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.

Intramolecular dual hydrogen bonded fluorescent "turn-on" probe for Al3+ and HSO4- ions: Applications in real water samples and molecular keypad lock.

Dual hydrogen bonded Schiff base containing unsymmetrical double proton transfer sites, one with imine bond (CN) and hydroxyl group (OH), and the other with benzimidazole and hydroxyl groups has been successfully synthesized. Probe 1 displayed intramolecular charge transfer and acts as a potential sensor for Al3+ and HSO4- ions. Probe 1 displayed two absorption peaks at 325 nm and 340 nm and an emission band at 435 nm upon excitation at 340 nm. Probe 1 behaves as a fluorescence "turn-on" chemosensor for both Al3+ and HSO4- ions in H2O-CH3OH solvent system. The proposed method allows the determination of Al3+ and HSO4- ions up to 39 nM and 23 nM at emission wavelength 385 nm and 390 nm, respectively. The binding behavior of probe 1 towards these ions is determined by the Job's plot method and 1H NMR titrations. Probe 1 is used to construct a molecular keypad lock where the absorbance channel can be opened only in the presence of the correct sequence. Further, it is used for the quantitative determination of HSO4- ion in different real-field water samples.

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.

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.

Traceless directing groups: a novel strategy in regiodivergent C-H functionalization.

The use of functional groups as internal ligands for assisting C-H functionalization, termed the chelation assisted strategy, is emerging as one of the most powerful tools for construction of C-C and C-X bonds from inert C-H bonds. However, there are various directing groups which cannot be either removed after functionalization or require some additional steps or reagents for their removal, thereby limiting the scope of structural diversity of the products, and the step and atom economy of the system. These limitations are overcome by the use of the traceless directing group (TDG) strategy wherein functionalization of the substrate and removal of the directing group can be carried out in a one pot fashion. Traceless directing groups serve as the most ideal chelation assisted strategy with a high degree of reactivity and selectivity without any requirement for additional steps for their removal. The present review overviews the use of various functional groups such as carboxylic acids, aldehydes, N-oxides, nitrones, N-nitroso amines, amides, sulfoxonium ylides and silicon tethered directing groups for assisting transition metal catalyzed C-H functionalization reactions in the last decade.

Synthesis, cytotoxicity, pharmacokinetic profile, binding with DNA and BSA of new imidazo[1,2-a]pyrazine-benzo[d]imidazol-5-yl hybrids.

Novel derivatives possessing imidazo[1,2-a]pyrazine and 1H-benzo[d]imidazole scaffolds were synthesized using Suzuki-Miyaura cross-coupling reactions. In vitro anticancer activities against NCI-60 cancer cell panels were tested at 10 µM concentration. The best results were obtained from substitution of two 1-cyclohexyl-1H-benzo[d]imidazole groups present at C-6 and C-8 positions of imidazo[1,2-a]pyrazine (31). Compound 31 was found to be cytotoxic against 51 cell lines and cytostatic against 8 cell lines with broad range of growth inhibitions (-98.48 to 98.86%). GI50 value of compound 31 was found in the range of 0.80-2.87 µM for 59 human cancer cell lines at five-dose concentration levels. DNA binding study of potent compound 31 was suggested that this compound was intercalated into DNA base pairs with binding constant of 1.25 × 104 M-1. Compound 31 showed effective binding with bovine serum albumin (BSA) and presented binding constant value of 3.79 ×104 M-1. Pharmacokinetic studies revealed that all compounds are following Lipinski's rule of five and expected to be orally active.

Spectroscopy and molecular docking approach for investigation on the binding of nocodazole to human serum albumin.

The interaction between nocodazole (Nz) and human serum albumin (HSA) under controlled physiological condition (pH 7.4) is examined using absorption, emission, fluorescence lifetime (FLT) and circular dichroism (CD) spectroscopic techniques. The binding constant (order of 105 M-1) from UV-vis and fluorescence spectroscopy reveals a strong interaction between Nz and HSA. Fluorescence quenching study shows that Nz binds with HSA through static quenching process. It is induced by formation of Nz-HSA complex because the Stern-Volmer quenching constant is inversely correlated with the temperature which is further verified by time-resolved fluorescence spectroscopy. The thermodynamic parameters at different temperatures indicate that the binding process is spontaneous where hydrogen bonding interactions and Van der Waals forces play major roles during the interaction between Nz and HSA. By means of spectroscopy and molecular modeling, we have discovered and interpreted the alteration of the secondary structure of HSA by Nz complexation. Synchronous, three-dimensional fluorescence and CD spectroscopic results reveal that the addition of Nz to HSA affects changes in the micro-environment and conformation of HSA. According to Förster Resonance Energy Transfer (FRET), the binding distance (r) between Nz and residue of HSA is <8 nm with excellent energy efficiency. The docking study suggests that nocodazole binds at Domain IIA in the hydrophobic pocket of human serum albumin.

Synthesis of naphthalimide-phenanthro[9,10-d]imidazole derivatives: In vitro evaluation, binding interaction with DNA and topoisomerase inhibition.

