Synthesis and biological evaluation of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thioglycosides

In the present study, the synthesis of 1, 3, 4-thiadiazole-based thioglycosides were accomplished in good yields with employing a convergent synthetic route. The starting material 5-amino-1, 3, 4-thiadiazole-2-thiol and followed by a series of 5-fatty-acylamido-1, 3, 4-thiadiazole-2-thiols (4a–4j) were synthesized with different fatty acid chlorides. The glycosylation of compounds 4a–4j were achieved with trichloroacetimidate methodology. Antimicrobial and cytotoxicity activities of title compounds were evaluated. Among the entire compounds lauric acid and myristic acid derivatives showed good and moderate antimicrobial activity. In case of cytotoxicity results of compounds 8a–8j and 9a–9j, the acetate protected short chain (C6:0, C8:0, C10:0) compounds and the free hydroxyl long chain saturated (C16:0, C18:0) and unsaturated (C18:1, C22:1) compounds exhibited good activity against different cancer cell lines. Further, the free hydroxyl compounds 9a, 9c–9j did not show any toxicity towards normal CHO-K1 cell line whereas acylated compounds 8a–8j exhibited toxicity.     

Synthesis and biological evaluation of 2',3'-didehydro-2',3'-dideoxy-9-deazaguanosine, a monophosphate prodrug and two analogues, 2',3'-dideoxy-9-deazaguanosine and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine

2',3'-Didehydro-2',3'-dideoxy-9-deazaguanosine (1), its monophosphate prodrug (2), and two analogues, 2',3'-dideoxy-9-deazaguanosine (3) and 2',3'-didehydro-2',3'-dideoxy-9-deazainosine (4), have been synthesized from benzoylated 9-deazaguanosine (5). Basic hydrolysis of 5, selective protection of the 2-amino and 5'-hydroxy functions with isobutyryl and silyl groups, respectively, followed by reaction with thiocarbonyldiimidazole gave the cyclic thiocarbonate, which, upon reaction with triethyl phosphite, followed by deprotection, afforded 1. Treatment of 1 with phenyl methoxyalaninylphosphochloridate and N-methylimidazole gave 2. Catalytic hydrogenation of 1 gave 3. Hydrodediazoniation of 1 with tert-butyl nitrite and tris(trimethylsilyl)silane gave 4. Compounds 1-4 were found to be inactive against the human immunodeficiency virus and exhibited minimal to no cytotoxic activity against the L1210 leukemia, CCRF-CEM lymphoblastic leukemia, and B16F10 melanoma in vitro.     

Prenatal developmental toxicity evaluation of 2',3'-dideoxyinosine (ddI) and 2',3'-didehydro-3'-deoxythymidine (d4T) co-administered to Swiss Albino (CD-1) mice

BACKGROUND: In pregnant women, antiretroviral drugs improve maternal health and reduce vertical transmission of human immunodeficiency virus to the infant. However, few nonclinical studies have examined the potential for adverse drug interactions. METHODS: On gestational days (GD) 6-16, mice were dosed with vehicle, ddI (360, 1440, or 2,880 mg/kg/day, p.o.), d4T (60, 240, or 480), or ddI/d4T combinations (360/60, 1,440/240, or 2,880/480). Daily doses were divided into two equal parts that were administered >or=6-hr apart. Body weight, clinical signs, and feed consumption were monitored. Pregnancies (22-24/group) were confirmed at necropsy. Maternal liver and gravid uterine weights (GUW), uterine implants (resorption, live or dead fetus), fetal body weight, gender, and morphologic anomalies (external, visceral, skeletal) were recorded. RESULTS: Maternal body weight, clinical signs, and GUW were unaffected. Maternal weight change corrected for GUW was greater than controls at 60 and 480 d4T. Relative feed consumption during treatment was increased relative to controls at 1,440 and 2,880 ddI and 2,880/480 ddI/d4T. Relative maternal liver weight was elevated above controls at 240 and 480 d4T and 2,880/480 ddI/d4T, and above the constituent dose of ddI at 1,440/240 and 2,880/480 ddI/d4T. Liver weight was not affected by ddI and there was no significant drug interaction. Prenatal mortality and morphologic anomalies were not increased. Fetal body weight showed only a decreasing trend for ddI/d4T, no effect for ddI or d4T, and no statistically significant drug interaction. CONCLUSIONS: In pregnant mice, ddI/d4T combinations were not associated with well-defined developmental toxicity or adverse drug interactions.     

