Design, synthesis and biological evaluation of phenanthridine amide and 1,2,3-triazole analogues against Mycobacterium tuberculosis.

The phenanthridine core exhibits antitubercular activity, according to reports from the literature. Several 1,2,3-triazole-based heterocyclic compounds are well-known antitubercular agents. A series of twenty-five phenanthridine amide and 1,2,3-triazole derivatives are synthesized and analyzed using ESI-MS, 1HNMR, and 13CNMR on the basis of our earlier findings that phenanthridine and 1,2,3-triazoles shown good antitubercular activity. The synthesized phenanthridine amide and 1,2,3-triazole analogues were tested in vitro against Mycobacterium tuberculosis H37Rv and minimum inhibitory concentration (MIC) values were determined utilizing non-replicating and replicating low-oxygen recovery assay (LORA) and microplate Alamar Blue assay (MABA) methodologies. The phenanthridine amide derivative PA-01 had an MIC of 61.31 µM in MABA and 62.09 µM in the LORA technique, showing intense anti-TB activity. Amongst the phenanthridine triazole derivatives, PT-09, with MICs of 41.47 and 78.75 µM against the tested strain of Mtb in both MABA and LORA was the most active one. The final analogues' drug-likeness is predicted using absorption, distribution, metabolism, excretion, and toxicity (ADMET) studies. The most active compounds PA-01 and PT-09 were further subjected to in silico docking studies. Using the Glide module of Schrodinger, molecular docking analysis was carried out to estimate the plausible binding pattern of PA-01 and PT-09 at the active site of Mycobacterial DNA topoisomerase II (PDB code: 5BS8). Further, molecular dynamics studies of PA-01 and PT-09 were also carried out.

Visible light sensing of ions by a cyanoquinoxaline 1,4-dioxide-based probe and its applications.

Inducting newer fluorophores for colourimetry/fluorimetry-assisted analyte sensing is of great importance. Towards this end, we have shown the application of quinoxaline-1,4-dioxide bioactive molecules for the first time as potential probes for cations and anions. The molecule (ACQ) used in this study is soluble in water and provides specific colour output upon interaction with copper and palladium ions. Changing the solvent to DMSO allows a change in selectivity to fluoride ions via pink to blue colour change. All the ions detected showed quenching of the fluorescence signal upon interaction with the probe. Analysis of the Stern-Volmer plot indicated the predominant role of static quenching in the selective ion-sensing behaviour of the probe. The stoichiometry of the ACQ and ion was 2 : 1 in the case of Cu2+ and Pd2+, whereas a ratio of 1 : 1 was seen in the case of F-. We have also applied ACQ to probe the above-mentioned analytes in practical settings.

Retrospective Review of Chromane Analogues as Anti-protozoal Leads: A Decade's Worth of Evolution.

Tropical, vector-borne, and neglected diseases with a limited number of medication therapies include Leishmaniasis, Malaria, Chagas and Human African Trypanosomiasis (HAT). Chromones are a large class of heterocyclic compounds with significant applications. This heterocycle has long aroused the interest of scientists and the general public from biosynthetic and synthetic points of view owing to its interesting pharmacological activities. Chromones and their hybrids and isomeric forms proved to be an exciting scaffold to investigate these diseases. The in vitro activities of Chromone, Chromane, and a panel of other related benzopyran class compounds against Trypanosoma brucei rhodesiense, Trypanosoma brucei gambiense, Trypanosoma cruzi, and numerous Leishmanial and Malarial species were investigated in our previous studies. The current article briefly describes the neglected diseases and the current treatment. This review aims to attempt to find better alternatives by scrutinizing natural and synthetic derivatives for which chromones and their analogues were discovered to be a new and highly effective scaffold for the treatment of neglected diseases, including compounds with dual activity or activity against multiple parasites. Additionally, the efficacy of other new scaffolds was also thoroughly examined. This article also discusses prospects for identifying more unique targets for the disease, focusing on flavonoids as drug molecules that are less cytotoxic and high antiprotozoal potential. It also emphasizes the changes that can be made while searching for potential therapies-comparing existing treatments against protozoal diseases and the advantages of the newer chromone analogues over them. Finally, the structure- activity relationship at each atom of the chromone has also been highlighted.

