ABSTRACT
Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC(50) 1.25 and 0.88 µM and chloroquine-resistant W2 strain with IC(50) 1.64 and 1.07 µM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC(50) 2.39 and 2.78 µM and IC(90) 11.27 and 12.76 µM, respectively. Three analogues 12c, 14c, and 14i were the most active against various pathogenic bacteria and fungi with IC(50) < 3.02 µM and MIC/MBC/MFC <6 µM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structural class for broad spectrum activity.
Subject(s)
Anti-Bacterial Agents/chemical synthesis , Anti-HIV Agents/chemical synthesis , Antifungal Agents/chemical synthesis , Antimalarials/chemical synthesis , Guanidine/chemistry , Guanidines/chemical synthesis , Animals , Anti-Bacterial Agents/chemistry , Anti-Bacterial Agents/pharmacology , Anti-HIV Agents/chemistry , Anti-HIV Agents/toxicity , Antifungal Agents/chemistry , Antifungal Agents/pharmacology , Antimalarials/chemistry , Antimalarials/pharmacology , Aspergillus fumigatus/drug effects , Candida/drug effects , Cell Survival/drug effects , Chlorocebus aethiops , Cryptococcus neoformans/drug effects , Guanidine/pharmacology , Guanidine/toxicity , Guanidines/pharmacology , Guanidines/toxicity , HIV-1/drug effects , Leishmania donovani/drug effects , Microbial Sensitivity Tests , Plasmodium falciparum/drug effects , Structure-Activity Relationship , Vero CellsABSTRACT
ß-carbolines from various natural and synthetic sources have been known to show diverse biological activities. As a part of our current ongoing project to search for potent natural product-derived anti-leishmanial compounds, we have synthesized a series of substituted 1-aryl-ß-carboline derivatives. A total of 22 compounds were synthesized and tested in vitro against Leishmania donovani, out of which 6 compounds (4, 5, 10, 11, 19 and 22) showed notably more activity than the standard miltefosine (IC(50) 12.07±0.82 µM), with compound 4 being the most potent (IC(50) 2.16±0.26 µM).
Subject(s)
Carbolines/chemical synthesis , Leishmania donovani/drug effects , Trypanocidal Agents/chemical synthesis , Carbolines/pharmacology , Cell Survival/drug effects , Humans , Inhibitory Concentration 50 , Leishmania donovani/growth & development , Phosphorylcholine/analogs & derivatives , Phosphorylcholine/pharmacology , Structure-Activity Relationship , Trypanocidal Agents/pharmacologyABSTRACT
Fifty analogues of batzelladine K were synthesized and evaluated for in vitro antimalarial (Plasmodium falciparum), antileishmanial (Leishmania donovani), antimicrobial (panel of bacteria and fungi), antiviral (HIV-1) activities. Analogues 14h and 20l exhibited potential antimalarial activity against chloroquine-sensitive D6 strain with IC50 1.25 and 0.88 µM and chloroquine-resistant W2 strain with IC50 1.64 and 1.07 µM, respectively. Analogues 12c and 14c having nonyl substitution showed the most potent antileishmanial activity with IC50 2.39 and 2.78 µM and IC90 11.27 and 12.76 µM respectively. Three analogues 12c, 14c and 14i were the most active against various pathogenic bacteria and fungi with IC50 <3.02 µM and MIC/MBC/MFC <6 µM. Analogue 20l having pentyl and methyl substituents on tricycle showed promising activities against all pathogens. However, none was found active against HIV-1. Our study demonstrated that the tricyclic guanidine compounds provide new structral class for broad spectrum activity. © 2012 John Wiley & Sons A/S.
ABSTRACT
Acquired immunodeficiency syndrome patients face great socio-economic difficulties in obtaining treatment. There is an urgent need for new, safe, and cheap anti-HIV agents. Traditional medicinal plants are a valuable source of novel anti-HIV agents and may offer alternatives to expensive medicines in future. Various medicinal plants or plant-derived natural products have shown strong anti-HIV activity and are under various stages of clinical development in different parts of the world. The present study was directed towards assessment of anti-HIV activity of various extracts prepared from Indian medicinal plants. The plants were chosen on the basis of similarity of chemical constituents with reported anti-HIV compounds or on the basis of their traditional usage as immunomodulators. Different extracts were prepared by Soxhlet extraction and liquid-liquid partitioning. Ninety-two extracts were prepared from 23 plants. Anti-HIV activity was measured in a human CD4+ T-cell line, CEM-GFP cells infected with HIV-1NL4.3. Nine extracts of 8 different plants significantly reduced viral production in CEM-GFP cells infected with HIV-1NL4.3. Aegle marmelos, Argemone mexicana, Asparagus racemosus, Coleus forskohlii, and Rubia cordifolia demonstrated promising anti-HIV potential and were investigated for their active principles.
Subject(s)
Anti-HIV Agents/pharmacology , HIV/drug effects , Plant Extracts/pharmacology , Plants, Medicinal/chemistry , Aegle/chemistry , Anti-HIV Agents/adverse effects , Anti-HIV Agents/chemistry , Argemone/chemistry , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/virology , Cell Line , Cell Line, Tumor , Coleus/chemistry , HIV/growth & development , Humans , Plant Extracts/adverse effects , Plant Extracts/chemistry , Rubia/chemistryABSTRACT
A series of beta-carboline derivatives were synthesized by utilizing aromatization and chemoselective alkylation method recently reported from our laboratory. Synthesized derivatives were evaluated for anti-HIV activity in human CD4+ T cell line (CEM-GFP) infected with HIV-1 NL(4.3) virus. 1-Formyl-beta-carboline-3-carbxylic acid methyl ester (15) showed inhibition of human immunodeficiency virus at IC(50)=2.9 microM.
Subject(s)
Anti-HIV Agents/chemical synthesis , Carbolines/chemistry , Formates/chemical synthesis , HIV/drug effects , Anti-HIV Agents/chemistry , Anti-HIV Agents/pharmacology , Carbolines/chemical synthesis , Carbolines/pharmacology , Cell Line , Formates/chemistry , Formates/pharmacology , HumansABSTRACT
Naturally occurring quinolone alkaloids, buchapine (1) and compound 2 were synthesized as reported in literature and evaluated for anti-HIV potential in human CD4+ T cell line CEM-GFP, infected with HIV-1(NL4.3) virus by p24 antigen capture ELISA assay. The compounds 1 and 2 showed potent inhibitory activity with IC(50) value of 2.99 and 3.80microM, respectively. Further, 45 alkylated derivatives of quinoline 2,4-diol were synthesized and tested for anti-HIV potential in human CD4+ T cell line CEM-GFP. Among these, 13 derivatives have shown more than 60% inhibition. We have identified three most potent inhibitors 6, 9 and 23; compound 6 was found to be more potent than lead molecule 1 with IC(50) value of 2.35microM and had better therapeutic index (26.64) as compared to AZT (23.07). Five derivatives 7, 19a, 19d, 21 and 24 have displayed good noticeable anti-HIV activity. All active compounds showed higher CC(50) values which indicate that they have better therapeutic indices.