (MIC = 50 microg/mL).     

Chemokine receptor-directed agents as novel anti-HIV-1 therapies

Historically, therapeutic benefit in the treatment of human immunodeficiency virus infection (HIV-1) infection has been best achieved by targeting viral proteins like HIV protease involved in viral replication rather than host cell proteins, like CD4, which facilitate the process of viral infection. Two discoveries in 1996 presented a novel opportunity to redress this issue: 1) the understanding that heptahelical G-protein coupled chemokine receptors on the surface of T cells and macrophages functioned together with CD4 to mediate viral entry, and 2) the observation that CD4 positive T cells from individuals homozygous for the CCR5 delta 32 null allele were resistant to infection by macrophage-tropic strains of the virus in vitro and in vivo. Since that time, data demonstrating that selective blockade of two chemokine receptors, CCR5 and CXCR4, by small molecule chemokine receptor antagonists or receptor-directed biologics could robustly inhibit the infection of human peripheral blood mononuclear cells (PBMCs) by macrophage-tropic and T-cell line tropic strains respectively in vitro has validated this potential approach to therapy. Early clinical trial data now also confirms that these types of agents will have anti-viral activity in some HIV-1 infected individuals; however to date, dose limiting off-target activities have prohibited a full test of their potential clinical value. It also remains to be seen how these types of agents will fare in synergy with existing HIV-1 targeted antivirals, or those currently in development.     

Synthesis andin vitro evaluation of some novel benzofuran derivatives as potential anti-HIV-1, anticancer, and antimicrobial agents

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and 6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2(1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound 5c was determined by X-ray crystallography. The compounds prepared were evaluated for their in vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds 5c and 9a produced a significant reduction [symbols, see text] the viral cytopathic effect (93.19% and 59.55%) at concentrations > 2.0 x 10(-4) M and 2.5 x 10(-5) M respectively. Compound 9a was confirmed to have moderate anti-HIV activity. Compounds 2a, 2d, and 5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.     

Synthesis, biological screening and ADME prediction of benzylindole derivatives as novel anti-HIV-1, anti-fungal and anti-bacterial agents

Present study is focused on design, synthesis, and biological evaluation of substituted benzylindole derivatives as anti-HIV, anti-fungal, and anti-bacterial agents. Out of the reported compounds, compound B1 and B2 showed potent Anti-HIV activity, whereas compound B1–B4 showed good anti-fungal and anti-bacterial activity. ADME properties of benzylindol analogs were analyzed using Qikprop 2.5 tool of Schrodinger.     

Synthesis of novel nalidixic acid-based 1,3,4-thiadiazole and 1,3,4-oxadiazole derivatives as potent antibacterial agents

Novel nalidixic acid-based 1,3,4-thia(oxa)diazoles, their thio ethers, sulfones, bis mercapto, and Mannich bases were synthesized and characterized by Infrared spectra, (1) H NMR, (13) C NMR, and elemental analysis. These compounds were evaluated for their antibacterial activity against two Gram-positive and three Gram-negative bacteria. The preliminary bioassay showed that most of the compounds had better antibacterial activity than the parent compounds, 1,3,4-thia(oxa)diazoles, at the dosage 50μg/mL toward five test bacteria. Four Mannich bases of nalidixic acid-based 1,3,4-thiadiazole exhibited maximum antibacterial activity against Bacillus subtilis, Klebsiella pneumoniae, and Pseudomonas aeruginosa with minimum inhibitory concentration in the range of 6.25-125μg/mL.     