Synthesis and antimycobacterial activity of isoniazid derivatives from renewable fatty acids

This work describes the synthesis of a series of fatty acid hydrazide derivatives of isoniazid (INH). The compounds were tested against Mycobacterium tuberculosis H37Rv (ATCC 27294) as well as INH-resistant (ATCC 35822 and 1896 HF) and rifampicin-resistant (ATCC 35338) M. tuberculosis strains. The fatty acid derivatives of INH showed high antimycobacterial potency against the studied strains, which is desirable for a pharmaceutical compound, suggesting that the increased lipophilicity of isoniazid plays an important role in its antimycobacterial activity.     

Synthesis and anti-HIV activity of 4'-cyano-2',3'-didehydro-3'-deoxythymidine

A new anti-HIV agent 4'-cyano-2',3'-didehydro-3'-deoxythymidine (9) was synthesized by allylic substitution of the 3',4'-unsaturated nucleoside 14, having a leaving group at the 2'-position, with cyanotrimethylsilane in the presence of SnCl4. Evaluation of the anti-HIV activity of 9 showed that this compound is much less potent than the recently reported 2',3'-didehydro-3'-deoxy-4'-(ethynyl)thymidine (1).     

Synthesis and antiviral activity of aryl phosphoramidate derivatives of beta-D- and beta-L-C-5-substituted 2',3'-didehydro-2',3'-dideoxy-uridine bearing linker arms

We have previously reported the synthesis and evaluation of potent anti-human immunodeficiency virus compounds based on beta-D-d4T analogues bearing a tether attached at the C-5 position and their beta-L-counterparts. Initial study revealed a requirement for an alkyl side-chain with an optimal length of 12 carbons for a weak antiviral activity. As a continuation of that work, we have now prepared the corresponding phosphoramidate derivatives as possible membrane-permeable prodrugs. Phosphorochloridate chemistry gave the target phosphoramidates which were tested for anti-human immunodeficiency virus type 1 activity; unfortunately, they were devoid of anti-HIV activity.     

Synthesis and biological evaluation of some 5-nitro- and 5-amino derivatives of 2'-deoxycytidine, 2',3'-dideoxyuridine, and 2',3'-dideoxycytidine

In this article, we describe the synthesis of 5-nitro-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)cytosine (4alpha), 5-nitro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)cytosine (4beta), 5-amino-1-(2-deoxy-alpha-D-erythro-pentofuranosyl)cytosine (5alpha), 5-nitro-1-(2-deoxy-beta-D-erythro-pentofuranosyl)cytosine (5beta), 5-nitro-1-(2,3-dideoxy-beta-D-ribofuranosyl)uracil (6beta), 5-amino-1-(2,3-dideoxy-alpha,beta-D-ribofuranosyl)uracil (7), 5-nitro-1-(2,3-dideoxy-alpha,beta-D-ribofuranosyl)cytosine (8) and 5-amino-1-(2,3-dideoxy-beta-D-ribofuranosyl)cytosine (9beta). The prepared compounds were tested for their activity against HIV and HBV viruses, but they did not show significant activity.     

Probing the allosteric activation of pyruvate carboxylase using 2',3'-O-(2,4,6-trinitrophenyl) adenosine 5'-triphosphate as a fluorescent mimic of the allosteric activator acetyl CoA

2′,3′-O-(2,4,6-Trinitrophenyl) adenosine 5′-triphosphate (TNP-ATP) is a fluorescent analogue of ATP. MgTNP-ATP was found to be an allosteric activator of pyruvate carboxylase that exhibits competition with acetyl CoA in activating the enzyme. There is no evidence that MgTNP-ATP binds to the MgATP substrate binding site of the enzyme. At concentrations above saturating, MgATP activates bicarbonate-dependent ATP cleavage, but inhibits the overall reaction. The fluorescence of MgTNP-ATP increases by about 2.5-fold upon binding to the enzyme and decreases on addition of saturating acetyl CoA. However, not all the MgTNP-ATP is displaced by acetyl CoA, or with a combination of saturating concentrations of MgATP and acetyl CoA. The kinetics of the binding of MgTNP-ATP to pyruvate carboxylase have been measured and shown to be triphasic, with the two fastest phases having pseudo first-order rate constants that are dependent on the concentration of MgTNP-ATP. The kinetics of displacement from the enzyme by acetyl CoA have been measured and also shown to be triphasic. A model of the binding process is proposed that links the kinetics of MgTNP-ATP binding to the allosteric activation of the enzyme.     

