Bacterial cell death to overcome drug resistance with multitargeting bis-naphthalimides as potent antibacterial agents against Enterococcus faecalis.

The increasing frequency of drug-resistant pathogens poses serious health issues to humans around the globe, leading to the development of new antibacterial agents to conquer drug resistance and bacterial infections. In view of this, we have synthesized a series of bis-naphthalimides to respond to awful drug resistance. Bioactivity assay and structure-activity relationship disclosed that compounds 5d and 5o exhibit potent antibacterial activity against E. faecalis, outperforming the marketed antibiotics. These drug candidates not only inhibit the biofilm formation of E. faecalis but also display rapid bactericidal properties, thus delaying the development of drug resistance within 20 passages. To explore the mechanism of antibacterial activity against E. faecalis, biofunctional examination was carried out which unveiled that 5d and 5o effectively disrupt bacterial cell membranes, causing the leakage of cytoplasmic contents and metabolic activity loss. Concurrently, 5d and 5o effectively intercalate with DNA to block DNA replication, causing the build-up of excessive reactive oxygen species and inhibiting the glutathione activity, ultimately leading to oxidative damage of E. faecalis and cell death. In addition, these compounds readily bind with HSA with a high binding constant, indicating that these drug candidates could be easily delivered to the target site. The above finding manifested that these newly synthesized bis-naphthalimides with multitargeting antibacterial properties offer a new prospect to overcome drug resistance.

Investigating the Serum Albumin Binding Behavior of Naphthalimide Based Fluorophore Conjugates: Spectroscopic and Molecular Docking Approach.

In the present study, naphthalimide-pyrazole-benzothiazole based fluorescent analogs were synthesized by substituting different primary and secondary amines on the naphthalimide nucleus and were evaluated for their sensitivity and selectivity towards serum albumin. Among various synthesized analogues compound 25 showed the most significant change with serum albumin and was further studied for selective detection and mode of interaction with serum albumin. Here, we compared the binding interaction of fluorescent probe 25 for variation/detection of two 76 % structurally resembling proteins HSA and BSA, by spectroscopic experiments. The compound shows more selectivity for HSA and BSA with a higher binding constant and evident visible change in the emission spectra of two serum albumins among different bioanalytes. The mode of interaction of 25 with human serum albumin and bovine serum albumin was investigated by FT-IR, circular dichroism, and DLS techniques to find out the change in the microenvironment and variation in the structure of serum albumin proteins. Higher binding affinity and specific selectivity of 25 with a limit of detection of 0.69 µM and 1.4 µM towards HSA and BSA compared to other bioanalytes make it a significant fluorescent probe for quantitatively detecting serum albumins at the very early stage of many fatal diseases.

Ruthenium(II)-Catalyzed Sequential C-H/N-H Alkene Annulation Cascade of Phenanthroimidazoles: Synthesis and Photophysical Studies.

We report ruthenium(II)-catalyzed sequential C-H/N-H alkenylation cascade of phenanthroimidazole and alkenes to form novel phenanthroimidazoisoindol acrylates via dual C-H activation and aza-Michael reaction. The two nitrogen atoms of the imidazole ring act as directing groups for regioselective dual sequential ortho C-H activation. These polycyclic N-heterocycles were evaluated for their photophysical properties.

Membrane-active substituted triazines as antibacterial agents against Staphylococcus aureus with potential for low drug resistance and broad activity.

A library of new naphthalimide-triazine analogues was synthesized as broad-spectrum antibacterial agents to overcome drug resistance. Bioactivity assay reveals that derivative 8e, with benzylamine in its structure, exhibits strong antibacterial properties against multi-drug resistance Staphylococcus aureus at a concentration of 1.56 µg/ml. It was also found to be better than chloromycin and amoxicillin. The active compound 8e efficiently inhibits the development of drug resistance within 11 passages. In addition, compound 8e inhibits the formation of biofilms in S. aureus and acts rapidly in bactericidal efficacy. Furthermore, mechanistic studies reveal that compound 8e effectively destroys the cytoplasmic membrane of bacteria, leading to leakage of intercellular protein content and loss in metabolic activity. Compound 8e binds to HSA readily with a binding constant of 1.32 × 105 M-1, indicating that the compound could be delivered to the target site effectively. Compound 8e can also form a supramolecular complex with DNA to obstruct DNA replications. These results suggest that analogue 8e could be further developed as a potential antibacterial agent. Furthermore, the cytotoxicity of all the synthesized compounds was evaluated against 60 human cancer cell lines to test their potential for anticancer agents.