Design, synthesis and evaluation of novel phenanthridine triazole analogs as potential antileishmanial agents.

Aim: To synthesize and screen phenanthridine and 1,2,3-triazole derivatives for antileishmanial activity. Methodology: Synthesized analogs were tested for antileishmanial activity against transgenic strain of Leishmania infantum promastigotes and ex vivo infections. Results: Compounds T01, T08 and T11 revealed significant activity with EC50 <30 µm and lacked toxicity in mouse spleen and HepG2 cells. T01 with EC50 3.07 µm is fourfold more potent than the drug miltefosine (EC50 12.6 µM) against L. infantum promastigotes. In silico studies indicate that the analogs are nontoxic. A molecular docking analysis was also carried out on the T01 and T08 to investigate the binding pattern at the active site of the chosen target trypanothione reductase. Conclusion: The results of this study reveal that phenanthridine triazoles exhibit antileishmanial activity.

Design, synthesis and anti-mycobacterial evaluation of imidazo[1,2-a]pyridine analogues.

Based on the molecular hybridization strategy, thirty-four imidazo[1,2-a]pyridine amides (IPAs) and imidazo[1,2-a]pyridine sulfonamides (IPSs) were designed and synthesized. The structures of the target compounds were characterized using 1H NMR, 13C NMR, LCMS, and elemental analyses. The synthesized compounds were evaluated in vitro for anti-tubercular activity using the microplate Alamar Blue assay against Mycobacterium tuberculosis H37Rv strain and the MIC was determined. The evaluated compounds exhibited MIC in the range 0.05-≤100 µg mL-1. Among these derivatives, IPA-6 (MIC 0.05 µg mL-1), IPA-9 (MIC 0.4 µg mL-1), and IPS-1 (MIC 0.4 µg mL-1) displayed excellent anti-TB activity, whereas compounds IPA-5, IPA-7 and IPS-16 showed good anti-TB activity (MIC 0.8-3.12 µg mL-1). The most active compounds with MIC of <3.125 µg mL-1 were screened against human embryonic kidney cells to check their cytotoxicity to normal cells. It was observed that these compounds were nontoxic (SI value ≥66). The ADMET characteristics of the final compounds were also predicted in silico. Further, using the Glide module of Schrodinger software, a molecular docking study of IPA-6 was carried out to estimate the binding pattern at the active site of enoyl acyl carrier protein reductase from Mycobacterium tuberculosis (PDB 4TZK). Finally, molecular dynamics simulations were performed for 100 ns to elucidate the stability, conformation, and intermolecular interactions of the co-crystal ligand and significantly active compound IPA-6 on the selected target protein. IPA-6, the most active compound, was found to be 125 times more potent than the standard drug ethambutol (MIC 6.25 µg mL-1).

Discovery of potent antitubercular agents: Design, synthesis and biological evaluation of 4-(3-(4-substitutedpiperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues.

A series of twenty-five novel 4-(3-(4-substituted piperazin-1-yl)-quinoxalin-2-yl)-naphthalen-1-ol analogues were synthesized, characterized and screened for in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain. These compounds exhibited minimum inhibitory concentration in the range of 1.56-50 µg/mL. Among these derivatives, compounds 5a, 5b, 5f, 5m, 5p, and 5r displayed moderate activity (MIC 6.25 µg/mL). Compounds 5c, 5d, 5g, 5l, and 5o showed significant antitubercular activity (MIC 3.125 µg/mL), while compounds 5h, 5n, and 5q exhibited potent antitubercular activity (MIC 1.56 µg/mL). In addition, MTT assay was performed on the active analogues of the series against mouse macrophage cells to assess the cytotoxic effect of the newly synthesized compounds, and a selectivity index of the compounds was established. Selectivity index values of the most active compounds (5h, 5n, and 5q) are >47, indicating the compounds' suitability for further potential drug development. A molecular docking study was performed to understand the putative binding mode and binding strength of the selected significantly active and weakly active compounds with the target enzyme mycobacterial topoisomerase II using moxifloxacin as standard. In-silico ADME prediction and bioavailability studies of the titled compounds obey Lipinski's rule of five and Jorgensen's rule of three. To further ascertain the structure of the compounds, a suitable single crystal for the compounds 5a, 6, and 7d was developed and studied.

