ABSTRACT
Background: Schiff bases are synthetically accessible compounds that have been used in medicinal chemistry. Methods & results: In this work, 27 Schiff bases derived from diaminomaleonitrile were synthesized in high yields (80-98%). Molecular docking studies suggested that the Schiff bases interact with the catalytic site of cruzain. The most active cruzain inhibitor, analog 13 (IC50 = 263 nM), was predicted to form an additional hydrophobic contact with Met68 in the binding site of the enzyme. A strong correlation between the IC50 values and ChemScore binding energies was observed (R = 0.99). Kernel-based 2D quantitative structure-activity relationship models for the whole dataset yielded sound correlation coefficients (R2 = 0.844; Q2 = 0.719). Conclusion: These novel and potent cruzain inhibitors are worthwhile starting points in further Chagas disease drug discovery programs.
Subject(s)
Chagas Disease/drug therapy , Diamines/pharmacology , Nitriles/pharmacology , Trypanocidal Agents/pharmacology , Trypanosoma cruzi/drug effects , Diamines/chemical synthesis , Diamines/chemistry , Molecular Docking Simulation , Molecular Structure , Nitriles/chemical synthesis , Nitriles/chemistry , Quantitative Structure-Activity Relationship , Schiff Bases/chemical synthesis , Schiff Bases/chemistry , Schiff Bases/pharmacology , Trypanocidal Agents/chemical synthesis , Trypanocidal Agents/chemistryABSTRACT
We report the synthesis of a series of diaminated terpenoids containing, as side-chain of the diamine core, the "head-to-tail" prenyl derivatives, with amino amino spacers of variable length. In vitro biological activity of these compounds was evaluated against Mycobacterium tuberculosis and Leishmania amazonensis, and the structure-activity relationships are discussed. Different biological results were observed depending on the terpenic side-chain length. The best results were obtained for trans,trans-farnesol derivatives. Moreover, these results demonstrated that the stereochemistry of the double bond could play an important role in determining antitubercular and antileishmanial activities of these compounds.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Antitubercular Agents/chemical synthesis , Antitubercular Agents/pharmacology , Diamines/chemical synthesis , Diamines/pharmacology , Leishmania mexicana/drug effects , Mycobacterium tuberculosis/drug effects , Terpenes/chemical synthesis , Terpenes/pharmacology , Drug Design , Leishmania mexicana/growth & development , Microbial Sensitivity Tests , Molecular Structure , Mycobacterium tuberculosis/growth & development , Parasitic Sensitivity Tests , Structure-Activity RelationshipABSTRACT
Different series of N-alkylated diamines and their derivatives condensed to quinic acid were synthesized and tested for antibacterial properties against Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa, and Mycobacterium tuberculosis. The lipophilic chain and carbohydrate moiety modulate the antibacterial activity and the compounds showed a structure-activity relationship. Overall, 11 compounds displayed better activity than chloramphenicol against Gram-positive and Gram-negative bacteria. Monoalkylated amines 2a-h displayed an activity similar to that of ethambutol against Mycobacterium tuberculosis.
Subject(s)
Amides/chemical synthesis , Amides/pharmacology , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/pharmacology , Diamines/chemical synthesis , Diamines/pharmacology , Quinic Acid/analogs & derivatives , Alkylation , Gram-Negative Bacteria/drug effects , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Quinic Acid/chemical synthesis , Quinic Acid/chemistry , Quinic Acid/pharmacology , Structure-Activity Relationship , Surface-Active Agents/pharmacologyABSTRACT
In continuation of our efforts to find new antimicrobial compounds, series of fatty N-acyldiamines were prepared from fatty methyl esters and 1,2-ethylenediamine, 1,3-propanediamine or 1,4-butanediamine. The synthesized compounds were screened for their antibacterial activity against Gram-positive bacteria (Staphylococcus aureus, Staphylococcus epidermidis), Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa) and for their antifungal activity against four species of Candida (C. albicans, C. tropicalis, C. glabrata and C. parapsilosis). Compounds 5a (N-(2-aminoethyl)dodecanamide), 5b (N-(2-aminoethyl)tetracanamide) and 6d (N-(3-aminopropyl)oleamide) were the most active against Gram-positive bacteria, with MIC values ranging from 1 to 16µg/mL and were evaluated for their activity against 21 clinical isolates of methicillin-resistant S. aureus. All the compounds exhibited good to moderate antifungal activity. Compared to chloramphenicol, compound 6b displayed a similar activity (MIC50=16µg/mL). A positive correlation could be established between lipophilicity and biological activity.
