Greener synthesis of indolizine analogues using water as a base and solvent: Study for larvicidal activity against Anopheles arabiensis

Greener synthesis of a series of novel indolizine analogues have been achieved by the cyclization of aromatic cycloimmonium ylides with electron-deficient alkynes in the presence of water as the base and solvent at 80 °C. Yield of the title compounds was good and reactions performed were eco-friendly. The structures of these newly synthesized compounds have been confirmed by spectroscopic techniques such as FTIR, NMR, LC-MS, and elemental analysis. Characterized title compounds were evaluated for larvicidal activity against Anopheles arabiensis by standard WHO larvicidal assay using Temefos as standard at 4 μg/mL. Title compounds 2e, 2f, and 2g emerged as promising larvicidal agents.Fil: Sandeep, Chandrashekharappa. Institute For Stem Cell Biology And Regenerative Medic; IndiaFil: Venugopala, Katharigatta N.. Durban University Of Technology; SudáfricaFil: Gleiser, Raquel M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinar de Biología Vegetal (P). Grupo Vinculado Centro de Relevamiento y Evaluación de Recursos Agrícolas y Naturales; ArgentinaFil: Chetram, Abeen. Durban University Of Technology; SudáfricaFil: Padmashali, Basavaraj. Rani Channamma University; IndiaFil: Kulkarni, Rashmi S.. Jain University; IndiaFil: Venugopala, Rashmi. University Of Kwazulu-natal; SudáfricaFil: Odhav, Bharti. Durban University Of Technology; Sudáfric

One-pot microwave assisted synthesis and structural elucidation of novel ethyl 3-substituted-7-methylindolizine-1-carboxylates with larvicidal activity against Anopheles arabiensis

In the present investigation a series of novel ethyl 3-substituted-7-methylindolizine-1-carboxylates was achieved by microwave assisted one-pot method. The purity of the compounds was ascertained by HPLC and structural elucidation of the title compounds was achieved by FT-IR, NMR (1H and 13C), LC-MS and elemental analysis. One randomly selected compound from the series was further studied by single crystal X-ray method for intra and intermolecular interactions. Larvicidal properties of the characterized compounds were evaluated against Anopheles arabiensis and it was found that indolizine pharmacophore influences larvicidal activity as we can see larvicidal activity for all the analogues. The synthesized analogues (2j, 2m and 2f) were the most potent compounds based on the functional groups on the indolizine pharmacophore for larvicidal assay.Fil: Chandrashekharappa, Sandeep. Institute For Stem Cell Biology And Regenerative Medicine; IndiaFil: Venugopala, Katharigatta N.. Durban University Of Technology; SudáfricaFil: Nayak, Susanta K.. Visvesvaraya National Institute Of Technology; IndiaFil: Gleiser, Raquel M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto Multidisciplinario de Biología Vegetal. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas Físicas y Naturales. Instituto Multidisciplinario de Biología Vegetal; ArgentinaFil: Garcia, Daniel Asmed. Universidad Nacional de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; ArgentinaFil: Kumalo, Hezekiel M.. University Of Kwazulu-Natal; SudáfricaFil: Kulkarni, Rashmi S.. Jain University; IndiaFil: Mahomoodally, Fawzi M.. University Of Mauritius; MauricioFil: Venugopala, Rashmi. University Of Kwazulu-Natal; SudáfricaFil: Mohan, Mahendra K.. Institute For Stem Cell Biology And Regenerative Medicine; IndiaFil: Odhav, Bharti. Durban University Of Technology; Sudáfric

Synthesis and characterization of pyrrolo[1,2-a]quinoline derivatives for their larvicidal activity against Anopheles arabiensis