Synthesis and biological evaluation of novel 4,5-dihydropyrazole derivatives as potent anticancer and antimicrobial agents

A focused library of 4,5-dihydropyrazole dervivatives (4, 5, 6, 7a–h, 8, 9a–g, and 10a–g) were synthesized from novel 5-(2,6-difluorophenyl)-3-phenyl-4,5-dihydropyrazole-1-carbothioamide 4. The synthesized compounds were characterized using elemental analysis and spectral data (IR, mass spectra, ¹H and ¹³C NMR) and evaluated for antimicrobial activity by broth dilution method and in vitro anticancer activity. Among the synthesized compounds 7a, 9c, 9g, and 10d exhibit broad spectrum antimicrobial activity against tested microbial strains. The in vitro cancer results ascertain 7a, 9c, and 10d are most potent molecules in comparison to reference standard cisplatin.     

Synthesis and evaluation of novel carbamate-substituted flavanone derivatives as potent acetylcholinesterase inhibitors and anti-amnestic agents

This study was designed to synthesize and evaluate flavanone derivatives with phenylcarbamate moiety as potent acetylcholinesterase (AChE) inhibitors and anti-amnestic agents for management of AD. The synthesis of carbamate-substituted flavanone derivatives involved base-catalysed Claisen-Schmidt condensation reaction of 2-hydroxy acetophenone/2-hydroxy-4,6-dimethoxyacetophenone with differently substituted benzaldehydes to yield differently substituted chalcones that underwent intra-molecular oxidative cyclization on refluxing with glacial acetic acid to yield flavanone compounds. Thereafter, refluxing of flavanone compounds with phenyl isocyanate in the presence of petroleum-ether and triethylamine provided phenyl carbamate-substituted flavanone derivatives. The synthesized compounds were screened in vitro for AChE inhibitory activity with donepezil as the standard drug. The most potent test compound (5f′) was evaluated in vivo for memory restorative actions in scopolamine (0.4 mg/kg)-induced amnesia in mice by Morris water maze test. All the compounds exhibited AChE inhibitory activity with carbamate substituted 5,7-dimethoxyflavanone derivatives (5a′–5g′) being the most potent compounds with IC₅₀ ranging from 21.5 ± 1.8 to 9.9 ± 1.6 nM. Compound 5f′ also ameliorated scopolamine-induced amnesia in mice in terms of restoration of time spent in target quadrant and escape latency time. It may be concluded that phenylcarbamate-substituted 5,7-dimethoxyflavanones may be a promising structural template for the development of novel AChE inhibitors in managing amnestic disorders including AD.     

Synthesis of some new amidine derivatives as potent hypoglycemic agents

A series of S-arylformamidino-N-(alkyl/arylisothiourea) Cyclicamino dihydrochlorides were synthesised and screened for their hypoglycemic activity in normal as well as alloxanized diabetic rats. Some of the compounds (Id, Ie, Ih-1) showed more than 30% lowering of blood sugar level of Albino rats.     

Synthesis of new quinoxaline-2-carboxylate 1,4-dioxide derivatives as anti-Mycobacterium tuberculosis agents

Twenty-nine new 6(7)-substituted quinoxaline-2-carboxylate 1,4-dioxide derivatives were synthesized and evaluated for in vitro antituberculosis activity. In general, the in vitro activity is significantly affected by substituents on the quinoxaline nucleus. It has been observed that the presence of a chloro, methyl, or methoxy group in position 7 of the benzene moiety reduces the MIC and IC(50) values. However, antituberculosis activity principally depends on the substituents in the carboxylate group, improving in the following order: benzyl > ethyl > 2-methoxyethyl > allyl > tert-butyl. Fourteen compounds have been selected for macrophage assay, and the results show that ethyl and benzyl 3-methylquinoxaline-2-carboxylate 1,4-dioxide derivatives with the chlorine group in position 7 of the benzene moiety (compounds 10 and 26) and the unsubstituted derivatives (compounds 11 and 27) have good antitubercular activity, including activity in macrophages. In addition, compounds 7 and 28 (the only ones tested up to now) are active against drug-resistant strains of M. tuberculosis H(37)Rv. In conclusion, the potency, selectivity, and low cytotoxicity of these compounds make them valid leads for synthesizing new compounds that possess better activity.     