Subject(s)
Anti-Bacterial Agents/pharmacology , Antifungal Agents/pharmacology , Candida/drug effects , Diamines/pharmacology , Gram-Negative Bacteria/drug effects , Anti-Bacterial Agents/chemical synthesis , Anti-Bacterial Agents/chemistry , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Diamines/chemical synthesis , Diamines/chemistry , Dose-Response Relationship, Drug , Gram-Positive Bacteria/drug effects , Microbial Sensitivity Tests , Molecular Structure , Structure-Activity RelationshipABSTRACT
A series of 25 N,N'-substituted diamines were prepared by controlled reductive amination of free aliphatic diamines with different substituted benzaldehydes. The library was screened in vitro for antiparasitic activity on the causative agents of human African trypanosomiasis, Chagas' disease and visceral leishmaniasis. The most potent compounds were derived from a subset of diamines that contained a 4-OBn substitution, having a 50% parasite growth inhibition in the submicromolar (against Trypanosoma cruzi) or nanomolar (against Trypanosoma brucei and Leishmania donovani) range. We conclude that members of this series of N,N'-substituted diamines provide new lead structures that have potential to treat trypanosomal and leishmanial infections.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Diamines/chemical synthesis , Diamines/pharmacology , Kinetoplastida/drug effects , Animals , Chagas Disease/drug therapy , Diamines/chemistry , Humans , Inhibitory Concentration 50 , Leishmaniasis, Visceral/drug therapy , Molecular Structure , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Small Molecule Libraries/pharmacology , Trypanosomiasis, African/drug therapyABSTRACT
Leishmania amazonensis is the etiologic agent of the cutaneous and diffuse leishmaniasis. This species is often associated with drug resistance, and the conventional treatments exhibit high toxicity for patients. Therefore, the search for new antileishmanial compounds is urgently needed since there is no vaccine available. In this study, using the in vitro traditional drug screening test, we have analyzed the effects of a series of diaminoalkanes monoprotected with t-butyloxycarbonyl (BOC) against L. amazonensis. Among the 18 tested compounds, 6 exhibited antileishmanial activity (2, 7-9, 17, and 18). Best IC(50) values (10.39 ± 0.27 and 3.8 ± 0.42 µg/mL) were observed for compounds 17 and 18 (H(2)N(CH(2))nNHBoc, n = 10 and 12), respectively. Although those compounds had higher lipophilicity as indicated by their cLog P values, compound 17 was very toxic. Determination of the selective indexes indicated that 50% of the active compounds were very toxic for HepG2 cells. However, compounds 2, 8, and 18 had good lipophilicity and were less toxic among all polyamine derivatives tested. The chemical properties of antileishmanial diamine derivatives, such as lipophilicity and cytotoxicity, are relevant factors for the design of new drugs. A higher lipophilicity is likely to improve the chances of reaching this intracellular parasite.
Subject(s)
Antiprotozoal Agents/chemical synthesis , Antiprotozoal Agents/pharmacology , Diamines/chemical synthesis , Diamines/pharmacology , Leishmania/drug effects , Animals , Antiprotozoal Agents/toxicity , Cell Line, Tumor , Diamines/toxicity , Hep G2 Cells , Humans , Inhibitory Concentration 50 , Lethal Dose 50 , Macrophages/drug effects , Macrophages/parasitology , Mice , Mice, Inbred BALB CABSTRACT
A series of diamines and amino alcohols derived from 1-dodecanol, 1-tetradecanol, 1,2-dodecanediol and 1,2-tetradecanediol were synthesized and tested for their antitubercular activity. Compounds 3, 8 and 9 were found to be the most active (MIC of 6.25 microg/mL). Nine other compounds displayed activity against Mycobacterium tuberculosis, with a MIC of 12.5 microg/mL.
