Anti-infective Potential of Manzamine Alkaloids - A Review.

BACKGROUND: From time immemorial, natural products have been used for the treatment of various diseases. Various natural products, their semisynthetic derivatives, and synthetic analogs have been explored for their anti-infective properties. One such group of natural compounds that has been widely explored is manzamine alkaloids. Manzamine alkaloids are complex natural compounds consisting of a ß-carboline nucleus attached to a pentacyclic ring system; they were first isolated from a marine sponge during the 1980s. OBJECTIVE: This review aims to provide a critical overview on the anti-infective potential of manzamine alkaloids. METHODS: A comprehensive and exhaustive review of the literature on manzamine alkaloids, and their isolation, anti-infective properties, and mechanism of action, is presented. RESULTS: Various manzamine alkaloids have been isolated and have been found to exhibit potent antiinfective activities like antibacterial, antimalarial, antiviral, antifungal, antileishmanial, among others. These manzamine alkaloids exhibit their anti-infective activity by inhibiting targets like GSK-3ß, MtSK. CONCLUSION: This present review along with structure-activity relationship study of manzamine alkaloids for their anti-infective activity will be useful for further development of semisynthetic manzamine analogs as potent anti-infective agents with better therapeutic potential and reduced toxicity.

Biological evaluation and structure activity relationship of 9-methyl-1-phenyl-9H-pyrido[3,4-b]indole derivatives as anti-leishmanial agents.

A series of piperazinyl-ß-carboline-3-carboxamide derivatives were designed through a molecular hybridization approach. Designed analogues were synthesized, characterized and evaluated for anti-leishmanial activity against Leishmania infantum and Leishmania donovani. In L. infantum inhibition assay, compounds 7d, 7g and 7c displayed potent inhibition of promastigotes (EC50 1.59, 1.47 and 3.73 µM respectively) and amastigotes (EC50 1.4, 1.9 and 2.6 µM respectively). SAR studies revealed that, para substitution of methoxy, chloro groups and methyl group on ortho position favored anti-leishmanial activity against L. infantum. Among these analogues 7d, 7h, 7n and 7g exhibited potent inhibition against L. donovani promastigotes (EC50 0.91, 4.0, 4.57 and 5.02 µM respectively), axenic amastigotes (EC50 0.9, 3.5, 2.2 and 3.8 µM respectively) and intracellular amastigotes (EC50 1.3, 7.8, 5.6 and 6.3 µM respectively). SAR studies suggested that, para substitution of methoxy group, para and meta substitution of chloro groups and benzyl replacement recommended for significant anti-leishmanial against L. donovani.

Synthesis and activity of benzopiperidine, benzopyridine and phenyl piperazine based compounds against Leishmania infantum.

In the present study, anti-leishmanial evaluation of twenty four structurally diverse compounds based on benzopiperidine, benzopyridine and phenylpiperazine nucleuses against Leishmania infantum has been reported. Cytotoxicity studies of all the compounds were performed on murine non-infected splenocytes. Tested compounds exhibited weak to potent activity against promastigote (IC50 3.21 ±â€¯1.40 to >100 µM) as well as amastigote (IC50 6.84 ±â€¯2.5 to 92.47 ±â€¯17.61 µM) forms of tested strains. Moreover, two compounds F13 and F15 exhibited potent activity (IC50 < 10 µM) against both forms of the parasite with selectivity index ranges from 11.40 to 22.10. Overall, the current study afforded few hits with novel anti-leishmanial activity in low micromolar concentration, further hit optimization studies can be performed to get more potent candidates against the selected species of parasite.

Design, synthesis and biological evaluation of piperazinyl-ß-carbolinederivatives as anti-leishmanial agents.

Molecular hybridization is a ligand based drug design approach is well known recent medicinal chemistry to design anti-parasitic agents. In the present study, we have designed a series of (1-phenyl-9H-pyrido [3,4-b]indol-3-yl) (4-phenylpiperazin-1-yl)methanone derivatives using molecular hybridization approach. Designed analogues were evaluated for cytotoxicity and inhibition activity against Leishmania infantum and Leishmania donovani. Among these reported analogues 7b, 7d, 7e, 7f and 7m displayed potent inhibition of both L. infantum and L. donovani. Compounds 7i and 7k exhibited selective potent inhibition of L. donovani. Especially, compounds 7e and 7k showed most potent anti-leishmanial activity against L. infantum and L. donovani respectively. Anti-leishmanial activity of these compounds is comparable with standard drugs miltefosine and pentamidine. SAR studies revealed that, electron donating group substitution on phenyl ring recommended for potent anti-leishmanial activity.