Synthesis and potent in vitro activity of novel 1H-benzimidazoles as anti-MRSA agents

A new class of 1H-benzimidazolecarboxamidines was synthesized and evaluated for in vitro antibacterial and antifungal activities, including drug-resistant bacterial strains. The most potent compound (32) has the same ratio of anti-MRSA activity as Vancomycin (minimal inhibitory concentrations value 0.78 μg/mL). The mechanism of action for 1H-benzimidazolecarboxamidine appears to be different from existing antibacterial agents. These compounds have potential for development as a new class of potent anti-MRSA agent.     

新型7-苯甲酰基中氮茚-1-羧酸乙酯类化合物的合成及HIV-1病毒感染因子抑制活性研究

目的设计合成7-苯甲酰基中氮茚-1-羧酸乙酯类化合物,并对其抗HIV-1活性进行初步研究。方法以异烟酸、溴乙酸苄酯、丙炔酸乙酯为原料,经取代、Friedel-Crafts反应、1,3-偶极环加成反应、水解、缩合得到目标化合物;采用荧光筛选方法对目标化合物抗HIV-1病毒感染因子(viral infectivity factor,VIF)活性进行评价。结果共合成30个未经文献报道的新化合物,其结构经1H-NMR、13C-NMR、HRMS确证;活性结果表明,化合物30、31、36、37等4个化合物抗HIV-1活性与先导化合物相当。结论 7-苯甲酰基中氮茚-1-羧酸乙酯类化合物作为HIV-1 VIF复合物抑制剂,中氮茚环与取代芳环之间含3～4个原子长度为保持活性所必须,进一步的构效关系值得继续研究。     

Synthesis of amide derivatives of 5,5-diphenylhydantoin as potential antiarrhythmic agents. I

5,5-Diphenylhydantoin derivatives containing amide groups at the position 3 were synthesized as potential antiarrhythmic agents. The most valuable was (X) whose antiarrhythmic activity is stronger than that of phenytoin.     

Synthesis of some novel azo derivatives of 3,5-dimethyl-1-(2-hydroxyethyl)pyrazole as potent analgesic agents

A series of 1-(2-hydroxyethyl)-3,5-dimethylpyrazolylazo derivatives, incorporating thiosemicarbazide 2a-c, 1,3,4-thiadiazole 3a-c, and 1,2,4-triazole-3-thione 4a-c were synthesized. The structure of these novel synthesized compounds 2a-c, 3a-c, and 4a-c was confirmed by spectral analysis. All these compounds were screened for their analgesic activity. Hot-plate and tail-immersion tests were used for the determination of the analgesic activity. Morphine, an analgesic through both spinal and supraspinal pathways, was used as a standard test drug. All compounds were administered at a dose of 100 mg/kg i.p. Among the compounds, 2-(butylamino)-5-[((1-(2-hydroxyethyl)-3,5-dimethylpyrazole-4-yl)azo)phenyl]-1,3,4-thiadiazole 3a and 4-[((1-(2-hydroxyethyl)-3,5-dimethylpyrazole-4-yl)azo)phenyl]-4-(2-phenethyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione 4c showed analgesic effects in both tests. Especially 4c exerted strong analgesia starting at 30 min after injection.     

Synthesis and biological evaluation of andrographolide derivatives as potent anti-HIV agents

In an attempt to develop potent anti-HIV drugs, 20 andrographolide derivatives were designed, synthesized, and evaluated for their in vitro anti-HIV activity. The screening results revealed that five compounds showed potent anti-HIV activities with therapeutic indices (TI) above 10. The most promising compound 6f shows a significant TI close to 34.07, with the potency to be a new lead.     