Subject(s)
Amino Alcohols/pharmacology , Antitubercular Agents/pharmacology , Diamines/pharmacology , Mycobacterium tuberculosis/drug effects , Amino Alcohols/chemical synthesis , Antitubercular Agents/chemistry , Diamines/chemical synthesis , Microbial Sensitivity TestsABSTRACT
A series of diamines and amino alcohols derived from 1-dodecanol, 1-tetradecanol, 1,2-dodecanediol and 1,2-tetradecanediol were synthesized and tested for their antitubercular activity. Compounds 3, 8 and 9 were found to be the most active (MIC of 6.25 µg/mL). Nine other compounds displayed activity against Mycobacterium tuberculosis, with a MIC of 12.5 µg/mL.
Subject(s)
Amino Alcohols/pharmacology , Antitubercular Agents/pharmacology , Diamines/pharmacology , Mycobacterium tuberculosis/drug effects , Amino Alcohols/chemical synthesis , Antitubercular Agents/chemistry , Diamines/chemical synthesis , Microbial Sensitivity TestsABSTRACT
Taking in account the increased prevalence of metronidazole-resistant infections, alternative drugs are necessary for the treatment of trichomonosis. We report in this work the preparation and the in vitro anti-trichomonads activity of two diamines 1 and 2, and three different lipophilic amino alcohol derivatives 3, 4 and 5. These compounds were tested for in vitro activity against two isolates of Trichomonas vaginalis and displayed inhibition of the parasite growth. Five concentrations of each compound were tested. The butanediamine derivative 1, at a final concentration of 5.85 microM, presented a cytotoxic effect against 47% of T. vaginalis trophozoites. Furthermore, the cytotoxicity of 1 did not present statistically significant difference when compared to metronidazole in the same range of concentration (0.1-1.5 microg/mL).
Subject(s)
Amino Alcohols/pharmacology , Antitrichomonal Agents/pharmacology , Diamines/pharmacology , Trichomonas vaginalis/drug effects , Amino Alcohols/chemical synthesis , Antitrichomonal Agents/chemical synthesis , Diamines/chemical synthesis , Dose-Response Relationship, Drug , Molecular Structure , Parasitic Sensitivity Tests , Structure-Activity Relationship , Trichomonas vaginalis/growth & developmentABSTRACT
In this work, we report the preparation and evaluation of the in vitro and in vivo of the immunosuppressive activity of a series of lipophilic amino alcohols and diamines. All compounds were evaluated for inhibition of cell proliferation, cytotoxicity and NO production. Compounds 9, 12, 13, 17, and 18 did not display inhibition of cell proliferation while decreased NO production. The two most potent compounds, 13 and 17, submitted to delayed-type hypersensitivity assays showed immunosuppressive activity.
Subject(s)
Amino Alcohols/pharmacology , Diamines/pharmacology , Immunosuppressive Agents/pharmacology , Amino Alcohols/chemical synthesis , Amino Alcohols/toxicity , Animals , Cells, Cultured , Diamines/chemical synthesis , Diamines/toxicity , Hypersensitivity, Delayed/chemically induced , Immunosuppressive Agents/chemical synthesis , Immunosuppressive Agents/toxicity , MiceABSTRACT
Mono- and diacylated derivatives of galactopyranosyl amines were obtained from d-galactose, via aminated intermediates prepared by reaction of 6-deoxy-6-iodo-1,2:3,4-di-O-isopropylidene-alpha-d-galactopyranose with 1,3-propanediamine, 1,2-ethanediamine or ethanolamine. Monoacylated derivatives displayed antitubercular activity.