Synthetic iminosugar derivatives as new potential immunosuppressive agents

Several iminosugar derivatives were synthesized, and their effects on the secretion of IL-4 and IFN-gamma from the mouse splenocytes were examined. The effects on membrane expression of other T cell-associated molecules (CD3, CD4, CD8) and B cell-associated molecules (CD19) were also investigated. The experimental data demonstrated that synthetic iminosugars hold potential as immunosuppressive agents.     

Synthesis of new indazole derivatives as potential antioxidant agents

New indazole derivatives were synthesized by reacting hydrazine hydrate and its derivatives with cyclohexenone derivatives, which in turn prepared from respective chalcones. The chemical structure of newly synthesized compounds was well characterized by using ¹H NMR, ¹³C NMR, IR and mass spectral data. All the synthesized products were screened for their antioxidant properties. All indazole derivatives exhibited noticeable DPPH radical scavenging activity, reducing power capacity and total antioxidant capacity in comparison with the respective standards.     

Synthesis of new benzimidazole derivatives as potential antimicrobial agents.

Barbiturates 3 as possible antimicrobial agents were obtained by reacting the N,N'-disubstituted urea 1a or the thiourea analogues 1b,c with the magic malonates 2a,b. On the other hand, reaction of 1a with ethoxycarbonyl isocyanate (4) yielded the substituted s-triazine-2,4,6(1H,3H,5H)-trione 5. The reaction of 4 with 2-aminomethyl-benzimidazole (6) gave the allophanate 7 which upon treatment with Na2CO3 yielded N-(1H-benzimidazol-2-yl)urea 8.     

Synthesis and evaluation of new triazolobenzothiazole derivatives as potential anti-tubercular agents

A series of sulfonamides and S-benzyl derivatives of substituted/unsubstituted S-triazolo-(3,4,-b)-benzothiazole-3-thiones were synthesized. These triazolobenzolobenzothiazole derivatives were evaluated for antitubercular activity against H37Rv strain of Mycobacterium tuberculosis. A number of promising compounds have been obtained.     

Quinolizidine derivatives as potential antitumoral agents

The activity against lymphocytic leukemia P 388 has been evaluated for thirteen compounds bearing a quinolizidine moiety bound respectively to a phenothiazine nucleus or other isosteric tricyclic systems (12-17), as well to a quinoxalinone (18-20) or an indole (21-24) nucleus. All tested compounds resulted inactive.     

Distamycin derivatives as potential anticancer agents

Distamycin A was used as DNA minor groove sequence-selective vector of alkylating functions and led to the synthesis of compounds endowed with relevant cytotoxic and antitumor activity. In particular, tallimustine (Pharmacia), a benzoic acid nitrogen mustard derivative of distamycin, showed excellent antitumor activity against murine transplanted solid tumors and human xenografts, and, in the early 1990s, prompted several groups to search for new cytotoxic agents derived from distamycin. Unfortunately, tallimustine showed severe myelotoxicity and its clinical development was discontinued. Nevertheless this compound has represented an important model for the design of new cytotoxic minor groove binders derived from distamycin and distamycin-like frames. Some recently reported derivatives of distamycin-like frames with high cytotoxicity and antitumor activity also show significantly improved cytotoxicity/myelotoxicity ratio, which promises drugs with clinical efficacy. Distamycin-derived cytotoxics have been extensively reviewed in the recent past. This review will focus on cytotoxics derived structurally from distamycin or distamycin-like frames disclosed between 1997 and the third quarter of 2000.     

Synthesis of new quinoline-2-pyrazoline-based thiazolinone derivatives as potential antimicrobial agents

A series of 2-(5-(2-chloro-6-methylquinolin-3-yl)-3-(aryl)-4,5-dihydro-1H-pyrazol-1-yl)thiazol-4(5H)ones (4a–l) were synthesized and characterized by IR, ¹H NMR, ¹³C NMR, and mass spectra. All the synthesized compounds were tested for their in vitro antimicrobial activity against Escherichia coli (MTCC 443), Pseudomonas aeruginosa (MTCC 1688), Staphylococcus aureus (MTCC 96), Streptococcus pyogenes (MTCC 442), Candida albicans (MTCC 227), Aspergillus niger (MTCC 282), and Aspergillus clavatus (MTCC 1323) by serial broth dilution. Compounds 4e, 4f, 4g, 4i, 4j, and 4l were the most distinctive derivatives identified in present study because of their remarkable in vitro antimicrobial potency.     

Synthesis of some new benzothiazole derivatives as potential antimicrobial and antiparasitic agents

Several thiazolidinonyl benzothiazoles 8a-b and thiazolinylbenzothiazoles 9a-j were synthesized by the reaction of 2-(N-substituted thiocarbamoyl hydrazino) benzothiazoles 7a-d with chloroacetic acid or phenacyl bromide respectively. The intermediate compounds 7a-d were prepared in a good yield by the reaction of 2-hydrazinobenzothiazole (6) with phenylisothiocyanates. Synthesis of hydrazones 10a-c were performed by the reaction of 6 with the corresponding aldehydes. Trials to cyclize the obtained hydrazones 10a-c into the corresponding triazolo derivatives 11a-c were unsuccessful. Addition of 4-morphylino carbonyl chloride to compound 6 yielded the corresponding 2-acid hydrazide derivative 12. Some of the prepared compounds were screened for their anti-parasitic activity. Most of them showed reasonable antinematodal or schistosomicidal activity. In addition, antimicrobial screening of all of the prepared new compounds was performed against Staphylococcus aeurus ATCC 6538, Escherichia coli ATCC 8735 and Candida albicans ATCC 10321 but non of them was active.     