Synthesis and in-vitro anti-leishmanial activity of (4-arylpiperazin-1-yl)(1-(thiophen-2-yl)-9H-pyrido[3,4-b]indol-3-yl)methanone derivatives.

In the present study, we have reported synthesis and biological evaluation of a series of fifteen 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole derivatives against both promastigotes and amastigotes of Leishmania parasites responsible for visceral (L. donovani) and cutaneous (L. amazonensis) leishmaniasis. Among these reported analogues, compounds 7b, 7c, 7f, 7g, 7i, 7j, 7m, 7o displayed potent activity (15.55, 7.70, 7.00, 3.80, 14.10, 9.25, 3.10, 4.85µM, respectively) against L. donovani promastigotes than standard drugs miltefosine (15.70µM) and pentamidine (32.70µM) with good selectivity index. In further, in-vitro evaluation against amastigote forms, two compounds 7g (8.80µM) and 7i (7.50µM) showed significant inhibition of L. donovani amastigotes. Standard drug amphotericin B is also used as control to compare inhibition potency of compounds against both promastigote (0.24µM) and amastigote (0.05µM) forms.

Design, synthesis and anti-HIV-1 RT evaluation of 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives.

In this study, using molecular hybridization approach, fourteen novel 2-(benzyl(4-chlorophenyl)amino)-1-(piperazin-1-yl)ethanone derivatives (7a-n) were designed as inhibitor of HIV-1 RT. The binding affinity of the designed compounds with HIV-1 RT as well as their drug-likeness behavior was predicted using in-silico studies. All the designed compounds were synthesized, characterized and in-vitro evaluated for HIV-1 RT inhibitory activity, in which tested compounds displayed significant to weak potency against the selected target. Moreover, best active compounds of the series, 7k and 7m inhibited the activity of RT with IC50 values 14.18 and 12.26µM respectively. Structure Activity Relationship (SAR) studies were also performed in order to predict the influence of substitution pattern on the RT inhibitory potency. Anti-HIV-1 and cytotoxicity studies of best five RT inhibitor (7a, 7d, 7k, 7L and 7m) revealed that, except compound 7d other compounds retained significant anti-HIV-1 potency with good safety index. Best scoring pose of compound 7m was analysed in order to predict its putative binding mode with wild HIV-1 RT.

Synthesis and anti-leishmanial evaluation of 1-phenyl-2,3,4,9-tetrahydro-1H-ß-carboline derivatives against Leishmania infantum.

In the present study, antileishmanial activity of sixteen novel series of tetrahydro-ß-carboline derivatives against transgenic infrared fluorescent Leishmania infantum strain has been reported. Among these reported analogues, most of the compounds exhibited potent inhibition against both promastigote (IC50 from 1.99 ± 1.40 to 20.69 ± 0.95 µM) and amastigote (IC50 from 0.67 ± 0.05 to 4.16 ± 0.008 µM) forms of L. infantum. Moreover, compound 7l, displayed most potent and selective inhibition of parasite amastigote form with IC50 0.67 ± 0.05 µM, selectivity index >298.5 and was comparable with standard drug amphotericin B. From this study, a new class of tetrahydro-ß-carboline derivatives with potent antileishmanial activity was identified and it needs further extensive study to optimize the lead molecules to win the battle against severe and neglected disease leishmaniasis.

Rational design, synthesis, anti-HIV-1 RT and antimicrobial activity of novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one derivatives.

