Unlocking InhA: Novel approaches to inhibit Mycobacterium tuberculosis.

Multidrug-resistant tuberculosis continues to pose a health security risk and remains a public health emergency. Antimicrobial resistance result from treatment regimens that are both insufficient and incomplete leading to the emergence of multidrug-resistant tuberculosis, extensively drug-resistant tuberculosis and totally drug-resistant tuberculosis. The impact of tuberculosis on the people suffering from HIV (Human immunodeficiency virus infection) have resulted in the increased research efforts in designing and discovery of novel antitubercular drugs that may result in decreasing treatment duration, minimising the need for multiple drug intake, minimising cytotoxicity and enhancing the mechanism of action of drug. While many drugs are available to treat tuberculosis, a precise and timely cure is still absent. Consequently, further investigation is needed to identify more recent molecular equivalents that have the potential to swiftly remove this disease. Isoniazid (INH), a treatment for tuberculosis (TB), targets the enzyme InhA (mycobacterium enoyl acyl carrier protein reductase), the Mycobacterium tuberculosis enoyl-acyl carrier protein (ACP) reductase, most common INH resistance is circumvented by InhA inhibitors that do not require KatG (catalase-peroxidase) activation, as a result, researchers are trying to work in the area of development of InhA inhibitors which could help in eradicating the era of tuberculosis from the world.

Direct Conversion of Carboxylic Acids to Various Nitrogen-Containing Compounds in the One-Pot Exploiting Curtius Rearrangement.

Herein we report, a single-pot multistep conversion of inactivated carboxylic acids to various N-containing compounds using a common synthetic methodology. The developed methodology rendered the use of carboxylic acids as a direct surrogate of primary amines, for the synthesis of primary ureas, secondary/tertiary ureas, O/S-carbamates, benzoyl ureas, amides, and N-formyls, exploiting the Curtius reaction. This approach has a potential to provide a diversified library of N-containing compounds, starting from a single carboxylic acid, based on the selection of the nucleophile.

Rhodium-catalyzed intramolecular [3+2+2] cycloadditions between alkylidenecyclopropanes, alkynes, and alkenes.

A Rh-catalyzed intramolecular [3+2+2] cycloaddition is reported. The cycloaddition affords synthetically relevant 5,7,5-fused tricyclic systems of type 2 from readily available dienyne precursors. The transformation takes place with moderate or good yields, high diastereoselectivity, and total chemoselectivity.

Perylene diimide appended with 8-hydroxyquinoline for ratiometric detection of Cu2+ ions and metal displacement driven "turn on" cyanide sensing.

Perylene diimide (PDI) 3 and 4 appended with 8-hydroxyquinoline derivatives have been synthesized and their photophysical and spectroscopic properties have been experimentally determined. Moreover, PDIs 3 and 4 show ratiometric behavior to detect Cu(2+) colorimetrically with visible color change from coral red to light pink, whereas 3 and 4 show "turn-off" behavior in fluorescence with lowest limit of detection 5 × 10(-7) M. The PDI 3 could be further utilized for ratiometric CN(-) detection colorimetrically and as "turn-on" sensor for CN(-) detection fluorometrically with lowest limit of detection 8 × 10(-6) M. The comparison of spectroscopic properties of PDI 1-4 highlights the importance of linking 8-hydroxyquinoline units on the PDI core at bay position for achieving Cu(2+) recognition event into ratiometric signal.

Rapid and Environmentally-Friendly Synthesis of Thiazolidinone Analogues in Deep Eutectic Solvent Complemented with Computational Studies.

A greener, safer, and more efficient methodology for the synthesis of (Z)-5-benzylidene-2-thioxothiazolidin-4-ones (3 a-u) and (Z)-5-benzylidenethiazolidine-2,4-diones (4 a-i) has been developed. The deep eutectic solvent (DES) ZnCl2/urea used as a greener solvent as well as a catalyst in this study accelerated the condensation of rhodanine and thiazolidine-2,4-dione with different aldehydes to afford the target scaffolds in excellent yields (88-98 %). The reaction methodology adopted offered significant advantages such as mild reaction conditions, functional group tolerance, quick reaction time, column-free isolation, catalytic recyclability, and applicability to gram-scale production. Moreover, density function theory calculations were carried out to investigate the global reactivity and stability profiles of these compounds. Finally, the green metrics analysis supported the greener nature of the present methodology.

Highly regioselective 6-exo-dig iodo/bromo cyclizations of functionalized 5-amino propargyl pyrimidinones: an efficient synthesis of functionalized pteridines.

The manuscript describes the highly regioselective 6-exo-dig iodo/bromo cyclization of functionalized N-propagyl-amino-pyrimidinones under ambient conditions. The cyclization afforded functionalized pteridines in excellent yields. The optimized procedures are mild, operationally simple and working successfully with different substrates. The synthesis of functionalized pteridines is of great significance because of their potential pharmacological profile.

Self-assembled nanofibers of perylene diimide for the detection of hypochlorite in water, bio-fluids and solid-state: exogenous and endogenous bioimaging of hypochlorite in cells.