Antiproliferative and apoptotic activity of new indazole derivatives as potential anticancer agents

To develop potent and selective anticancer agents, a series of novel polysubstituted indazoles was synthesized and evaluated for their in vitro antiproliferative and apoptotic activities against two selected human cancer cell lines (A2780 and A549). Several compounds showed an interesting antiproliferative activity, with IC₅₀ values ranging from 0.64 to 17 µM against both cell lines. The most active indazoles were then tested in different pharmacological dilution conditions, adding five new cell lines (A2780, A549, IMR32, MDA-MB-231, and T47D) as targets, confirming their antiproliferative activity. Furthermore, selected compounds were able to trigger apoptosis to a significant extent and to cause, in part, a block of cells in the S phase of the cell cycle, with a concomitant decrease of cells in the G2/M and/or G0/G1 phases and the generation of hypodiploid peaks. However, molecule 7d caused a great increase of cells in G2/M and the appearance of polyploid cells. Altogether, our results suggest a good pharmacological activity for our selected polysubstituted indazoles, which are suggestive of a preferential mechanism of action as cell cycle-specific antimetabolites or as an inhibitor of enzyme activities involved in DNA synthesis, except for 7d , which, on the contrary, seems to have a mechanism involving the microtubule system.     

Pyrimidoacridine derivatives as potential antitumor agents.

A series of some N-alkylaminoalkyl derivatives of pyrimido[5,6,1-d,e]acridine-1,3,7-trione (3) was synthesized as new potential antitumor drugs, starting from the suitable 9,10-dihydro-9-oxo-4-acridinecarboxamides and using phosgene as cyclizing agent. 1-(9,10-dihydro-9-oxo-4-acridinecarbonyl)-3-alkyl-2-imidazolido nes were also obtained as side products. The final products 3 and some carboxamides were tested "in vitro" against L 1210 leukemia and "in vivo" against P388 leukemia. Of the tested compounds, one is active "in vivo", another shows significant cytotoxic activity "in vitro", but is inactive or toxic "in vivo".     

New pyridine derivatives as potential antimicrobial agents

A set of pyridine derivatives bearing a substituted alkylthio chain or a piperidyl ring in position 2 or 4 were synthesized, and their antimycobacterial and antifugal activities were evaluated. Chemical structures were confirmed by IR and NMR data, and by elemental analysis. Minimum inhibitory concentrations (MIC) were used for the evaluation of microbiological activity in vitro. The compounds were moderately active against both Mycobacterium tuberculosis and nontuberculous mycobacteria. The most active compound was 2-cyanomethylthiopyridine-4-carbonitrile (7) with MIC against Mycobacterium kansasii in the range of 8-4 mumol/l. The antifungal activities of the compounds were relatively low.     

Synthesis and study of some new N-substituted imide derivatives as potential anticancer agents

A new series of N-substituted imide derivatives have been synthesized by treating phthalic anhydride, naphthalic anhydride and their substituted derivatives with 2-hydrazino-1-imidazoline hydrobromide, various para-substituted aryl amines, aminoglutethimide and 2,4-dinitrophenyl hydrazine. Compounds 9, 10, 12, 18, 19, 23, 24 and 34-36 have been selected and screened for antineoplastic activity by National Cancer Institute, Bethesda, USA. Some newer aminoglutethimide derivatives 37-39 have also been prepared in order to study the effect of N-substitution on its pharmacological profile for the treatment of carcinoma. These compounds (37-39) have exhibited weak inhibition of human placental aromatase as compared to aminoglutethimide.     

Carbamate derivatives of felbamate as potential anticonvulsant agents

Several monocarbamate compounds derived from felbamate were synthesized and 11 target compounds (1, 4, and 6–14) were initially evaluated in mice MES and PTZ models in our laboratory. Carbamate compounds with varying substituents on the oxygen (1–4) gave anticonvulsant activity with a wide range of ED₅₀ in MES test from <20 mg/kg (2) to >300 mg/kg (4) and compounds with different groups on the nitrogen (5–14) also were quite active in the range of 15 mg/kg (14) to 170.5 mg/kg (6). This suggested that the spatial limitation in the MES model seemed flexible especially on the nitrogen end. All tested compounds showed some activity against mice scPTZ test, but none had the ED₅₀ value <50 mg/kg. Ten selected compounds (1 and 6–14) for subsequent pharmacological evaluation in NIH all gave positive mice MES activity except 8 and 9, which were unexpectedly active in rats after further evaluations. Among the compounds, 1, 8, and 9 advanced to the quantitative study and 1 and 9 provided the highest PI values, 15 and 21, respectively, in the rat oral MES test.     

Synthesis of alkyloxybenzamide derivatives as potential antimicrobial agents

Three series of alkyloxybenzamido derivatives have been prepared. The first comprises N1-[4-(4-alkyloxybenzamido)benzoyl]-N2-substituted alkylidene hydrazine, the second involves 1-[4-(4-alkyloxybenzamido)benzoyl]-4-alkyl, aryl, or aralkyl-3-thiosemicarbazides, and the third includes 1-substituted-5-[4-(4-alkyloxybenzamido)phenyl]-1,3,4-triazole-2-t hione. Representative samples of the prepared compounds were tested for their in-vitro antimicrobial activity.     

Synthesis of benzimidazole derivatives as potential antimicrobial agents

Three novel series of benzimidazol derivatives were prepared. Namely; 2-alkyl-1-(4-substituted-4H-1,2,4-triazole-5-thion-3-yl)methylb enzimidazoles; 2-alkyl-1-(5-substituted amino-1,3,4-thiadiazol-2-yl)methylbenzimidazoles; and 2-alkyl-1-[(3,4-disubstituted thiazolin-2-ylidene)hydrazinocarbonyl] methylbenzimidazoles. The antimicrobial testing of the prepared compounds as well as of the key intermediate thiosemicarbazides was performed.