Design, synthesis and structure-activity relationship studies of novel spirochromanone hydrochloride analogs as anticancer agents.

Aim: Literature reports suggest spirochromanone derivatives exhibit anticancer activity. Methodology: The authors designed and synthesized 18 spirochromanone derivatives (Csp 1-18). The compounds were characterized and evaluated for anticancer activity against human breast cancer (MCF-7) and murine melanoma (B16F10) cell lines. Results: The anticancer activity ranged from 4.34 to 29.31 µm. The most potent compounds, Csp 12 and Csp 18, were less toxic against the human embryonic kidney (HEK-293) cell line and ∼ two/∼fourfold selective toward MCF-7 than B16F10 in comparison to the reference, BG-45. Csp 12 caused 28.6% total apoptosis, leading to significant cytotoxicity, and arrested the G2 phase of the cell cycle in B16F10 cells. A molecular docking study of Csp 12 exhibited effective binding at the active site of the epidermal growth factor receptor kinase domain. Conclusion: This study highlights the importance of spirochromanones as anticancer agents.

Design, synthesis and evaluation of novel ß-carboline ester analogues as potential anti-leishmanial agents.

Leishmaniasis is one of today's most neglected diseases. The emergence of new anti-leishmanial therapies emphasizes several study groups funded by the World Health Organization. The present investigation will focus on the research to determine a few new potential derivatives of ß-carboline ester derivatives against leishmaniasis. The in-silico predicted ADMET properties of most of the titled compounds are in an acceptable range and having drug like properties. Among all the tested analogs, compound ES-3 (EC50 3.36 µM; SI > 29.80) showed comparable and equipotent anti-leishmanial activity as that of standard drug miltefosine (EC50 4.80 µM; SI > 20.80) against amastigote forms of the tested L. infantum strain. Two compounds ES-6 and ES-10 exhibited significant activity with EC50 10.16, 13.56 µM; SI > 4.90, 7.37, respectively. In-silico based molecular docking and dynamics study of the significantly active analog also performed to study the putative binding mode, interaction pattern at the active site of the target leishmanial trypanothione reductase enzyme as well as stability of the target-ligand complex. The changes in the conformation of molecules during MD (frame wise trajectory analysis) provided new insights for the development of novel potent molecules. These findings will further give insight that will help modify the compound ES-3 for better potency and the design of novel inhibitors for leishmaniasis.Communicated by Ramaswamy H. Sarma.

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.

Novel phenanthridine amide analogs as potential anti-leishmanial agents: In vitro and in silico insights.

In the current work, sixteen novel amide derivatives of phenanthridine were designed and synthesized using 9-fluorenone, 4-Methoxy benzyl amine, and alkyl/aryl acids. The characterization of the title compounds was performed using LCMS, elemental analysis, 1HNMR, 13CNMR and single crystal XRD pattern was also developed for compounds A8. All the final analogs were screened in vitro for anti-leishmanial activity against promastigote form of L. infantum strain. Among the tested analogs, four compounds (A-06, A-11, A-12, and A-15) exhibited significant anti-leishmanial activity with EC50 value ranges from 8.9 to 21.96 µM against amastigote forms of tested L. infantum strain with SI ranges of 1.0 to 4.3. From the activity results it was found that A-11 was the most active compound in both promastigote and amastigotes forms with EC50 values 8.53 and 8.90 µM respectively. In-silico ADME prediction studies depicted that the titled compounds obeyed Lipinski's rule of five as that of the approved marketed drugs. The predicted in-silico toxicity profile also confirmed that the tested compounds were non-toxic. Finally, molecular docking and molecular dynamics study was also performed for significantly active compound (A-11) in order to study it's putative binding pattern at the active site of the selected leishmanial trypanothione reductase target as well as to understand the stability pattern of target-ligand complex for 100 ns. Single crystal XRD of compound A-08 revealed that the compound crystallizes in monoclinic C2/c space group and showed interesting packing arrangements.

Oxindole and its derivatives: A review on recent progress in biological activities.

