Synthesis and evaluation of A-seco type triterpenoids for anti-HIV-1protease activity

2,3-Seco-dioic acids derived from four different triterpene skeletons were prepared and evaluated for their anti-HIV-1 protease activity. Two A-seco derivatives showed potent inhibitory activity against HIV-1 protease (3c and 3e, IC₅₀ 5.7 and 3.9 μM, respectively), while four other derivatives showed moderate to weak inhibition (3a, 3b, 3d and 3f, IC₅₀ 15.7–88.1 μM). The combination of a 2,3-seco-2,3-dioic acid functional group in ring A and a free acid group at C-28 or C-30 significantly enhanced HIV-1 protease inhibitory activity (3a, 3c–3e, IC₅₀ 3.9–17.6 μM). On the other hand, all A-seco derivatives were found to be very weak inhibitors of HCV, renin and trypsin proteases (IC₅₀ > 80 μM). These findings indicate that A-seco triterpenes with a carboxyl group at C-28 or C-30 are novel and highly selective HIV-1 protease inhibitors.     

Novel modified steroid derivatives of androstanolone as chemotherapeutic anti-cancer agents

The aim of the present study is to synthesize and evaluate new potential chemotherapeutic anti-tumor agents. Several thiazolo-, pyrido-, pyrano- and lactam steroid derivatives were obtained using 17β-hydroxy-5α-androstan-3-one (androstanolone) 1 as starting steroid. The structure of the novel steroid derivatives was confirmed using the analytical and spectral data. The most pure and structurally promising compounds 7a, 10a, 12b, 18 and 23 were evaluated as anti-tumor agents. The in vitro cytotoxic activity was evaluated against hepatoma cell lines using MTT assay. Also the in vivo anti-tumor activity was evaluated against Ehrlich ascites carcinoma (EAC). The results of the in vitro study showed that at incubation time 72 h, in olive oil, compound 7a was the most effective cytotoxic compound with IC₅₀ of 30 μM, while the effects of compounds 18 and 23 were approximately similar with IC₅₀ of 37 μM and 35 μM respectively. While the tested compounds when dissolved in DMSO showed approximately the same IC₅₀ at both 48 and 72 h incubation period, compound 23 was the most effective cytotoxic with IC₅₀ 42 μM at 48 h and 40 μM at 72 h. The results of the in vivo study showed that all the tested novel compounds at 25 mg/kg were effective against EAC. Our novel steroid derivatives are promising candidates as anti-cancer agents, none of the mice treated with our novel derivatives showed any toxic symptoms, but they also completely inhibited tumor growth and retained the hemoglobin content, body weight, and WBCs near normal values and similar to what obtained for the standard drug 5-flurouracil.     

New pyridone, thioxopyridine, pyrazolopyridine and pyridine derivatives that modulate inflammatory mediators in stimulated RAW 264.7 murine macrophage

The reaction of 2-acetyl-5,6,7,8-tetrahydronaphthalene 1 with some aldehydes was conducted in the presence of ethyl cyanoacetate and ammonium acetate, yielded the cyanopyridones 2a–c, which react with phosphorous pentasulphide to afford the corresponding thioxopyridine derivatives 3a–c, respectively. Compounds 2a,b were converted to 2-chloropyridine derivatives 4a,b by heating with phosphorous oxychloride and phosphorous pentachloride, which were fused with hydrazine hydrate and benzyl amine to afford the corresponding pyrazolopyridine 5a,b and cyanopyridine derivatives 6a,b respectively. Compounds 2a,b also afforded 3-cyanopyridinyl oxy acetic acid ethyl ester 7a,b by reaction with ethyl bromoacetate in dry acetone in the presence of anhydrous potassium carbonate, which upon condensation with hydrazine hydrate gave the corresponding acid hydrazide 8a,b and with benzyl amine gave the corresponding acetamide 9a,b. We investigated the effect of those new compounds on the macrophage growth, macrophage binding affinity to fluorescein isothiocyanate-conjugated bacterial lipoopolysaccharide (FITC-LPS), phagocytosis of FITC-zymosan, and radical scavenging affinity against OH, ROO, and O₂⁻, in addition to their influence of the inflammatory mediators [nitric oxide (NO), tumor necrosis factor-α (TNF-α), prostaglandin E-2 (PGE-2), cycloxygenase-2 (COX-2), and 5-lipoxygenase (5-LO)] in LPS-stimulated macrophages. The findings revealed that the derivatives 2b, 3b, 5a, 7b, 9a and 9b can be recognized as promising multi-potent anti-inflammatory agents.     