One-Pot Cascade Access to Ru(II)-Catalyzed Regioselective C(sp2)-H Activation/Alkenylation of Chromeno[4,3-c]pyrazol-4-ones and Their Emission Solvatochromic Studies.

Herein, one-pot cascade synthesis of chromeno[4,3-c]pyrazol-4-ones and their Ru(II)-catalyzed regioselective ortho-alkenylation using imine as a weak directing group are done with moderate to good yields. The reaction proceeds through a three-step domino process during which intermediates are also isolated in excellent yields. In addition, this methodology generates a number of interesting fluorophores with donor and acceptor groups, which show positive solvatochromism.

Ru(II)-Catalyzed Regioselective C(5)-H Functionalization of Quinazolinone-Coumarin Conjugates: Synthesis and Photophysical Studies.

The quinazolinone template offers an exciting potential for transforming molecules into useful bioactivity. Herein, we report the first regioselective C-5 alkenylation of quinazolinone-coumarin conjugates via ruthenium(II) catalyst using amide as a weak directing group. This methodology permits excellent regioselectivity, extensive substrate tolerance, and mild reaction conditions. In addition, it generates interesting fluorophores that show positive solvatochromism in the range from 404 nm (toluene) to 541 nm (methanol).

Synthesis, characterization and antitubercular activities of heterocyclic selenosemicarbazones.

Reaction of cyclohexanoneselenosemicarbazone with aldehydes and ketones containing heterocyclic rings (2-oxindole, 6-cholro-2-oxindole, 3-methyl-2-oxindole, isatin, 1-methyl isatin, furfural, pyrrole-2-carboxldehyde) in ethanol yielded, respective, selenosemicarbazones {2-oxindoleselenosemicarbazone (2-HOxsesc,H1L), 6-chloro-2-oxindole selenosemicarbazone (6-ClHOxsesc, H2L), 3-methyl-2-oxindole selenosemicarbazone (3-MeHOxses, H3L), isatinselenosemicarbazone (HIstsesc, H4L), 1-methyl isatinselenosemicarbazone (1-MeHIstsesc, H5L), 2-thiopheneselenosemicarbazone (2-Hthiosesc, H6L), 2-furfuralselenosemicarbazone (2-Hfursesc, H7L) and 2-pyrrole selenosemicarbazone (2-Hpysesc, H8L)}. However the similar reaction with aldehyde containing single aromatic ring (3-chlorobenzaldehyde and 4-chlorobenzaldehyde) formed 1, 2-bis(3-chlorobenzylidiene) hydrazine (A) and 1, 2-bis(4-chlorobenzylidiene) hydrazine (B) rather than selenosemicarbazone. All the synthesized compounds were characterized using IR and NMR (1H, 13C) spectroscopy. Structure of A and B were confirmed by single crystal X-ray crystallography. The synthesized selenosemicarbazones were tested for their anti-tubercular activities and H1L, H3L, H5L and H6L are found to exhibit excellent anti-TB activity. The experimental data will give an opportunity to examine their anti-tubercular activities and identify the lead molecule.

Recent developments on 1,8-Naphthalimide moiety as potential target for anticancer agents.

1,8-Naphthalimide moiety is well known to possess various biological activities as it can very well intercalate with DNA. In recent years, much of the attention has been given to the preparation of naphthalimide derivatives by substitution at various positions of the 1,8-naphthalimide ring for their exploration as anticancer agents. These derivatives possess different anticancer properties, which cover a broader range of cancer cell lines. Interestingly, some derivatives include enhanced activity than the reference standards like cisplatin, amonafide, mitonafide, etc., and be selective against the cell lines. The aim is to study the effect of different modulations at various positions of the 1,8-naphthalimide ring with a polyamine, thiourea, benzothiazole, benzimidazole, and formation of metal complexes and bis-naphthalimides that affects the overall cytotoxic properties of the resulting 1,8-naphthalimides. Moreover, the structure-activity relationship of these variations for the resulting derivatives' anticancer properties has also been discussed. Thus, this review will be important for a wide range of researchers to design and development of various 1,8-naphthalimide derivatives with desired drug profiles.