Synthesis of novel benzimidazole derivatives: as potent analgesic agent

1-(1-Alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols have been synthesized using o-phenylinediamine and naphthaldehyde in the presence of sodium hydride and THF. 1-(1-Alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols were evaluated for the analgesic activity by tail flick method in rats. Synthesized1-(1-alkyl-6-substituted-1H-benzimidazol-2-yl)-naphthalen-2-ols in doses of 50 mg/kg increased the pain threshold significantly after 0, 30, 60, 90, and 120 min of administration in the tail flick model. Compounds B₃a, B₂b, and B₁b showed time-dependent action in all the experimental models. The present study indicates that Compounds B₃a, B₂b, and B₁b show analgesic properties.     

Anti-AIDS agents 69. Moronic acid and other triterpene derivatives as novel potent anti-HIV agents

In a continuing structure-activity relationship study of potent anti-HIV agents, seven new triterpene derivatives were designed, synthesized, and evaluated for in vitro antiviral activity. Among them, moronic acid derivatives 19, 20, and 21 showed significant activity in HIV-1 infected H9 lymphocytes. Compounds 19 and 20 were also evaluated against HIV-1 NL4-3 and drug resistant strains in the MT-4 cell line. Compounds 19 and 20 showed better antiviral profiles than the betulinic acid analogue 8 (PA-457), which has successfully completed a Phase IIa clinical trial. Compound 20 showed potent anti-HIV activity with EC50 values of 0.0085 microM against NL4-3, 0.021 microM against PI-R (a multiple protease inhibitor resistant strain), and 0.13 microM against FHR-2 (an HIV strain resistant to 8). Promising compound 20 has become a new lead for modification, and further development of 20-related compounds as clinical trial candidates is warranted.     

Discovery of novel negletein derivatives as potent anticancer agents for acute myeloid leukemia

Baicalin and its aglycone baicalein derived from Scutellaria baicalensis exhibited potent anticancer effects in various types of cancer cell lines. However, the unfavorable pharmaceutical properties became the main obstacle for their potential clinical development. With the aim of development of novel anticancer agents based on the skeleton of baicalin, a series of novel negletein derivatives were designed and synthesized. Among them, compound 8 ( FZU ‐02,006 ) with an N,N‐dimethylamino ethoxyl moiety at the C‐6 position exhibited significant enhanced antiproliferative effect against HL‐60 cells in vitro through regulating multisignaling pathways. These results revealed that compound 8 with the improved aqueous solubility (as HCl salt, >1 mg/ml) and enhanced antileukemia potency might serve as a promising lead for further development.     

Synthesis and evaluation of novel benzimidazole derivatives as antimicrobial agents

Benzimidazole analogs bearing electron-withdrawing as well as electron-donating substituent were synthesized to achieve bioactive molecules with significant antimicrobial property. The desired compounds were prepared by multi-step synthesis process. The formation of intermediates and their corresponding derivatives (III _1–13 ) was confirmed by spectral characterization such as ¹H NMR, ¹³C NMR, mass spectra, IR, and elemental analysis. The compounds were screened for their antimicrobial properties against a broad panel of Gram-positive and Gram-negative bacteria as well as fungi. From the SAR study data, it was observed that the derivatives with electron-withdrawing functional groups were more bioactive than that with electron-donating functional groups.     

Synthesis and pharmacological evaluation of some novel 4-isopropyl thiazole-based sulfonyl derivatives as potent antimicrobial and antitubercular agents

A series of novel sulfonyl derivatives 3-(substituted benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-4-phenyl-4H-1,2,4-triazoles 4a–4e, isopropyl thiazole-derived schiff bases 8a–8l, and 2-(substituted benzylsulfonyl)-5-(4-isopropylthiazol-2-yl)-1,3,4-oxadiazoles 11a–11e were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, elemental, and mass spectral analysis. All the compounds exhibited moderate to significant antibacterial and antifungal activities. Results of the antitubercular screening against Mycobacterium tuberculosis H37Rv ascertain compounds 4e, 8b, and 8f as excellent antitubercular molecules, when compared with first line drug isoniazid (0.25 μg/mL).