In the present study, fifteen novel 3-(6-methoxy-3,4-dihydroquinolin-1(2H)-yl)-1-(piperazin-1-yl)propan-1-one (6a-o) derivatives were designed as inhibitor of HIV-1 RT using ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT strain. Among the tested compounds, four compounds (6a, 6b, 6j and 6o) exhibited significant inhibition of HIV-1 RT (IC50⩽10µg/ml). All synthesized compounds were also evaluated for anti-HIV-1 activity as well as cytotoxicity on T lymphocytes, in which compounds 6b and 6l exhibited significant anti-HIV activity (EC50 values 4.72 and 5.45µg/ml respectively) with good safety index. Four compounds (6a, 6b, 6j and 6o) found significantly active against HIV-1 RT in the in-vitro assay were in-silico evaluated against two mutant RT strains as well as one wild strain. Further, titled compounds were evaluated for in-vitro antibacterial (Escherichia coli, Pseudomonas putida, Staphylococcus aureus and Bacillus cereus) and antifungal (Candida albicans and Aspergillus niger) activities.

Design, synthesis and biological evaluation of novel quinoline-based carboxylic hydrazides as anti-tubercular agents.

In this study, seventeen novel quinoline-based carboxylic hydrazides were designed as potential anti-tubercular agents using molecular hybridization approach and evaluated in-silico for drug-likeness behavior. The compounds were synthesized, purified, and characterized using spectral techniques (like FTIR, (1) H NMR, and Mass). The in-vitro anti-tubercular activity (against Mycobacterium tuberculosisH37Ra) and cytotoxicity against human lung fibroblast cells were studied. Among the tested hydrazides, four compounds (6h, 6j, 6l, and 6m) exhibited significant anti-tubercular activity with MIC values below 20 µg/mL. The two most potent compounds of the series, 6j and 6m exhibited MIC values 7.70 and 7.13 µg/mL, respectively, against M. tuberculosis with selectivity index >26. Structure-activity relationship studies were performed for the tested compounds in order to explore the effect of substitution pattern on the anti-tubercular activity of the synthesized compounds.

Design, synthesis and in-vitro evaluation of novel tetrahydroquinoline carbamates as HIV-1 RT inhibitor and their antifungal activity.

Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are vital class of drugs in treating HIV-1 infection, but drug resistance and toxicity drive the need for effective new inhibitors with potent antiviral activity, less toxicity and improved physicochemical properties. In the present study, twelve novel 1-(4-chlorophenyl)-2-(3,4-dihydroquinolin-1(2H)-yl)ethyl phenylcarbamate derivatives were designed as inhibitor of HIV-1 RT using the ligand based drug design approach and in-silico evaluated for drug-likeness properties. Designed compounds were synthesized, characterized and in-vitro evaluated for RT inhibitory activity against wild HIV-1 RT. Among these, four compounds (6b, 6i, 6j and 6l) exhibited significant inhibition of HIV-1 RT (IC50 ⩽ 20 µM). Among four compounds, most active compounds 6b and 6j inhibited the RT activity with IC50 8.12 and 5.42 µM respectively. Docking studies of compounds 6b and 6j were performed against wild HIV-1 RT in order to predict their putative binding mode with selected target. Further, cytotoxicity and anti-HIV activity of compounds 6b and 6j were evaluated on T lymphocytes (C8166 cells). All the synthesized compounds were also evaluated for antifungal activity against Candida albicans and Aspergillus niger fungal strains.

De-novo design, synthesis and evaluation of novel 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as HIV-1 reverse transcriptase inhibitors.

BACKGROUND: Acquired Immune Deficiency Syndrome (AIDS) is the advanced stage of infection caused by Human Immunodeficiency Virus (HIV). HIV/AIDS had a great impact on society, both as an illness and as a source of discrimination. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) are structurally diverse group of compounds which binds to Reverse Transcriptase (RT) enzyme of HIV. Like other anti-HIV drugs, long-term clinical effectiveness of approved NNRTIs has been hampered due to the rapid development of drug resistance. So, there is an urgent need to discover the NNRTIs, which can be effective against the drug sensitive as well as drug resistant strains of HIV-1 RT. RESULTS: Two series of novel thirty, 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline analogues (5a-o) and (8a-o) were designed and synthesized as inhibitor of HIV-1 reverse transcriptase. All the synthesized compounds were characterized by infrared spectroscopy, proton nuclear magnetic resonance spectroscopy, mass spectroscopy and evaluated for in-vitro RT inhibitory activity. Among the tested compounds, eighteen compounds exhibited more than 50 % inhibition at tested 100 µM concentration, in which two compounds 8h and 8l showed promising inhibition (74.82 and 72.58 %) respectively. The preliminary structure-activity relationship (SAR) of the test compounds and docking studies of the two significantly active compounds 8h and 8l were performed to examine their putative binding with HIV-RT. Predicted physiochemical parameters of the synthesized compounds were within the acceptable range of drugable properties. CONCLUSION: The results obtained from this investigation revealed that, the synthesized compounds (5a-o) and (8a-o) showed moderate to promising HIV-1 RT inhibition activity. The overall SAR studies can help in identification of further lead as well as in designing of newer potential inhibitor of HIV-1 RT. Graphical AbstractBest docked pose of compound 8h inside the non-nucleoside inhibitory binding pocket of 3MEE enzyme.