Oxindole has been shown to be a pharmacologically advantageous scaffold having many biological properties that are relevant to medicinal chemistry. The simplicity and widespread occurrence of this scaffold in plant-based alkaloids have further reinforced oxindole's merit in the domain of novel drug discovery. First extracted from Uncaria tomentosa, commonly the known as cat claw's plant which was found abundantly in the Amazon rainforest, molecules with the oxindole moiety have been shown to be common in a wide variety of compounds extracted from plant sources. The role of oxindole as a chemical scaffold for fabricating and designing biological drugs agents can be ascribed to its ability to be modified by a number of chemical groups to generate novel biological functions. This review is aimed at providing a description of the general chemistry based on existing corresponding structure-activity relationships (SARs) and compile all recent developmentary studies on oxindole-derived compounds as a successful pharmaceutical agent. A substantial group of oxindole derivatives are chiefly being tested as anticancer agents, however, a several oxindole derivatives have been shown to possesses antimicrobial, α-glucosidase inhibitory, antiviral, antileishmanial, antitubercular, antioxidative, tyrosinase inhibitory, PAK4 inhibitory, antirheumatoid arthritis and intraocular pressure reducing activities, to name a few. In this review we show the potential value of developing newer oxindole derivatives with an improved range of pharmacological implications as well as identifying drugs possessing oxindole core, that are showing and serving increased efficacy in clinical practice.

Medicinal chemistry perspectives of 1,2,3,4-tetrahydroisoquinoline analogs - biological activities and SAR studies.

Isoquinoline alkaloids are a large group of natural products in which 1,2,3,4-tetrahydroisoquinolines (THIQ) form an important class. THIQ based natural and synthetic compounds exert diverse biological activities against various infective pathogens and neurodegenerative disorders. Due to these reasons, the THIQ heterocyclic scaffold has garnered a lot of attention in the scientific community which has resulted in the development of novel THIQ analogs with potent biological activity. The present review provides a much-needed update on the biological potential of THIQ analogs, their structural-activity relationship (SAR), and their mechanism of action. In addition, a note on commonly used synthetic strategies for constructing the core scaffold has also been discussed.

Seeking potent anti-tubercular agents: design and synthesis of substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents.

Pyrazinamide is an important first-line drug used in shortening TB therapy. In our current work, a series of novel substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Ra. Among the tested compounds, five compounds (6a, 6e, 6h, 6j and 6k) from Series-I and one compound (7e) from Series-II exhibited significant activity against Mycobacterium tuberculosis H37Ra with 50% inhibitory concentrations (IC50) ranging from 1.35 to 2.18 µM. To evaluate the efficacy of these compounds, we examined their IC90 values. Five of the most active compounds were found to be more active with IC90s ranging from 3.73 to 4.00 µM and one compound (6e) showed an IC90 of 40.32 µM. Moreover, single crystals were developed for 6d, 6f and 6n. In addition, most active compounds were evaluated for their cytotoxicity on HEK-293 (human embryonic kidney) cells. Our results indicate that the compounds are nontoxic to human cells. The molecular interactions of the derivatised conjugates in docking studies reveal their suitability for further development.

Synthesis, study of antileishmanial and antitrypanosomal activity of imidazo pyridine fused triazole analogues.

Four groups, thirty-five compounds in total, of novel 1,2,3-triazole analogues of imidazo-[1,2-a]-pyridine-3-carboxamides were designed and synthesized using substituted pyridine, propargyl bromide, 2-azidoethyl 4-methyl benzenesulfonate and substituted acetylenes. These compounds were characterized using 1H NMR, 13C NMR, LCMS and elemental analyses and a crystal structure was obtained for one of the significantly active compounds, 8f. All the synthesized and characterized compounds were screened in vitro for antileishmanial and antitrypanosomal activity against Leishmania major and Trypanosoma brucei parasites, respectively. Among the tested analogues, five compounds (8d, 8f, 8j, 10b and 10d) exhibited significant antileishmanial activity while three compounds (10b, 11a and 11b) showed substantial activity against T. brucei parasite. In silico ADME prediction studies depicted that the essential compounds obeyed Lipinski's rule of five. The predicted in silico toxicity profile suggested that the tested compounds would be non-toxic, which was confirmed experimentally by the lack of cytotoxicity against HeLa cells. Finally, a molecular docking study was also performed, for 10d the most active antileishmanial compound, to study its putative binding pattern at the active site of the selected leishmanial trypanothione reductase target.