A fluorescent probe PDI-DAMN based on perylenediimide containing diaminomaleonitrile at the bay-position was designed and synthesized for the detection of ClO-. PDI-DAMN self-assembled as nanofibers with diameters in the range of 100-200 nm in H2O : CH3CN (1 : 1). The addition of ClO- into PDI-DAMN resulted in the disintegration of nanofibers into flake-like aggregates of smaller size (50-80 nm) as supported by SEM and DLS data. The addition of ClO- to HEPES buffer-CH3CN solution (1 : 1, v/v, pH 7.4) of PDI-DAMN caused a hypochromic effect on the ICT band at 528 nm and 'turn-on' fluorescence enhancement at 508/554 nm due to the oxidative cleavage of -C[double bond, length as m-dash]N- bond. A linear correlation plot between the concentration of ClO-versus fluorescence intensity (R2 = 0.9968)/absorbance (R2 = 0.9988) in the concentration range 0-7 nM (fluorescence)/0-90 nM (absorbance) could determine ClO- with the detection limits of 1 and 10 nM, respectively. Optical studies performed on spiked urine and blood serum samples showed good estimation and recovery of ClO- (100 ± 5%). TLC-based test-strips coated with PDI-DAMN changed colour upon the addition of ClO- with detection as low as 7.44 ng cm-2. The application of PDI-DAMN for the bio-imaging of both exogenous and endogenous ClO- in MG-63 cells with good biocompatibility has also been demonstrated. The detailed mechanism of the interactions of ClO- with PDI-DAMN using 1H NMR titration, DFT studies and response mechanism of pH are also discussed.

Transition metal catalyzed [6 + 2] cycloadditions.

The [6 + 2] cycloaddition reactions are one of the important synthetic transformations to construct eight membered carbo-/heterocyclic systems. The present review is an attempt to update readers on transition metal catalyzed [6 + 2] cycloaddition reactions of various 6π-contributing substrates such as cycloheptatrienes (CHT), cyclooctatetrenes (COTT), allenals, vinylcyclobutanones, fulvene etc. employing rhodium, cobalt, titanium, copper, platinum, ruthenium, rhenium and diphenylprolinolsilyl ethers etc. as catalysts. The transition metal catalyzed [6 + 2] cycloaddition reactions with a variety of functionalized substrates provide straightforward access to eight membered cyclic and/or 5/8, 6/8 etc. condensed carbo-/heterocyclic molecules in moderate to good yields.

Perylene diimide-Cu2+ based fluorescent nanoparticles for the detection of spermine in clinical and food samples: a step toward the development of a diagnostic kit as a POCT tool for spermine.

The sustainable development of point-of-care testing (POCT) for spermine detection is important to check for food spoilage, early diagnosis of various malignancies and diminished anticonvulsant drug carbamazepine response in chronic epilepsy. Herein, the synthesis, characterization and spectroscopic properties of perylene diimide EA-PDI∩Cu2+ complex based nanoparticles towards spermine were studied in detail. This EA-PDI∩Cu2+ complex can be used for the ultrasensitive detection of spermine as low as 86.3 nM (UV-vis) and 90 pM (fluorescence) in aqueous medium, in urine and blood serum samples (recovery 99 ± 3) and in the solid state (0.1 µg L-1), and EA-PDI shows minimal cytotoxicity to cells and can easily enter into Human Osteosarcoma MG-63 cells for bio-imaging of Cu2+ and spermine. This EA-PDI∩Cu2+ complex can be established as a cost-effective method to develop a diagnostic kit for POCT of spermine in terms of a solution-based test kit for real time detection of spermine in vapor and solution form released from fermented food samples.

PASS-assisted exploration of antidepressant activity of 1,3,4-trisubstituted-beta-lactam derivatives.

Assisted by PASS predictions, the antidepressant activity of 1,3,4-trisubstituted monocyclic beta-lactams in seasonal affective disorders is described.

Multifunctional metallo-supramolecular interlocked hexagonal microstructures for the detection of lead and thiols in water.

We report Pb2+-mediated interlocked hexagonal self-assembly associated with the near-IR (660 nm) 'turn-on' detection of Pb2+ ions (LOD = 25 nM) in water using a perylene diimide derivative (PDI-HQ). The PDI-HQ-Pb2+ complex was further used to develop a fluorescent NIR ensemble for the detection of thiols.

Ionic Self-Assembled Platform of Perylenediimide-Sodium Dodecylsulfate for Detection of Spermine in Clinical Samples.

