Dipak Chetia

Synthesis and in vitro and in vivo antimalarial activity of novel 4-anilinoquinoline Mannich base derivatives

Development of resistance has severely limited the choice of available antimalarial drugs, which clearly highlights the urgent need of novel chemotherapeutic agents for the treatment of malaria. The purpose of this study was to develop new potential antimalarial agents with 4-anilinoquinoline ring. A series of novel 4-anilinoquinoline Mannich base drug molecules have been synthesized. The synthesis involves the preparation of Mannich base and these bases subsequently coupled with 4,7-dichloroquinoline to get targeted drug molecules (Burckhalter et al. in J Am Chem Soc 70:1363–1373, 1948). Their structures were confirmed by IR, NMR, and mass spectral data. The synthesized molecules were evaluated for in vitro and in vivo antimalarial activity against the chloroquine sensitive 3D7 (West Africa) and RKL-2 strain of Plasmodium falciparum and rodent malaria parasite Plasmodium yoelii (strain N-67) in Swiss mice model, respectively (Charmot et al. in Prev Med 15:889, 1986). Except one molecule (containing diphenylamine), all the tested molecules showed activity while one of them (containing morpholine) showed promising in vitro and significant in vivo antimalarial activity under given test conditions.

Synthesis, antimalarial-, and antibacterial activity evaluation of some new 4-aminoquinoline derivatives

Some new 4-aminoquinoline derivatives were synthesized, characterized by their analytical and spectral data (IR, 1HNMR, 13CNMR and MS), and screened for in vitro antimalarial activity against a chloroquine-sensitive strain of Plasmodium falciparum (3D7). Results clearly reveal that all the synthesized compounds possess in vitro antimalarial activity at the tested dose which, however, was considerably less than that of the standard reference drug, chloroquine. From results, it could be assumed that the presence of an aromatic bulky group with optimal lipophilicity at 1,3-thiazinan-4-one ring system might be an important requirement for the antimalarial activity of synthesized compounds, 6a–g. In addition to the evaluation of antimalarial activity, the synthesized compounds were also screened for antibacterial activity against six different strains of Gram-positive (Bacillus subtilis, Bacillus cereus, and Staphylococcus aureus) and Gram-negative bacteria (Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae). All the compounds at the tested doses were found to be active against all the tested organisms, but were less active as compared to the standard drug, ofloxacin. Results of antibacterial study indicate that aromatic bulky substituents have greater contributing effect than the aliphatic non-bulky group toward the antibacterial activity of the prepared 4-aminoquinoline derivatives.

Screening of fruit and leaf essential oils of Litsea cubeba Pers. from north-east India – chemical composition and antimicrobial activity

Essential oils from the leaves and fruits of Litsea cubeba Pers. collected in the Assam and Arunachal Pradesh states in north-east India, were analyzed by gas chromatography (GC) and GC–mass spectrometry (GC–MS). On the whole, 117 components have been characterized. The two leaf oils (LC1, LC2) show sabinene as the main component; the other significant compounds for LC1 oil are α-pinene, terpinen-4-ol, α-terpineol and myrcene, whereas for LC2 1,8-cineole and α-pinene are the other most important compounds. The three fruit oils (LC3, LC4 and LC5) were characterized by different profiles, indeed LC3 and LC4 showed a similar composition with citronellol and citronellal the main components, accounting for 70% and 10% of total oils, respectively. LC5, instead, presents geranial (c. 44%) and neral (c. 40%) as the main components, whereas citronellal reaches only c. 3%. Essential oils were evaluated for their antimicrobial activity against Staphylococcus aureus, Listeria monocytogenes, Escherichia coli, Pseudomonas aeruginosa, Candida albicans and Aspergillus niger. All microbial strains appeared sensitive to the cytotoxic activity of the essential oils under investigation. Leaf and fruit oils showed different levels of inhibition depending on their particular chemical composition; however, the LC5 sample was broadly the most effective.

Ruthenium(II)‐Catalyzed Synthesis of Spirobenzofuranones by a Decarbonylative Annulation Reaction

The first decarbonylative insertion of an alkyne through C-H/C-C activation of six-membered compounds is reported. The Ru-catalyzed reaction of 3-hydroxy-2-phenyl-chromones with alkynes works most efficiently in the presence of the ligand PPh3 to provide spiro-indenebenzofuranones. Unlike previously reported metal-catalyzed decarbonylative annulation reactions, in the present decarbonylative annulation reaction, the annulation occurs before extrusion of carbon monoxide.