Design, synthesis and biological evaluation of 1,2,3-triazole based 2-aminobenzimidazoles as novel inhibitors of LasR dependent quorum sensing in Pseudomonas aeruginosa.

Bacteria regulate their phenotype, growth and population via a signalling pathway known as quorum sensing. In this process, bacteria produce signalling molecules (autoinducers) to recognize their population density. Inhibiting this quorum sensing signalling pathway is one of the potential methods to treat bacterial infection. 2-Aminobenimdazoles are reported to be the strongest inhibitors of quorum sensing against wild-type P. aeruginosa. 1,2,3-Triazole based acyl homoserine lactones are found to be good inhibitors of the quorum sensing LasR receptor. Hence, in our current study, forty 1,2,3-triazole based 2-aminobenzimdazoles were synthesized and characterized using IR, NMR, MS and elemental analysis. A single crystal was developed for N-(1H-benzo[d]imidazol-2-yl)-2-(4-nonyl-1H-1,2,3-triazol-1-yl)acetamide (6d). All final compounds were screened for in vitro quorum sensing inhibitory activity against Pseudomonas aeruginosa. The quorum sensing inhibitory activity was determined in the LasR expressing P. aeruginosa MH602 reporter strain by measuring green fluorescent protein production. Among the title compounds, N-(1H-benzo[d]imidazol-2-yl)-2-(4-(4-chlorophenyl)-1H-1,2,3-triazol-1-yl)acetamide (6i) exhibited good quorum sensing inhibitory activity of 64.99% at 250 µM. N-(1H-Benzo[d]imidazol-2-yl)-2-(4-(4-nitrophenyl)-1H-1,2,3-triazol-1-yl)acetamide (6p) exhibited the most promising quorum sensing inhibitory activity with 68.23, 67.10 and 63.67% inhibition at 250, 125 and 62.5 µM, respectively. N-(1H-Benzo[d]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)acetamide (6o) and N-(5,6-dimethyl-1H-benzo[d]imidazol-2-yl)-2-(4-(4-(trifluoromethyl)phenyl)-1H-1,2,3-triazol-1-yl)acetamide (7l) also exhibited 64.25% and 65.80% quorum sensing inhibition at 250 µM. Compound 6p, the most active quorum sensing inhibitor, also displayed low cytotoxicity at the tested concentrations (25, 50 and 100 µM) against normal human embryonic kidney cell lines. Finally, a docking study using Schrodinger Glide elucidated the possible putative binding mode of the significantly active compound 6p at the active site of the target LasR receptor (PDB ID: 2UV0).

Design and synthesis of 9H-fluorenone based 1,2,3-triazole analogues as Mycobacterium tuberculosis InhA inhibitors.

We prepared fifty various 9H-fluorenone based 1,2,3-triazole analogues varied with NH, -S-, and -SO2 - groups using click chemistry. The target compounds were characterized by routine analytical techniques, 1 H, 13 CNMR, mass, elemental, single-crystal XRD (8a) and screened for in vitro antitubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain and two "wild" strains Spec. 210 and Spec. 192 and MIC50 was determined. Further, the compounds were evaluated for MTB InhA inhibition study as well. The final analogues exhibited minimum inhibitory concentration (MIC) ranging from 52.35 to >295 µm. Among the -NH- analogues, one compound 5p (MIC 58.34 µm), among -S- containing analogues four compounds 8e (MIC 66.94 µm), 8f (MIC 74.20 µm), 8g (MIC 57.55 µm), and 8q (MIC 56.11 µm), among -SO2 - containing compounds one compound 10p (MIC 52.35 µm) showed less than MTB MIC 74.20 µm: Compound 4-(((9H-fluoren-9-yl)sulfonyl)methyl)-1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazole (10p) was found to be the most active compound with 73% InhA inhibition at 50 µm; it inhibited MTB with MIC 52.35 µm. Further, 10f and 10p were docked to crystal structure of InhA to know binding interaction pattern. Most active compounds were found to be non-cytotoxic against HEK 293 cell lines at 50 µm.

Seeking potent anti-tubercular agents: Design, synthesis, anti-tubercular activity and docking study of various ((triazoles/indole)-piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole derivatives.