Synthesis of 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines as novel analgesic/anti-inflammatory compounds

In this study, a new class of 4-amino-3-substituted-1,2,4-triazole-5-thiones (1–4) and their corresponding condensed derivatives 3,6-disubstituted 7H-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazines (1a–4c) were synthesized and evaluated for their analgesic/anti-inflammatory activities. All synthesized compounds were also tested for their gastric toxicity and antioxidant activity on acute administration. Most of the compounds showed significant activity in both carrageenan-induced oedema and acetic acid-induced writhing tests besides negligible gastrointestinal toxicity. The compounds showing less ulcerogenic effect also showed less lipid peroxidation (LPO) level. Most promising results were obtained with the compounds that placed a fluoro or a chloride on the phenyl ring at the sixth position of the fused ring.     

Synthesis of novel bioactive derivatives of 3-(4-chlorophenyl)-2-hydrazino-5,6,7,8-tetrahydrobenzo(b)thieno[2,3-d]pyrimidine-4(3H)-ones

A series of triazolo[4,3-a]tetrahydrobenzo(b)thieno[3,2-e]pyrimidine-5(4H)-ones (12a–n) were synthesized and evaluated for CNS depressant, skeletal muscle relaxant and anticonvulsant activities by photoactometer, Rotarod and pentylenetetrazole induced the convulsions method respectively in Swiss albino mice. Diazepam was used as standard drug. The five derivatives 12b, 12c, 12d, 12i and 12m showed the CNS depressant and skeletal muscle relaxant activities comparable to those of diazepam at a dose of 5 mg/kg. These derivatives also exhibited good activity when tested for anticonvulsant activity in mice at different dose levels. The ED₅₀ values for these derivatives are in the range of 4.40–9.33 mg/kg.     

Structure–activity relationship of dopaminergic halogenated 1-benzyl-tetrahydroisoquinoline derivatives

Two series of halogenated 1-benzyl-7-chloro-6-hydroxy-tetrahydroisoquinolines were prepared to explore the influence of each series on the affinity for dopamine receptors. All the compounds displayed a high affinity for D₁-like and/or D₂-like dopamine receptors in striatal membranes, although they were unable to inhibit [³H]-dopamine uptake in striatal synaptosomes. The halogen placed on the benzylic ring in 1-benzyl-THIQs, compounds of the series 1, 2′-bromobenzyl derivatives with K_i values into the nanomolar range, and the series 2, 2′,4′-dichlorobenzyl-THIQ homologues, proves to be an important factor to modulate affinity at dopamine receptor.     

Synthesis, antimicrobial, antioxidant, anti-hemolytic and cytotoxic evaluation of new imidazole-based heterocycles

In the present work, 1-(5-methyl-2-phenyl-1H-imidazol-4-yl)ethanone 1 was prepared and used as a precursor for the synthesis of new thiazole, arylidiene and coumarin derivatives. The antimicrobial, antioxidant, anti-hemolytic, and cytotoxic activities of new compounds have been screened. Compound 12 showed an excellent antibacterial activity for all the tested bacteria with minimal inhibitory concentration (MIC) ranged between 21.9 and 43.8 μg/mL. While, compounds 2, 8 and 10a were the best antioxidant reagents using the DPPH method. Compounds 6a and 10b proved to exhibit potent antioxidative activity as reflected in the ability to inhibit lipid per-oxidation in rat brain and kidney homogenates and rate erythrocyte hemolysis. Compounds 6a proved to have the highest cytotoxic activity (81.9%) followed by 2, 6c, 7b and 12 using in vitro Ehrlich ascites assay. The details synthetic methods, spectroscopic data and biological results are recorded.     

Synthesis and antimycobacterial activity of some isonicotinoylhydrazones

Aseries of isonicotinoylhydrazones 2 were prepared by addition of some aryloxyacetonitriles with isonicotinoylhydrazine in basic medium. These compounds have been further reacted with pyridinecarboxaldehydes to give the corresponding pyridylmethyleneamino derivatives 3–5. The new synthesized hydrazones and their pyridylmethyleneamino derivatives were tested for their activity against mycobacteria, Gram-positive and Gram-negative bacteria. The cytotoxicity was also tested. Several compounds showed a good activity against Mycobacterium tuberculosis H37Rv and some isonycotinoylhydrazones 2 showed a moderate activity against a clinically isolated M. tuberculosis which was isoniazid resistant.     