Synthesis and antimicrobial evaluation of carbohydrate and polyhydroxylated non-carbohydrate fatty acid ester and ether derivatives

A series of fatty acid ester and ether derivatives have been chemically synthesised based on carbohydrate and non-carbohydrate polyhydroxylated scaffolds. The synthesised compounds, along with their corresponding fatty acid monoglyceride antimicrobials, were evaluated for antimicrobial activity against Staphylococcus aureus and Escherichia coli. Of the derivatives synthesised, several of the carbohydrate-based compounds have antimicrobial efficacy comparable with commercially available antimicrobials. The results suggest that the nature of the carbohydrate core plays a role in the efficacy of carbohydrate fatty acid derivatives as antimicrobials.     

Synthesis and biological evaluation of novel indenopyrazole derivatives

A series of novel indenopyrazole derivatives 2a‐j and 3a‐j were synthesized from the reaction of 1‐(4‐(hydroxy(1‐oxo‐1,3‐dihydro‐2 H‐inden‐2‐ylidene)methyl)phenyl)‐3‐phenylurea derivatives 1a‐j with hydrazine and phenylhydrazine, respectively. The obtained novel indenopyrazoles ( 2a‐j and 3a‐j ) were evaluated for anticancer activity against HeLa and C6 cell lines. Antiproliferative activity was determined by the BrdU proliferation ELISA assay; 2a , 2b , 2d , 2h , and 3h were found to be the most active compounds. The compounds were also screened for antimicrobial activity, and all compounds showed moderate activity against used microorganisms.     

Synthesis and anti-HIV activity of some S-acyl-2-thioethyl (SATE) phosphoramidate derivatives of 3'-azido-2',3'-dideoxythymidine.

The synthesis and in vitro anti-HIV activity of tBuSATE phosphoramidate derivatives of AZT incorporating several methyl-esterified alpha-amino acids are reported. The biological evaluation strongly supports the hypothesis that such compounds exert their anti-HIV effects via intracellular delivery of the corresponding 5'-mononucleotide.     

Design,synthesis and biological evaluation of 3-benzyloxy-linked pyrimidinylphenylamine derivatives as potent HIV-1 NNRTIs

A novel series of 3-benzyloxy-linked pyrimidinylphenylamine derivatives (8a–8s) was designed, synthesized and evaluated for their in vitro anti-HIV activity in MT-4 cell cultures. Most of the compounds inhibited wild-type (wt) HIV-1 replication in the lower micromolar concentration range (EC₅₀ = 0.05–35 μM) with high selectivity index (SI) values (ranged from 10 to >4870). In particular, 8h and 8g displayed excellent antiretroviral activity against wt HIV-1 with low cytotoxicity (EC₅₀ = 0.07 μM, CC₅₀ >347 μM, SI >4870; EC₅₀ = 0.05 μM, CC₅₀ = 42 μM, SI = 777, respectively), comparable to that of the marked drug nevirapine (EC₅₀ = 0.113 μM, CC₅₀ >15 μM, SI >133). In order to confirm the binding target, 8h was selected to perform the anti-HIV-1 RT assay. Additionally, preliminary structure activity relationship (SAR) analysis and molecular docking studies of newly synthesized compounds were also discussed, as well as the predicted physicochemical properties.     

Synthesis and biological evaluation of arctigenin ester and ether derivatives as activators of AMPK

A series of new arctigenin and 9-deoxy-arctigenin derivatives bearing different ester and ether side chains at the phenolic hydroxyl positions are designed, synthesized, and evaluated for activating AMPK potency in L6 myoblasts. Initial biological evaluation indicates that some alkyl ester and phenethyl ether arctigenin derivatives display potential activities in AMPK phosphorylation improvement. Further structure–activity relationship analysis shows that arctigenin ester derivatives 3a, 3h and 9-deoxy-arctigenin phenethyl ether derivatives 6a, 6c, 6d activate AMPK more potently than arctigenin. Moreover, the 2-(3,4-dimethoxyphenyl)ethyl ether moiety of 6c has been demonstrated as a potential functional group to improve the effect of AMPK phosphorylation. The structural optimization of arctigenin leads to the identification of 6c as a promising lead compound that exhibits excellent activity in AMPK activation.     

Conjugates of 2',3'-didehydro-3'-deoxythymidine with thymogen. Synthesis and anti-HIV activity

An effective synthesis of thymogen was developed. Conjugates of 2',3'-didehydro-3'-deoxythymidine (nucleoside d4T) with thymogen were prepared in which the nucleoside hydroxyl group was linked to the thymogen carboxyl group of either tryprophan or glutamic acid residues. It was shown that the anti-HIV activity of the d4T-thymogene conjugate with the tryptophan linkage was comparable to that of d4T, whereas its cytotoxicity was nil. The d4T-tryptophan conjugate also displayed high anti-HIV activity.