The synthesis and characterization of a series of naphthalimide and phenanthro[9,10-d]imidazole conjugate is described. These compounds are evaluated in vitro for their cytotoxicity towards 60 human cancer cell lines. Derivative 16 shows excellent cytotoxic activity against these cancer cell lines with the range of growth inhibition from -55.78 to 94.53. The most potent derivative (ethylpiperazine, 16) is further studied to evaluate the interaction with ct-DNA using absorption and emission spectroscopy as well as DNA viscosity measurement. The DNA binding studies indicate that compound 16 is significantly interacted with DNA through groove binding having binding constant value of 7.81 × 104 M-1 alongwith partial intercalation between the base pairs of DNA strands. Further, topoisomerase inhibition study suggests that compound 16 is induced apoptosis and inhibits human topoisomerase (Topo-IIα) as a possible intracellular target. Molecular docking study of compound 16 with ct-DNA shows good docking score.

Effective synthesis of benzimidazoles-imidazo[1,2-a]pyrazine conjugates: A comparative study of mono-and bis-benzimidazoles for antitumor activity.

A novel series of 6-substituted-8-(1-cyclohexyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine and 6-substituted-8-(1-benzyl-1H-benzo[d]imidazole-6-yl)imidazo[1,2-a]pyrazine is first time synthesized and screen in vitro biological activity for 60 human cancer cell lines representing nine different cancer types. Derivatives 10 and 36 show antitumor activity for all tested cell lines, display comparable full panel mean-graph midpoint growth inhibition (MG_MID GI50) values of 2.10 and 2.23 µM, respectively. Furthermore, these derivatives show strong binding interactions with DNA and bovine serum albumin (BSA), studied through absorption, emission, and circular dichroism techniques. These spectroscopic studies reveal that imidazo[1,2-a]pyrazine-benzimidazoles 10 and 36, intercalate with ct-DNA as a leading interaction for fundamental biologically significant effects, with monobenzimidazole show better activity than bisbenzimidazole. These experiments have confirmed that the imidazo[1,2-a]pyrazine and benzimidazole moieties are efficient pharmacophores to trigger binding to DNA. These compounds have also interacted with bovine serum albumin protein that demonstrating high values of binding constant.

Synthesis and in vitro evaluation of naphthalimide-benzimidazole conjugates as potential antitumor agents.

A series of novel naphthalimide-benzimidazoles was designed and synthesized for the first time and studied for their effect on antiproliferative activity. Some of these compounds possessed good antitumor activity towards the tested cancer cell lines. Noticeably, (diethylamino)ethyl 15 and (dimethylamino)ethyl 23 derivatives displayed superior antiproliferative activity towards human cancer cell lines with MG_MID GI50 values of 1.43 and 1.83 µM, respectively. Preliminary investigation revealed that compounds 15 and 23 might bind with ct-DNA through the intercalation mode which is responsible for potent bioactivity. Moreover, transportation behaviour indicated that these molecules could efficiently bind to and be carried by bovine albumin, and the hydrogen bonding and hydrophobic interactions played important roles in interaction with serum albumin.

Synthesis of 5-(4-(1H-phenanthro[9,10-d]imidazol-2-yl)benzylidene)thiazolidine-2,4-dione as promising DNA and serum albumin-binding agents and evaluation of antitumor activity.

A series of phenanthro[9,10-d]imidazole/oxazole and acenaphtho[1,2-d]imidazole with different aryl groups at C2-position has been synthesized. These compounds were in vitro evaluated for antitumor activity against a panel of 60 human cancer cell lines. Compound 8 exhibits higher cytotoxicity towards leukemia, colon, melanoma, renal, and breast cancer cell lines than the other evaluated cell panels and low toxicity against normal cell line Hek293. The binding properties of compound 8 with DNA have been investigated with absorption, emission and circular dichroism as well as thermal denaturation experiments which indicate intercalation with base pairs of human and calf thymus DNA. The molecular docking and site-selective binding studies also reveal the predominant intercalation of compound 8 in base pairs of DNA. The interaction between thiazolidine based phenanthrene 8 and serum albumins (HSA and BSA), transport proteins, has also been explored which shows quenching of fluorescence through static mechanism. The thermodynamic parameters, obtained from van't Hoff relationship indicate the prevalence of hydrogen-bonding/hydrophobic interactions for the binding phenomenon.

Recent Advances and Developments of in†vitro Evaluation of Heterocyclic Moieties on Cancer Cell Lines.

Besides worthy development in cancer therapy, cancer is still one of the leading causes of death, worldwide. The future burden of cancer will probably be even larger because people are adopting poor lifestyles with poor diet, frequently smoking and less physical activity. The effective anticancer drugs having efficacy and selectivity with low toxicity is still a challenge for the scientific fraternity. The advances in the cancer study have its origin on the availability of different types of experimental model systems that review the various forms of this disease. Cell lines emerge as a feasible alternative for anticancer activities, being at the same time easy to manipulate and molecularly characterize. Heterocycles are key structural components of many of the anti-cancer drugs available on the market today. Indeed, of the novel molecular anti-cancer agents approved by the FDA between 2010 and 2017, almost two-thirds contained heterocyclic rings within their structures. This review summarizes and provides updated literature on heterocyclic compounds using various cancer cell lines reported during the period of 2014-2017 together with the structure-activity relationships.