Synthesis and evaluation of in vivo activity of diphenylhydantoin basic derivatives

During the search for antiarrhythmic agents among amide derivatives of phenytoin, compound 7 3-ethyl-1-[2-hydroxy-3-(4-phenyl-piperazin-1-yl)-propyl]-2,4-dioxo-5,5-diphenyl-imidazolidine was selected as it showed antiarrhythmic as well as antihypertensive activity. Treating this compound as a lead, new derivatives 8–19 were synthesised, differing in piperazine phenyl ring substitution (2-, 3-, 4-Cl, 2-CH₃O) as well as in hydantoin N₃ alkyl chain (ethyl, ethyl acetate or ethyl 2-propionate). The obtained compounds in form of hydrochlorides 7a–19a were examined for prophylactic antiarrhythmic and antihypertensive properties. Compounds containing ethyl 2-propionate moiety (17a, 18a) exhibited the highest antihypertensive properties. Water-soluble compounds, containing 2-methoxyphenylpiperazine group (11a, 19a), showed strong antiarrhythmic properties in adrenaline-induced arrhythmia; compound 9a 1-[3-(4-(3-chloro-phenyl)-piperazin-1-yl)- 2-hydroxy-propyl]- 3-ethyl-2,4-dioxo-5,5-diphenyl-imidazolidine hydrochloride exhibited the highest antiarrhythmic activity in barium chloride arrhythmia model.     

Synthesis and antiproliferative activity of novel symmetrical alkylthio- and alkylseleno-imidocarbamates

The study described here concerns the synthesis of a series of thirty new symmetrically substituted imidothiocarbamate and imidoselenocarbamate derivatives and their evaluation for antitumoral activity in vitro against a panel of five human tumor cell lines: breast adenocarcinoma (MCF-7), colon carcinoma (HT-29), lymphocytic leukemia (K-562), hepatocarcinoma (Hep-G2), prostate cancer (PC-3) and one non-malignant mammary gland-derived cell line (MCF-10A). The GI₅₀ values for eighteen of the compounds were below 10 μM in at least one cell line. Two cancer cells (MCF-7 and HT-29) proved to be the most sensitive to five compounds (1b, 2b, 3b, 4b and 5b), with growth inhibition in the nanomolar range, and compounds 1b, 3b, 7b, 8b and 9b gave values of less than 1 μM. In addition, all of the aforementioned compounds exhibited lower GI₅₀ values than some of the standard chemotherapeutic drugs used as references. The results also reveal that the nature of the aliphatic chain (methyl is better than benzyl) at the selenium position and the nature of the heteroatom (Se better than S) have a marked influence on the antiproliferative activity of the compounds. These findings reinforce our earlier hypothesis concerning the determinant role of the selenomethyl group as a scaffold for the biological activity of this type of compound. Considering both the cytotoxic parameters and the selectivity index (which was compared in MCF-7 and MCF-10A cells), compounds 2b and 8b (with a selenomethyl moiety) displayed the best profiles, with GI₅₀ values ranging from 0.34 nM to 6.07 μM in the five cell lines tested.Therefore, compounds 2b and 8b were evaluated by flow cytometric analysis for their effects on cell cycle distribution and apoptosis in MCF-7 cells. 2b was the most active, with an apoptogenic effect similar to camptothecin, which was used as a positive control. Both of them provoked cell cycle arrest leading to the accumulation of cells in either G₂/M and S phase.These two compounds can therefore be considered as the most promising candidates for the development of novel generations of antitumor agents.     

Imidazo[2,1-b]benzothiazoles 3: syntheses and immunosuppressive activities of 2-(m-acyloxyphenyl)imidazo[2,1-b]benzothiazoles

A series of acyl derivatives of 2-(m-hydroxyphenyl)imidazo[2,1-b]benzothiazole 2, a selective immunosuppressive agent for delayed type hypersensitivity (DTH), was prepared and tested for its suppressive activity of DTH in mice after oral administration. Six compounds 3e, f, k, n, p and q were found to be more potent immunosuppressive agents than 2 but they showed no effect on humoral immunity as in the case of 2.     

Synthesis of substituted 3-amino-N-phenyl-1H-indazole-1-carboxamides endowed with antiproliferative activity

Several new N-phenyl-1H-indazole-1-carboxamides 1c-h and 4l,m were prepared by reacting phenyl isocyanate derivatives 3a,b with 3-amino-1H-indazole derivatives 2c,e,g or 1H-indazole 2l respectively. Chemical transformations of compounds 1a,b and 1g,h gave 3-acetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 5a,b, and 3,5-diamino-N-phenyl-1H-indazole-1-carboxamide derivatives 4i, j respectively. Finally, 3,5-diacetamido-N-phenyl-1H-indazole-1-carboxamide derivatives 6a,b were prepared by acetylation of 4i, j. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell lines panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). Compound 1c, the most active of the series, was able to inhibit cell growth showing GI₅₀ values in the 0.041-33.6 μM range, mean GI₅₀ 1.90 μM, being very effective against colon and melanoma cell lines. Cell cycle analysis in K562 cells showed that 1c causes a marked increase of cells in G0-G1 phase. Moreover, it increases the ratio between hypophosphorylated pRb and total pRb.     

