Sankaranarayanan Murugesan

Antibacterial, antifungal and anticonvulsant evaluation of novel newly synthesized 1-[2-(1H-tetrazol-5-yl)ethyl]-1H-benzo[d][1,2,3]triazoles

Several novel 1-[2-(1H-tetrazol-5-yl) ethyl]-1H-benzo[d][1,2,3]triazoles (3a-h) have been synthesized by the condensation of 1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-benzotriazole (2) and appropriate acid chlorides. 1-[2-(1H-tetrazol-5-yl)-ethyl]-1H-benzotriazole (2) was synthesized by reacting 3-(1H-benzo[d][1,2,3]triazol-1-yl)propanenitrile with sodium azide and ammonium chloride in the presence of dimethylformamide. The synthesized compounds were characterized by IR and PMR analysis. The titled compounds were evaluated for theirin vitro antibacterial and antifungal activity by the cup plate method and anticonvulsant activity evaluated by the maximal electroshock induced convulsion method in mice. All synthesized compounds exhibited moderate antibacterial activity againstBacillus subtilis and moderate antifungal activity againstCandida albicans. Compounds 5-(2-(1H-benzo[d][1,2,3]triazo-1-yl)ethyl)-1H-tetrazol-1-yl)(4-aminophenyl)methanone3d and 5-(2-(1H-benzo[d][1,2,3]triazo-1-yl)ethyl)-1H-tetrazol-1-yl)(2-aminophenyl)methanone3e elicited excellent anticonvulsant activity.

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

In the present study, a new series of β-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.

Review on in-vitro anti-Malarial activity of Natural β-carboline Alkaloids

Malaria is one of the major health problems in developing countries. It kills 1-2 million people every year and also it affects financial status of many countries. Developed resistance to aminoquinoline (chloroquine), quinoline methanols (Quinine, Mefloquine) created troubles in malarial chemotherapy and signs of appearance of resistance to artemisinin based combination therapy (ACT) created emergency to develop novel antimalarial agents with high efficacy before spreading of resistance to ACT. From the ages natural products played an important role in antimalarial therapy, identification of natural products, semisynthetic and synthetic analogs with potent antiplasmodium activity is one of the best methods to develop novel antimalarial agents. In this review, we are presenting the antimalarial activity of natural β-carboline alkaloids and special interest on manzamine alkaloids and their structure activity relationship.

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 β-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 β-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.

Design and Synthesis of 2-Methylthio-3-substituted-5,6-dimethylthieno [2,3-d] pyrimidin-4(3H)-ones as Analgesic, Anti-Inflammatory and Antibacterial Agents

Pain and inflammation are simultaneous responses in bacterial infections. In current clinical practice, two groups of agents like antibacterial and non-steroidal anti-inflammatory drugs (NSAIDs) are prescribed simultaneously. Regrettably, none of the drug possesses these activities in a single component. Exploiting the bioisosterism concept, we have documented that 2-phenyl-3-substituted quinazolines, 2,3-disubstituted quinazolines, 2-methyl-3-substituted quinazolin-4-(3H)-ones and 2-methylthio-3-substituted quinazolin-4-(3H)-ones exhibited good analgesic and anti-inflammatory activities. The present work is an extension of our ongoing efforts towards the development and identification of lead molecules by bioisostere concept, for which we designed some of 2-methylthio-3-substituted-5,6-dimethylthieno[2,3-d] pyrimidin-4(3H)-ones. The title compounds were investigated for analgesic, anti-inflammatory and antibacterial activities. While the test compounds exhibited significant activity, the compounds (6-9) showed more potent analgesic activity, and the compounds (8, 9) showed anti-inflammatory activity comparable to the reference standard diclofenac.

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.

Synthesis and pharmacological investigation of novel 3-(benzyl)-2-substituted amino-3H-quinazolin-4-ones as analgesic and anti-inflammatory agents

A variety of novel 3-(benzyl)-2-substituted amino-quinazolin-4(3H)-ones were synthesized by reacting the amino group of 3-benzyl-2-hydrazino quinazolin-4(3H)-one with a variety of aldehydes and ketones. The starting material, 3-benzyl-2-hydrazino quinazolin-4(3H)-one, was synthesized from benzyl amine. The title compounds were investigated for analgesic, anti-inflammatory, and ulcerogenic index activities. The compound 3-benzyl-2-[N’-(1-ethyl-propylidene)-hydrazino]-3H-quinazolin-4-one (AS2) emerged as the most active compound of the series and is moderately more potent in its analgesic and anti-inflammatory activities when compared to the reference standard diclofenac sodium. Interestingly the test compounds showed only mild ulcerogenic potential when compared to aspirin.

De novo design and in-silico studies of novel 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid derivatives as HIV-1 reverse transcriptase inhibitors

AbstractIn the present study, we have designed 50 novel 1-phenyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic acid analogs as non-nucleoside inhibitors of HIV-1 reverse transcriptase. Docking studies of the designed analogs were performed by molecular modeling software autodock 4.2 using HIV-1 reverse transcriptase (PDB ID: 1rt2) as receptor. Lipinski rule of five parameters and toxicity parameters was derived through online servers like molinspiration and Osiris property explorer. Docking parameters such as binding free energy and predicted inhibitory constant (Ki) values of the designed analogs were compared with standard drug efavirenz and co-crystallized ligand TNK-651. Among the designed analogs, TBB-II-5, TBB-II-7, TBB-II-21, TBB-II-22, TBB-II-24, TBB-II-25, TBB-II-26, TBB-II-33, TBB-II-37, TBB-II-38, and TBB-II-43 showed significant and comparable binding-free energy and predicted inhibitory constant values as that of standard drug efavirenz and TNK-651. These results indicate that, the designed analogs adopt a similar orientation and share the same binding mode as that of some of the classical non-nucleoside reverse transcriptase inhibitors within the active site of non-nucleoside inhibitory binding pocket of HIV-1 reverse transcriptase.

Molecular docking and molecular dynamics simulation based approach to explore the dual inhibitor against HIV-1 reverse transcriptase and Integrase

BACKGROUND HIV integrase (IN) and reverse transcriptase (RT) are key enzymes for the replication of HIV-1. DNA polymerase and ribonuclease H (RNase H) are the two catalytic domains of HIV-1 RT which are validated as drug targets because of their essence for replication. IN and RNase H domain of RT shares striking structural similarity; it contains conserved DDE triad (two aspartates and one glutamate) and a pair of divalent Mg2+/Mn2+ ions at their catalytic core domain. OBJECTIVE To search for novel compounds with dual inhibition of IN and RNase H for the drug development against both wild and drug-resistant strains of HIV. METHODS In the present work, attempts have been made to search compounds against both IN and the RNase H domain of RT. Using structure-based virtual screening approach; Asinex database of small molecules was screened against the viral IN. Top thirty ranked hits obtained, were further evaluated against RNase H domain of RT using Extra Precision (XP) mode of Glide docking. Furthermore, eleven common potential hits were observed which were subjected to the in-silico prediction of drug-likeness properties. Later on, molecular dynamics simulation was performed for the best common active hit (AS6), in the complex with selected enzymes. RESULT In silico screening of Asinex database compounds against IN and RNase H resulted in total seven compounds namely AS3, AS5, AS6, AS15, AS17, AS18, and AS20 having dual inhibition activity. CONCLUSION This study warrants the dual inhibition activity of AS6 against IN and RNase H confirms its anti-HIV activity.