A series of thirty eight novel 3-(4-((substituted-1H-1,2,3-triazol-4-yl)methyl)piperazin-1-yl/1,4-diazepan-1-yl)benzo[d]isoxazole and 1-(4-(benzo[d]isoxazol-3-yl)piperazin-1-yl/1,4-diazepan-1-yl)-2-(1H-indol-3-yl)substituted-1-one analogues were synthesised, characterised using various analytical techniques and evaluated for in vitro anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain and two 'wild' strains Spec. 210 and Spec. 192. The titled compounds exhibited minimum inhibitory concentration (MIC) ranging from 6.16 to >200µM. Among the tested compounds, 7i, 7y and 7z exhibited moderate activity (MIC=24.03-29.19µM) and 7j exhibited very good anti-tubercular activity (MIC=6.16µM). Furthermore, 7i, 7j, 7y and 7z were found to be non-toxic against mouse macrophage cell lines when screened for toxicity. All the synthesised compounds were docked to pantothenate synthetase enzyme site to know deferent binding interactions with the receptor.

Design, synthesis and antimycobacterial activity of various 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole derivatives.

In this communication, we synthesized a series of twenty four novel 3-(4-(substitutedsulfonyl)piperazin-1-yl)benzo[d]isoxazole analogues, characterized using various spectroscopic techniques and evaluated for their in vitro anti-tubercular activity against Mycobacterium tuberculosis (MTB) H37Rv strain. The titled compounds exhibited Minimum inhibitory concentration (MIC) between 3.125 and >50 µg/mL. Among the tested compounds, 5c, 6a, 6j and 6p exhibited moderate activity (MIC = 12.5 µg/mL), while 5a and 6i exhibited good activity (MIC = 6.25 µg/mL) and 6b (MIC = 3.125 µg/mL) exhibited very good anti-tubercular activity. In addition, the analogues 5a, 5c, 6a, 6b, 6i, 6j and 6p were subjected to toxicity studies against mouse macrophage (RAW 264.7) cell lines to analyse the selectivity profile of the newly synthesized compounds and selectivity index of the most active compound was found to be >130 indicating suitability of the compound for further drug development. Structure of 6b was further substantiated through single crystal XRD.

Design, synthesis and antimycobacterial evaluation of 1-(4-(2-substitutedthiazol-4-yl)phenethyl)-4-(3-(4-substitutedpiperazin-1-yl)alkyl)piperazine hybrid analogues.

A series of twenty six new 1-(4-(2-substitutedthiazol-4-yl)phenethyl)-4-(3-(4-substitutedpiperazin-1-yl)alkyl)piperazine analogues were synthesized by seven steps and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv strain. Among the tested compounds, 7j, 7p, and 7r exhibited moderate activity (MIC = 6.25 µg/mL) and compounds 7a, 7f, 7g, 7n and 7v exhibited good activity (MIC = 3.125 µg/mL), while 7h displayed excellent activity (MIC = 1.56 µg/mL) by inhibiting 99% growth of M. tuberculosis H37Rv strain. In addition, all the active compounds were subjected to cytotoxic studies against mouse macrophage (RAW264.7) cell lines and the selectivity index values for most of the compounds is >10 indicating suitability of compounds in an endeavour to attain lead molecule for further drug development.

Synthesis and evaluation of anti-tubercular activity of 6-(4-substitutedpiperazin-1-yl) phenanthridine analogues.

A series of seventeen new 6-(4-substitutedpiperazin-1-yl)phenanthridine derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv by Microplate Alamar Blue Assay and most active compounds were tested for cytotoxicity studies against mouse macrophage cell lines (RAW264.7). Among the tested compounds, ten compounds exhibited significant activity against the growth of M. tuberculosis (MIC ranging from 1.56 to 6.25 µg/mL). In particular, compounds 5e, 5j and 5k displayed excellent activity against the growth of M. tuberculosis (MIC 1.56 µg/mL). The selectivity index values were found to be >25, indicating compounds likeliness in drug development for tuberculosis. The structure of 5k is substantiated by X-ray crystallographic study. Structure-activity correlation indicates the importance of substituent at 4th position of piperazinyl phenanthridine ring.