Synthesis of new 4-isopropylthiazole hydrazide analogs and some derived clubbed triazole, oxadiazole ring systems – A novel class of potential antibacterial, antifungal and antitubercular agents

In the present study a series of 4-isopropylthiazole-2-carbohydrazide analogs, derived clubbed oxadiazole–thiazole and triazole–thiazole derivatives have been synthesized and characterized by IR, ¹H NMR, ¹³C NMR, elemental and mass spectral analyses. The synthesized compounds were evaluated for their preliminary in vitro antibacterial, antifungal and antitubercular activity against Mycobacterium tuberculosis H₃₇Rv strain by broth dilution assay method.The synthesized compounds 7a, 7b, 7d and 4 showed an antitubercular efficacy considerably greater than that of the parent 4-isopropyl-1,3-thiazole-2-carbohydrazide 1, suggesting that the substituted 4-isopropylthiazole-2-carbohydrazide moiety plays an important role in enhancing the antitubercular properties of this class of compounds. Compounds 2c, 3, 4, 6d, 7a and 7b exhibited good or moderate antibacterial and antifungal activity. Compounds 4 and 7b showed appreciable cytotoxicity at a concentration of 250 μM.     

3-(Methyleneaminoxy)methylpiperidine derivatives as uptake inhibitors of biogenic amines in the brain synaptosomal fraction

A series of 3-(methyleneaminoxy)methylpiperidines (5a–h) and their corresponding N-methyl derivatives (6a–h) with a variety of substituents on the imino carbon were synthesized and tested for their potential antidepressant properties; their capacity to inhibit the re-uptake of biogenic amines (NA, 5-HT and DA) in rabbit brain synaptosomal fractions was also evaluated. The biological results obtained for the piperidine derivatives 5a–h and 6a–h and viloxazine 1, the reference drug, on the 3 re-uptake systems revealed that compounds 5 and 6 are generally able to inhibit biogenic amine uptake. The IC₅₀ values for 5 and 6 were often lower than that of viloxazine 1, in particular for the serotonin- and/or dopamine-uptake systems. A higher activity was found for compounds substituted with at least one phenyl ring on the imino carbon with respect to completely aliphatic systems, and for N-unsubstituted compounds with respect to N-methyl-substituted compounds.     

Pentacyclo-undecane derived cyclic tetra-amines: Synthesis and evaluation as potent anti-tuberculosis agents

As part of an ongoing effort to develop highly potent anti-tuberculosis agents, fourteen pentacyclo-undecane (PCU) tetra-amine compounds were synthesized and screened for their in vitro anti-mycobacterial activity against two TB strains, H37Rv and XDR 194 [an extensively drug-resistant strain of tuberculosis]. Using the broth macrodilution method, nitrofuranylamide based compounds (6a and 6b) showed almost similar activities against the H37Rv strain of Mycobacterium tuberculosis when compared with the control drug, ethambutol. N-Geranyl piperazine PCU (8a) and trans–trans farnesyl piperazine PCU (8b) were 3.2 and 3.7 times more potent than commercially available ethambutol. Both isoprenyl PCU tetra-amine derivatives and N-decyl piperazine PCU (9a) were highly active against the XDR 194 strain of tuberculosis with MICs in the range of 0.63–3.02 μM. Cytotoxicities (IC₅₀) of isoprenyl based compounds (8a, 8b) and compound 9a were tested on a mammalian cell line [MDBK (Madin Darby bovine kidney epithelium)] with values of 30, 24 and 25 μM respectively.     

Synthesis and pharmacological evaluations of novel 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives as a new class of anti-cancer agents

The synthesis of novel 2H-benzo[b][1,4]oxazin-3(4H)-one derivatives has been carried out using trifluoroacetic anhydride/phosphoric acid mediated C-C bond forming reaction as a key step. This method does not require the use of environmentally harmful AlCl₃ or moisture sensitive acid chloride. A number of compounds containing the benzooxazinone moiety attached to a five-membered central heterocyclic ring was synthesized and tested for their anti-cancer properties in vitro against three cell lines e.g. A549 (lung), DLD-1 (colorectal adenocarcinoma) and MV4-11 (acute myeloid leukemia). Some of them showed anti-cancer activities along with a number of reference compounds tested. Few of them showed promising anti-leukemic properties. A brief Structure-Activity-Relationship study within the series is presented. An imidazole derivative 9c containing benzene ring with a para-CF₃ group at C-2 position was identified as a potent anti-leukemic agent.     