Interleukin Receptor Antagonists and Janus Kinase Inhibitors Repurposed for Treatment of COVID-19.

SARS-CoV-2 infection is the most contagious among the three coronavirus infections the world has witnessed to date, which has affected almost all parts of the world in millions of population since its outbreak in China in December 2019. Moreover, it has severely hit the world economy and therefore there is a dire need to develop the treatment of this deadly disease. A number of potential vaccines are in the early or advanced stage of clinical trials. But the development of a vaccine is a very tedious and time-consuming task. Therefore, various groups are working on repurposing of drugs with already known safety and efficacy profiles to shorten the time of development of the potential treatment. The main aim of this review article is to summarize the clinical outcomes of Interleukin receptor antagonists and Janus kinase inhibitors based drugs which have been repurposed for the treatment of COVID-19 associated with SARS-CoV-2.

A review on diverse heterocyclic compounds as the privileged scaffolds in non-steroidal aromatase inhibitors.

Breast cancer, emerging malignancy is common among women due to overexpression of estrogen. Estrogens are biosynthesized from androgens by aromatase, a cytochrome P450 enzyme complex, and play a pivotal role in stimulating cell proliferation. Therefore, deprivation of estrogen by blocking aromatase is considered as the effective way for the inhibition and treatment of breast cancer. In recent years, various non-steroidal heterocyclic functionalities have been extensively developed and studied for their aromatase inhibition activity. This review provides information about the structural-activity relationship of heterocycles (Type II) towards aromatase. This aids the medicinal chemist around the significance of different heterocyclic moieties and helps to design potent aromatase inhibitors.

Synthesis of Triphenylethylene-Naphthalimide Conjugates as topoisomerase-IIα inhibitor and HSA binder.

A series of triphenylethylene-naphthalimide (TPE-naph) conjugates was synthesized by a molecular hybridization technique, and their anticancer activity was evaluated in vitro on 60 human cancer cell lines through their cytotoxicity. The ratios of E and Z isomers were determined on the basis of HPLC methodology and NMR spectroscopy. The structure-activity relationship for anticancer activity was deduced on the basis of the nature and bulkiness of the amine attached to the C-4 position of the naphthalene ring. Experimental and molecular modeling studies of the most active TPE-naph conjugate bearing a morpholinyl group showed that it was able to inhibit topoisomerase-II (TOPO-II) as a possible intracellular target. Moreover, the transportation behavior of TPE-naph conjugate towards human serum albumin (HSA) indicated efficient binding affinity. The steady-state and time-dependent fluorescent results suggested that this conjugate quenched HSA significantly through static as well as dynamic quenching. Thus, this report discloses the scope of triphenylethylene-naphthalimide (TPE-naph) conjugates as efficient anticancer agents.

Insights of 8-hydroxyquinolines: A novel target in medicinal chemistry.

8-Hydroxyquinoline (8-HQ) is a significant heterocyclic scaffold in organic and analytical chemistry because of the properties of chromophore and is used to detect various metal ions and anions. But from the last 2 decades, this moiety has been drawn great attention of medicinal chemists due to its significant biological activities. Synthetic modification of 8-hydroxyquinoline is under exploration on large scale to develop more potent target-based broad spectrum drug molecules for the treatment of several life-threatening diseases such as anti-cancer, HIV, neurodegenerative disorders, etc. Metal chelation properties of 8-hydroxyquinoline and its derivatives also make these potent drug candidates for the treatment of various diseases. This review comprises 8-hydroxyquinoline derivatives reported in the literature in last five years (2016-2020) and we anticipate that it will assist medicinal chemists in the synthesis of novel and pharmacologically potent agents for various therapeutic targets, mainly anti-proliferative, anti-microbial, anti-fungal and anti-viral as well as for the treatment of neurodegenerative disorders.

Recent Approaches of Repositioning and Traditional Drugs for the Treatment of COVID-19 Pandemic Outbreak.

The recent emergence of novel, pathogenic COVID-19 disease associated with SARSCoV- 2 virus in China and its rapid national and international spread pose a global health emergency. The development of a new drug is tedious and may take decades to develop and involve multiple steps like the development of prototypes and phase I to III human trials, which involve the study on small to large populations to examine the safety and side effects associated with the drug under trials. Due to continous increase in the number of confirmed cases and deaths, there is an urgent need to develop a drug that is effective to kill the SARS-CoV-2 virus with fewer side effects to the human body. Therefore, this review focus on the latest advances in the development for the treatment of COVID-19 disease associated with SARS-CoV-2 with repositioning of already marketed drug with small molecules, as well as Chinese traditional medicines with established safety and efficacy which are being used for different therapeutic uses.