Certain tetrahydropyrido[1,2-a]quinolines and pyrroloquinoline homologs have shown various biological activities such as antimicrobials, crop-protectings, diuretics, antioxidants, anticoagulants, and antimalarial activities. Keeping this observation in mind, we envisaged to synthesize and characterize a series of novel ethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-3-carboxylates and dimethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylates (2a-k). Quaternary salts of lepidine such as 1-[2-(substituted phenyl)-2-oxoethyl]-4-methylquinolin-1-ium bromide (1a-f) were obtained by stirring lepidine with different phenacyl bromides in acetone at room temperature separately. These quaternary salts of lepidine (1a-f) were then treated with electron-deficient ethyl propiolate and dimethyl-but-2-yne-dioate separately, in the presence of anhydrous K2CO3 and dimethylformamide (DMF) solvent to obtain ethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-3-carboxylates and dimethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylates, respectively (2a-k). The newly synthesized compounds were assessed by spectroscopic techniques to determine their structures. Based on our previous study on the similar pharmacophore, the synthesized compounds 2a-k were screened for their larvicidal activity against Anopheles arabiensis using a standard World Health Organization larvicidal assay; compounds 2b and 2e at 8.12 and 9.2 μM exhibited the highest larval mortality at 78 and 89%, respectively, when compared with the negative control acetone, and it demonstrated less activity, which was similar to the positive control, temephos. Finally, the test compound 2e at 9.2 μM, resulted in an 89% mortality rate after 48 h of exposure, followed by compound 2b at 8.12 μM with a 78% mortality rate. Compounds 2f, 2d, and 2c showed intermediate toxicity, and the mortality rate was lower than 60% for larvae exposed to any of the remaining test compounds.Fil: Uppar, Vijayakumar. Rani Channamma University; IndiaFil: Chandrashekharappa, Sandeep. National Centre For Biological Sciences; IndiaFil: Venugopala, Katharigatta N.. King Faisal University; Arabia Saudita. Durban University Of Technology; SudáfricaFil: Deb, Pran Kishore. Philadelphia University; JordaniaFil: Kar, Supratik. Jackson State University; Estados UnidosFil: Alwassil, Osama I.. King Saud Bin Abdulaziz University For Health Sciences; Arabia SauditaFil: Gleiser, Raquel M.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinar de Biología Vegetal (P). Grupo Vinculado Centro de Relevamiento y Evaluación de Recursos Agrícolas y Naturales; ArgentinaFil: Garcia, Daniel Asmed. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones Biológicas y Tecnológicas. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Instituto de Investigaciones Biológicas y Tecnológicas; Argentina. Universidad Nacional de Córdoba. Facultad de Ciencias Exactas, Físicas y Naturales. Departamento de Química. Cátedra de Química Biológica; ArgentinaFil: Odhav, Bharti. Durban University Of Technology; SudáfricaFil: Mohan, Mahendra K.. National Centre For Biological Sciences; IndiaFil: Venugopala, Rashmi. University of KwaZulu-Natal; SudáfricaFil: Padmashali, Basavaraj. Rani Channamma University; Indi

Computational, crystallographic studies, cytotoxicity and anti-tubercular activity of substituted 7-methoxy-indolizine analogues.

Indolizines are heteroaromatic compounds, and their synthetic analogues have reportedly showed promising pharmacological properties. In this study, a series of synthetic 7-methoxy-indolizine derivatives were synthesised, characterised and evaluated for in vitro whole-cell anti-tuberculosis (TB) screening against susceptible (H37Rv) and multi-drug-resistant (MDR) strains of Mycobacterium tuberculosis (MTB) using the resazurin microplate assay method. The cytotoxicity was evaluated using the MTT assay. In silico molecular-docking study was conducted for compounds 5a-j against enoyl-[acyl-carrier] protein reductase, a key enzyme of the type II fatty acid synthesis that has attracted much interest for the development of novel anti-TB compounds. Thereafter, molecular dynamic (MD) simulation was undertaken for the most active inhibitors. Compounds 5i and 5j with the methoxy functional group at the meta position of the benzoyl group, which was at the third position of the indolizine nucleus, demonstrated encouraging anti-TB activity against MDR strains of MTB at 16 μg/mL. In silico studies showed binding affinity within the range of 7.07-8.57 kcal/mol, with 5i showing the highest binding affinity. Hydrogen bonding, π-π- interactions, and electrostatic interactions were common with the active site. Most of these interactions occurred with the catalytic amino acids (Pro193, Tyr158, Phe149, and Lys165). MD simulation showed that 5j possessed the highest binding affinity toward the enzyme, according to the two calculation methods (MM/PBSA and MM/GBSA). The single-crystal X-ray studies of compounds 5c and 5d revealed that the molecular arrangements in these two structures were mostly guided by C-H···O hydrogen-bonded dimeric motifs and C-H···N hydrogen bonds, while various secondary interactions (such as π···π and C-H···F) also contributed to crystal formation. Compounds 5a, 5c, 5i, and 5j exhibited no toxicity up to 500 μg/mL. In conclusion, 5i and 5j are promising anti-TB compounds that have shown high affinity based on docking and MD simulation results