Design, synthesis of new ß-carboline derivatives and their selective anti-HIV-2 activity.

In the present study, a new series of ß-carboline derivatives were synthesized and evaluated for inhibition activity against both HIV-1 and HIV-2 strains. Among these reported analogues, surprisingly (1-phenyl-9H-pyrido[3,4-b]indol-3-yl)(4-p-tolylpiperazin-1-yl)methanone (7b), (4-(2-methoxyphenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7f), (4-(4-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7k), (4-(2-fluorophenyl)piperazin-1-yl)(1-phenyl-9H-pyrido[3,4-b]indol-3-yl)methanone (7l) displayed selective inhibition of HIV-2 strain with EC50 values of 3.3, 3.2, 2.6 and 5.4µM, respectively, which are comparable with nucleoside reverse transcriptase inhibitors lamivudine and dideoxyinosine. As these analogues have not shown in vitro HIV-2 reverse transcriptase inhibition, it could be excluded as potential target for their specific anti-HIV-2 activity.

Design, Synthesis, and Biological Evaluation of 1-(thiophen-2-yl)-9H-pyrido[3,4-b]indole Derivatives as Anti-HIV-1 Agents.

A novel series of 1-(thiophen-2-yl)-9H-pyrido [3,4-b]indole derivatives were synthesized using DL-tryptophan as starting material. All the compounds were characterized by spectral analysis such as (1) H NMR, Mass, IR, elemental analysis and evaluated for inhibitory potency against HIV-1 replication. Among the reported analogues, compound 7g exhibited significant anti-HIV activity with EC(50) 0.53 µm and selectivity index 483; compounds 7e, 7i, and 7o displayed moderate activity with EC(50) 3.8, 3.8, and 2.8 µm and selectivity index >105, >105, and 3.85, respectively. Interestingly, compound 7g inhibited p24 antigen expression in acute HIV-1(IIIB) infected cell line C8166 with EC50 1.1 µm. In this study, we also reported the Lipinski rule of 5 parameters, predicted toxicity profile, drug-likeness, and drug score of the synthesized analogues.

Manzamine alkaloids as antileishmanial agents: A review.

Leishmaniasis is considered as one of the most Neglected Tropical Diseases (NTDs) in the world, caused by protozoan parasites of the genus Leishmania. Leishmaniasis control profoundly depends upon chemotherapy which includes pentavalent antimonials, paromomycin, pentamidine, amphotericin B and miltefosine. Miltefosine is the only oral drug used for the treatment of Visceral Leishmaniasis with high cure rate but decrease in susceptibility is observed in countries like India where it is extensively used. Hence, there is an urgent need to develop novel antileishmanial agents with good potency and better therapeutic profile. Manzamines are unique group of ß-carboline alkaloids isolated from marine sponges and exhibited potent antileishmanial activity. In the present study, we described antileishmanial activity, cytotoxicity and structure activity relationship of natural manzamine alkaloids.

Manzamine alkaloids: isolation, cytotoxicity, antimalarial activity and SAR studies.

The infectious disease Malaria is caused by different species of the genus Plasmodium. Resistance to quinoline antimalarial drugs and decreased susceptibility to artemisinin-based combination therapy have increased the need for novel antimalarial agents. Historically, natural products have been used for the treatment of infectious diseases. Identification of natural products and their semi-synthetic derivatives with potent antimalarial activity is an important method for developing novel antimalarial agents. Manzamine alkaloids are a unique group of ß-carboline alkaloids isolated from various species of marine sponge displaying potent antimalarial activity against drug-sensitive and -resistant strains of Plasmodium. In this review, we demonstrate antimalarial potency, cytotoxicity and antimalarial SAR of manzamine alkaloids.