Dual-channel ratiometric recognition of Al3+ and F- ions through an ESIPT-ESICT signalling mechanism.

An optical probe 1 has been synthesized comprising naphthalimide unit conjugated with Schiff base, exhibiting excited state intramolecular proton transfer and intramolecular charge transfer as a potential sensor for Al3+ and F- ions using standard spectroscopic techniques. The probe 1 exhibited local and charge-transfer excitation at 340 nm and 460 nm, respectively. On excitation at 460 nm, probe 1 displayed two emission bands at 510 nm and 610 nm, accompanied by Stokes' shift of 50 nm and 150 nm, respectively. The solvatochromic effect and theoretical calculation depicted that the representative emissions resulted from the ESICT/ESIPT phenomenon. Upon addition of Al3+ ions, the charge transfer excitation at 460 nm was enhanced ratiometrically to local excitation at 340 nm and showed a color change from orange to yellow. Similarily, probe 1.Al3+ displayed emission enhancement at 540 nm in H2O/CH3CN (1:9; v/v) and showed a color change from yellow to blue-green emission. Following the detection of Al3+ ions, hydrolysis of probe 1 to its reacting precursors was observed. The detection of Al3+ ions was also demonstrated in surfactant-containing water. The limit of detection (LOD) of probe 1 (H2O/CH3CN (1:9; v/v)) towards Al3+ ions was measured to be 3.2 × 10-8 M. The probe 1 displayed a ratiometric absorption response towards F- ions with a new peak at 570 nm and showed a color change from orange to purple. The probe 1.F- displayed a decrease in emission at 635 nm. The LOD of probe 1 (CH3CN) towards F- ions was measured to be 7.5 × 10-7 M.

Synthesis and photobiological applications of naphthalimide-benzothiazole conjugates: cytotoxicity and topoisomerase IIα inhibition.

Conjugates of naphthalimide, benzothiazole, and indole moieties are synthesized that show excellent cytotoxicity against A549 (lung), MCF7 (breast), and HeLa (cervix) cancer cell lines with IC50 values in the range of 0.14-8.59 µM. Compounds 12 and 13 substituted with ethanolamine and propargyl groups reveal potent cytotoxicity towards A549 cancer cells with IC50 values of 140 and 310 nM, respectively. These compounds are further evaluated as potent inhibitors of human type IIα topoisomerase. These conjugates also reveal strong interaction towards human serum albumin (HSA) with binding constant values of 1.75 × 105 M-1 and 1.88 × 105 M-1, respectively, and formation of the stable complex at ground state with static quenching. Docking studies also confirm the effective interactions between conjugates and topoisomerase.

Current progress, challenges and future prospects of indazoles as protein kinase inhibitors for the treatment of cancer.

The indazole core is an interesting pharmacophore due to its applications in medicinal chemistry. In the past few years, this moiety has been used for the synthesis of kinase inhibitors. Many researchers have demonstrated the use of indazole derivatives as specific kinase inhibitors, including tyrosine kinase and serine/threonine kinases. A number of anticancer drugs with an indazole core are commercially available, e.g. axitinib, linifanib, niraparib, and pazopanib. Indazole derivatives are applied for the targeted treatment of lung, breast, colon, and prostate cancers. In this review, we compile the current development of indazole derivatives as kinase inhibitors and their application as anticancer agents in the past five years.

Copper(I) and silver(I) complexes of anthraldehyde thiosemicarbazone: synthesis, structure elucidation, in vitro anti-tuberculosis/cytotoxic activity and interactions with DNA/HSA.