Novel Series of Methyl 3-(Substituted Benzoyl)-7-Substituted-2-Phenylindolizine-1-Carboxylates as Promising Anti-Inflammatory Agents: Molecular Modeling Studies

The cyclooxygenase-2 (COX-2) enzyme is considered to be an important target for developing novel anti-inflammatory agents. Selective COX-2 inhibitors offer the advantage of lower adverse effects that are commonly associated with non-selective COX inhibitors. In this work, a novel series of methyl 3-(substituted benzoyl)-7-substituted-2-phenylindolizine-1-carboxylates was synthesized and evaluated for COX-2 inhibitory activity. Compound 4e was identified as the most active compound of the series with an IC50 of 6.71 μM, which is comparable to the IC50 of indomethacin, a marketed non-steroidal anti-inflammatory drug (NSAID). Molecular modeling and crystallographic studies were conducted to further characterize the compounds and gain better understanding of the binding interactions between the compounds and the residues at the active site of the COX-2 enzyme. The pharmacokinetic properties and potential toxic effects were predicted for all the synthesized compounds, which indicated good drug-like properties. Thus, these synthesized compounds can be considered as potential lead compounds for developing effective anti-inflammatory therapeutic agents

Antitubercular, Cytotoxicity, and Computational Target Validation of Dihydroquinazolinone Derivatives

A series of 2,3-dihydroquinazolin-4(1H)-one derivatives (3a–3m) was screened for in vitro whole-cell antitubercular activity against the tubercular strain H37Rv and multidrug-resistant (MDR) Mycobacterium tuberculosis (MTB) strains. Compounds 3l and 3m with di-substituted aryl moiety (halogens) attached to the 2-position of the scaffold showed a minimum inhibitory concentration (MIC) of 2 µg/mL against the MTB strain H37Rv. Compound 3k with an imidazole ring at the 2-position of the dihydroquinazolin-4(1H)-one also showed significant inhibitory action against both the susceptible strain H37Rv and MDR strains with MIC values of 4 and 16 µg/mL, respectively. The computational results revealed the mycobacterial pyridoxal-5′-phosphate (PLP)-dependent aminotransferase (BioA) enzyme as the potential target for the tested compounds. In vitro, ADMET calculations and cytotoxicity studies against the normal human dermal fibroblast cells indicated the safety and tolerability of the test compounds 3k–3m. Thus, compounds 3k–3m warrant further optimization to develop novel BioA inhibitors for the treatment of drug-sensitive H37Rv and drug-resistant MTB

Cytotoxicity and Antimycobacterial Properties of Pyrrolo[1,2-a]quinoline Derivatives: Molecular Target Identification and Molecular Docking Studies

A series of ethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-3-carboxylates 4a–f and dimethyl 1-(substituted benzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylates 4g–k have been synthesized and evaluated for their anti-tubercular (TB) activities against H37Rv (American Type Culture Collection (ATCC) strain 25177) and multidrug-resistant (MDR) strains of Mycobacterium tuberculosis by resazurin microplate assay (REMA). Molecular target identification for these compounds was also carried out by a computational approach. All test compounds exhibited anti-tuberculosis (TB) activity in the range of 8–128 µg/mL against H37Rv. The test compound dimethyl-1-(4-fluorobenzoyl)-5-methylpyrrolo[1,2-a]quinoline-2,3-dicarboxylate 4j emerged as the most promising anti-TB agent against H37Rv and multidrug-resistant strains of Mycobacterium tuberculosis at 8 and 16 µg/mL, respectively. In silico evaluation of pharmacokinetic properties indicated overall drug-likeness for most of the compounds. Docking studies were also carried out to investigate the binding affinities as well as interactions of these compounds with the target proteins