Novel series of 1,2,4-trioxane derivatives as antimalarial agents

Abstract Among three series of 1,2,4-trioxane derivatives, five compounds showed good in vitro antimalarial activity, three compounds of which exhibited better activity against P. falciparum resistant (RKL9) strain than the sensitive (3D7) one. Two best compounds were one from aryl series and the other from heteroaryl series with IC50 values of 1.24 µM and 1.24 µM and 1.06 µM and 1.17 µM, against sensitive and resistant strains, respectively. Further, trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, 1,2,4-trioxane derivative(s) reported herein may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.

Synthesis and antimalarial activity evaluation of some isoquine analogues

The worldwide diffusion of resistance in malaria parasite, especially the Plasmodium falciparum, towards currently available drugs has become a major health and development challenges to human society. Isoquine, an isomeric analogue of amodiaquine, has been reported recently as a second generation lead compound for development of cost-effective and potentially safer alternative to amodiaquine which cause adverse effects including agranulocytosis and liver damage. In this study, a series of seven analogues of isoquine have been synthesized and subjected to in vitro antimalarial activity screening against the chloroquine sensitive 3D7 strain of Plasmodium falciparum. A simple two-step Mannich reaction was used to synthesize the compounds. All the seven compounds possessed little to moderate antimalarial activity. However, the analogues with aliphatic alcoholic amino group side chain having promising activity than the compounds with substituted aromatic ring side chain and compounds substituted with urea while analogues with heterocyclic ring side chain exhibits moderate antimalarial activity.

Newer series of trioxane derivatives as potent antimalarial agents

Among synthesized 1,2,4-trioxane derivatives, six compounds were found to be considerably potent, with better activity against resistant strain of P. falciparum than the sensitive strain. The IC50 values of the best compound with 4-hydroxyphenyl substitution were found to be 0.391 and 0.837 µg/mL against sensitive and resistant strain of P. falciparum, respectively. Results of the tested compounds were comparable with that of the standard drug, chloroquine (IC50 = 0.044 and 0.205 µg/mL against sensitive and resistant strain of P. falciparum, respectively). Docking simulation, in silico drug-likeness and ADMET studies further validated the results of in vitro antimalarial activity. Trioxane derivatives exhibited good binding affinity for the P. falciparum cysteine protease falcipain 2 receptor (PDB id: 3BPF) with well defined drug-like and pharmacokinetic properties based on Lipinski’s rule of five with additional physicochemical and ADMET parameters. In view of having antimalarial potential, newly reported 1,2,4-trioxane derivative(s) may be useful as novel antimalarial lead(s) in the discovery and development of future antimalarial drug candidates as P. falciparum falcipain 2 inhibitors against resistant malaria.

Synthesis, antimalarial activity evaluation and docking studies of some novel tetraoxaquines

Tetraoxaquines, molecular hybrids of 1,2,4,5-tetraoxane and 4-aminoquinoline, were designed via molecular docking analysis against Falcipain-2. Among the studied compounds, 11 top scoring analogues showing low binding energy were further selected for synthesis and evaluated for their in vitro antimalarial activity. In inhibitory assay, five compounds showed significant activity against chloroquine-resistant strain of P. falciparum-RKL-9 with IC50 values of 3.906, 3.942, 4.272, 3.906, 4.814 µg/ml.

Ethno-medicinal Survey on Tai-Ahom Community of Assam

Abstract An ethno-medicinal survey among the Tai-Ahom community of Assam was undertaken to gather knowledge on different medicinal formulations that are prepared and administered by their bejes/bejinis (medicine men/women). In this study, treatments mentioned in ancestral manuscripts, their methods of preparation, formulations and their applications in different diseases have been described. Ways of diagnosing the diseases, precautions to be maintained while on treatment, adverse effects, and follow up treatments have also been mentioned. The objective was to search for novel plants having medicinal value and to understand the importance of their traditional medicinal preparations and their relevance in the modern era. Besides providing information about the properties of some uncommon plants the data offers new insight to the usage of some of these medicinal preparations and reinforces the need for safeguarding these methods for further assessment.

Synthesis and Evaluation of Some New Isoquine Analogues for Antimalarial Activity

Amodiaquine is a 4-aminoquinoline antimalarial that can cause adverse side effects including hepatic and haematological toxicity. The drug toxicity involves the formation of an electrophilic metabolite, amodiaquine quinoneimine (AQQI), which binds to cellular macromolecules leading to hepatotoxicity and agranulocytosis. Interchange of the 3ʼ hydroxyl and the 4ʼ Mannich side-chain function of amodiaquine provides an amodiaquine regioisomer (isoquine) that cannot form toxic quinoneimine metabolites. By a simple two-step procedure, four isoquine analogues were synthesized and subsequently evaluated against the chloroquine sensitive RKL-2 strain of Plasmodium falciparum in vitro. All synthesized analogues demonstrated differential level of antimalarial activity against the test strain. However, no compound was found to exhibit better antimalarial property as compared to chloroquine.