A reaction of copper(i) halides (X = I, Br, Cl) and silver(i) halides with 9-anthraldehyde thiosemicarbazone (9-Hanttsc, H1L) and triphenylphosphine produced halogen-bridged dinuclear complexes, [M2(µ2-X)2(η1-S-9-Hanttsc)2(Ph3P)2] (M = Cu, X = Cl, 1; Br, 2; I, 3; M = Ag, X = Cl, 4; Br, 5). A similar reaction of 9-anthraldehyde-N1-methyl thiosemicarbazone (9-Hanttsc-N1-Me, H2L) with Ph3P and silver(i) halides yielded sulfur-bridged dimers, [Ag2X2(µ2-S-9-Hanttsc-N1-Me)2(Ph3P)2] (X = Cl, 9; Br, 10), however with copper(i) halides insoluble compounds were formed, which upon the addition of one extra mole of Ph3P gave mononuclear complexes of the formula [CuX(η1-S-9-Hanttsc-N1-Me)(Ph3P)2] (X = Cl, 6; Br, 7; I, 8). All of the complexes have been characterized by elemental analysis, NMR (1H, 13C) spectroscopy and single crystal X-ray crystallography (2, 5, 6, and 9). Both the ligands (H1L and H2L) and their complexes (1-10) were tested for their anti-tubercular and anticancer activities. The interactions of the ligands and their complexes (copper and silver) with calf thymus DNA (ct-DNA) and human serum albumin (HSA) were examined through UV-visible and fluorescence spectroscopy. Results showed that copper complex 2 displayed strong interactions with ct-DNA and HSA having binding constant values of 6.66 × 104 M-1 and 3.28 × 104 M-1, respectively, followed by silver complex 10 which gave binding constant values of 4.60 × 104 M-1 and 3.06 × 104 M-1, respectively. All of the complexes also showed good interactions with DNA in docking studies.

8-Hydroxyquinoline Fluorophore for Sensing of Metal Ions and Anions.

Among various known hydroxyquinolines, 8-hydroxyquinoline (8-HQ) is the most prevalent moiety due to excellent property for the formation of the complex with different metal ions and anions, and utilized in a wide variety of applications in pharmacological and medicinal fields. 8-Hydroxyquinoline moiety and its analogues acts as fluorophoric ligands on complex formation with alkali and alkaline as well as transition metal ions and anions, thus, considered as an ideal building block in metallo-supramolecular chemistry for recognition, separation, and quantitative investigation of cations. 8-Hydroxyquinoline moiety is also used in various applications for the advancement of novel fluorescent chemosensors in a wide variety of areas viz., material chemistry, bioorganic chemistry, molecular imaging, analytical chemistry, molecular recognition, medical and biological science communities. The present review emphasises on the progress of sensing properties of 8-HQ centred small-molecule fluorescent chemosensors towards several metal ions viz., Fe3+ , Al3+ , Ag+ , Hg2+ , Cu2+ , Pd2+ , Zn2+ , Cr3+ , Cd2+ , Mn2+ , Ca2+ , and K+ and anions such as F- , CN- and PPi, from 2008 to 2020, because of their sensitivity and selectivity in terms of diverse colour changes for different species. This critical and comprehensive review might facilitate the improvement of more prevailing chemosensors for future exciting and broad applications.

Di-2-pyridylketone-N1-substituted thiosemicarbazone derivatives of copper(II): Biosafe antimicrobial potential and high anticancer activity against immortalized L6 rat skeletal muscle cells.

The basic aim of this study pertains to developing antimicrobial or anticancer agents based on N, S-donor organic ligands bonded to metals. In the present investigation, di-2-pyridylketone-N1-substituted thiosemicarbazone (py2tscH-N1HR2, Chart 2) thio-ligands were reacted with copper(I) halides in organic solvents yielding copper(II) complexes of stoichiometry, [Cu(N,N,S-py2tsc-N1HR2)X] (X = I, R2 = H, 1; Me, 2; Et, 3; Ph, 4; X = Br, R2 = H, 5; Me, 6; Et, 7; Ph, 8; X = Cl, R2 = H, 9; Me, 10; Et, 11; Ph, 12); the formation of CuII probably occurs through a proton coupled electron transfer (PCET) process. Electron spin resonance, ultraviolet-visible spectroscopy and X-ray crystallography (2, 3, 5, 7, 11) supported a distorted square planar geometry of these complexes. Moderate to high antimicrobial activities of these complexes against methicillin resistant Staphylococcus aureus, Gram positive bacteria, Staphylococcus aureus and Gram negative bacteria, Klebsiella pneumoniae 1, Salmonella typhimurium 2 and one yeast Candida albicans were recorded. Complexes were found to be biosafe with 88-91% cellular viability. All complexes have shown high anticancer activity against the immortalized L6 rat skeletal muscle cell line with very low IC50 values.