The detection and quantification of spermine in clinical practice is important for early diagnosis of many diseases. Chromatographic and immunoassay-based methods are commonly used. However, a fluorescence-based assay could provide real-time detection. Herein, the synthesis and aggregation properties of a dicationic perylene probe (N1 -dodecyl-N3 -(4-phenyl)benzimidazolium-functionalized perylenediimide (DAB-PDI)) used to develop a fluorescent "turn-on" ensemble for the detection of spermine are discussed. The fluorescence of DAB-PDI (10 µm, Φ=0.55) is efficiently quenched by negatively charged sodium dodecylsulfate (SDS) through the formation of ionic self-assembled aggregates (charge ratio of negative (N) in SDS to positive (P) in DAB-PDI (N/P)=9). This negatively charged ionic self-assembly between DAB-PDI and SDS has been characterized by using photophysical, microscopic, dynamic light scattering, isothermal titration calorimetry, and HRMS techniques. The addition of spermine to this ensemble solution results in the breakdown of the DAB-PDI-SDS ensemble owing to strong binding of spermine with SDS and, as a result, the fluorescence of DAB-PDI is recovered. This ensemble exhibits high sensitivity and selectivity for spermine detection in water, urine, and blood serum. The lowest limit of detection is 27.5 nm, which is at least about 36 times lower than that required for early diagnosis of cancer (1 to 10 µm for urinary spermine).

Self-assembled vesicle and rod-like aggregates of functionalized perylene diimide: reaction-based near-IR intracellular fluorescent probe for selective detection of palladium.

Herein, we report design, synthesis, and self-assembly of perylene diimide (PDI) based near-IR intracellular probe (PS-PDI). PS-PDI molecules undergo aggregation to form self-assembled nanospheres and nanorods morphology in THF : H2O (1 : 1) and DMSO : H2O (1 : 9), respectively. The nanospheres have an open hole on surface reminiscent of vesicle structure (with a diameter of internal void in the range of 20-25 nm) whereas lengths of the nanorods extended up to few µm range. The Pd0 based depropargylation leads to de-aggregation of these PS-PDI aggregates into smaller spherical aggregates as evidenced by DLS, SEM, and TEM studies. Interestingly, these aggregates of PS-PDI in solution show highly sensitive behavior in the presence of Pd0 showing absorbance changes in NIR region (λmax = 710 nm) and quenching of emission at λem 630 nm (DMSO : H2O, 1 : 9) with a limit of detection = 6.6 × 10-9 M or at λem 564 nm (THF : H2O, 1 : 1) with limit of detection = 2.1 × 10-8 M. Time and concentration dependent kinetics profiles of PS-PDI aggregates revealed an impressive rate constant value of 0.4 s-1 and 0.21 s-1 (DMSO : H2O, 1 : 9), respectively in fluorescence and UV-Vis spectroscopy using 2 × 10-5 M concentration of Pd0. PS-PDI undergoes rapid internalization into HeLa cells with low cytotoxicity and was successfully used as an intracellular imaging reagent for Pd0 in live HeLa cells. For practical applications, we exploited these nano-aggregates of PS-PDI for estimation of Pd2+ in the presence of a NaBH4-PPh3 mixture, Pd0 in drug and environmental samples, and Pd2+ in urine samples with excellent selectivity and sensitivity.

Bay functionalized perylenediimide as a deaggregation based intracellular fluorescent probe for perchlorate.

The aggregates of perylenediimide based chemosensor (PDI 1) undergo de-aggregation induced fluorescence quenching selectively with ClO4(-) ions both in the solution and in the solid phase and can detect ClO4(-) ions in drinking water and fireworks. PDI 1 is permeable to C6 glioma cells, and ClO4(-) can be detected using confocal microscopy.

N-Propargylated isatin-Mannich mono- and bis-adducts: synthesis and preliminary analysis of in vitro activity against Tritrichomonas foetus.

Cu(I)Cl promoted synthesis of N-propargylated-isatin Mannich mono- and bis-adducts with an extension towards the synthesis of N-propargylated-isatin-7-chloroquinoline conjugates was described. The synthesized scaffolds were evaluated for their in vitro activity against the veterinary protozoal pathogen Tritrichomonas foetus and cytotoxicity against human prostate (PC-3) cancer cell line. The preliminary evaluation data revealed the enhancement in the activity profiles with the introduction of 7-chloroquinoline ring with the most active conjugates 7a, 7c and 7d exhibiting an IC50 of 22.2, 11.3 and 24.5 µM respectively against T. foetus and minimal toxicity against human prostate (PC-3) cell lines.

ß-Lactam synthon-interceded diastereoselective synthesis of functionalized octahydroindole-based molecular scaffolds and their in vitro cytotoxic evaluation.

A convenient and unprecedented synthesis of functionally enriched octahydroindole-based scaffolds has been developed via inter- and intra-molecular amidolysis of C-3 functionalized ß-lactams. The cytotoxic evaluation on oesophageal cancer cell line WHCO1 has revealed 7d as the most potent of the test compounds exhibiting an IC(50) value of 12.97 µM. The developed strategy further assumes significance as it entails the preparation of highly functionalized indoles without the aid of transition metal catalysis or pre-functionalization of substrates.

Palladium-catalyzed [3C + 2C + 2C] cycloaddition of enynylidenecyclopropanes: efficient construction of fused 5-7-5 tricyclic systems.

We report a Pd-catalyzed intramolecular [3C + 2C + 2C] cycloaddition between alkylidenecyclopropanes, alkynes and alkenes. The method provides synthetically relevant 5-7-5 tricyclic structures, with good chemoselectivity and complete diastereoselectivity.