Synthesis, in vitro antimicrobial and in vivo antitumor evaluation of novel pyrimidoquinolines and its nucleoside derivatives

Seven series of pyrimidoquinoline derivatives have been synthesized, tetrazolo[4′,3′:-1,2]pyrimido[4,5-b]quinoline (3), 2-aminopyrimido[4,5-b]quinoline (4), triazolo[4′,3′:1,2]-pyrimidoquinoline (5a,b, 10), imidazolo[3′,2′:1,2]pyrimido[4,5-b]-quinoline (8a,b), 6-chloro-2-methylthiopyrimido[4,5-b]quinoline (12), acetylated nucleosides (16, 17a,b) and deacetylated nucleosides (18, 19a,b). Some of the novel pyrimidoquinoline derivatives possess highly activity toward the bacteria and fungi species. The new quinolines derivatives were evaluated for their anticancer activity toward human cancer cell lines by the National Cancer Institute (NCI). Most of them had excellent growth inhibition activity, having LD₅₀ values in the low micromolar to nanomolar concentration range.     

Curcumin analogues as possible anti-proliferative & anti-inflammatory agents

A series of novel curcumin analogues has been designed, synthesized and tested in vitro/in vivo as potential multi-target agents. Their anti-proliferative and anti-inflammatory activities were studied. Compounds 1b and 2b were stronger inhibitors of soybean lipoxygenase (LOX) than curcumin. Analogue 1b was also the most potent aldose reductase (ALR2) inhibitor. Two compounds, (1a and 1f) exhibited in vivo anti-inflammatory activity comparable to that of indomethacin, whereas derivative 1i exhibited even higher activity. The derivatives were also tested for their anti-proliferative activity using three different human cancer cell lines. Compounds 1a, 1b, 1d and 2b exhibited significant growth inhibitory activity as compared to curcumin, against all three cancer cell lines. Lipophilicity was determined as R_M values using RPTLC and theoretically. The results are discussed in terms of the structural characteristics of the compounds. Docking simulations were performed on LOX and ALR2 inhibitor 1b and curcumin. Compound 1b is well fitted in the active site of ALR2, binding to the ALR2 enzyme in a similar way to curcumin. Allosteric interactions may govern the LOX-inhibitor binding.     

Synthesis and calcium channel antagonist activity of dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylates

Reaction of dialkyl 1′,4′-dihydro-2′,6′-dimethyl[bipyridine]-3′,5′-dicarboxylates 2 with methyl iodide yielded the corresponding 4′-(1-methylpyridinium) iodide salts 3 in quantitative yield. The sodium borohydride reduction of 3 in aqueous ethanol gave the corresponding dialkyl hexahydro-1,2′,6′-trimethyl[bipyridine]-3′,5′-dicarboxylate analogs 4–5. The calcium channel antagonist activities for 4–5 were determined using the muscarinic receptor-mediated Ca²⁺-dependent contraction of guinea pig ileal longitudinal smooth muscle. The relative activities for the 3′,5′-diethyl series 5 was 3-tetrahydropyridinyl 5b > 4-tetrahydropyridinyl 5c > 2-tetrahydropyridinyl 5a. Increasing the size of the 3′,5′-alkyl substituents enhanced activity. An approximate 1:1 correlation between the IC₅₀ value for the inhibition of [³H]nitrendipine binding and inhibition of the tonic component of the muscarinic-induced contractile response was observed for 4a and 5b. NMR studies suggest that the 4′-[2-(1-methyl-1,2,3,6-tetrahydropyridinyl)] ring systems of 4a and 5a are anti-periplanar to the 1,4-dihydropyridine ring system.     

Inhibition of neutrophil O2 production by unsymmetrical methylene derivatives of benzopyrans: their use as potential antiinflammatory agents

Some unsymmetrical derivatives of benzopyrans 9 were synthesized and tested to verify their PKC inhibitory activity. For this purpose, the Mannich bases of 7-hydroxycoumarins 6 were treated with 2-(dialkylamino)benzopyran-4-ones or 3-(dialkylamino)naphtho[2,1-b]pyran-1-ones 8 in the presence of acetic or propionic anhydride, yielding compounds 9. Human neutrophils stimulated with either PMA and f-MLF were used as the cellular model. The efficiency of the compounds 9 was established on their capacity to reduce the O₂⁻ production by activated human neutrophils. Compounds 9d and 9f, bearing an acetoxy group in position 7 of the chromone moiety, seem to counteract the neutrophil activation efficiently.