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.

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.

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.

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.

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.

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.

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.

High-Yielding Synthesis of Chiral Donor-Acceptor Catenanes.

We report the synthesis of [2]catenanes (Hopf links) in water utilizing disulfides and aromatic donor-acceptor interactions. The electron-rich dialkoxynaphthalene (DN) building blocks interact with electron-deficient naphthalenediimide (NDI) moieties connected by a polyamine chain. We study the effect of the polyamine linkers on the behavior of the library. The polyamine's length and the number of nitrogen atoms in the chain affect the library distribution, leading in some cases to the assembly of catenanes in up to 93% yield.

1,8-Naphthalimide: A Potent DNA Intercalator and Target for Cancer Therapy.

The poor pharmacokinetics, side effects and particularly the rapid emergence of drug resistance compromise the efficiency of clinically used anticancer drugs. Therefore, the discovery of novel and effective drugs is still an extremely primary mission. Naphthalimide family is one of the highly active anticancer drug based upon effective intercalator with DNA. In this article, we review the discovery and development of 1,8-naphthalimide moiety, and, especially, pay much attention to the structural modifications and structure activity relationships. The review demonstrates how modulation of the moiety affecting naphthalimide compound for DNA binding that is achieved to afford a profile of antitumor activity. The DNA binding of imide and ring substitution at naphthalimide, bisnaphthalimide, naphthalimide-metal complexes is achieved by molecular recognition through intercalation mode. Thus, this synthetic/natural small molecule can act as a drug when activation or inhibition of DNA function, is required to cure or control the cancer disease. The present study is a review of the advances in 1,8-naphthalimide-related research, with a focus on how such derivatives are intercalated into DNA for their anticancer activities.

Synthesis, in vitro antitumor activity, dihydrofolate reductase inhibition, DNA intercalation and structure-activity relationship studies of 1,3,5-triazine analogues.

A series of triazine-benzimidazoles with 4-fluoroaniline substitution has been designed and synthesized. These compounds were further substituted with different primary and secondary amines. The structures of newly synthesized compounds were confirmed by (1)H, (13)C NMR, mass spectrometry and, in case of compound 18, by single crystal X-ray diffraction analysis. The newly synthesized compounds were evaluated against 60 human tumor cell lines at one dose and five dose concentration levels. Compounds 7, 8 and 22 have been found to be the most active antitumor agents with GI50 values of 1.77, 1.94 and 2.87µM, respectively. The synthesized compounds were then evaluated for their inhibitory activity to mammalian dihydrofolate reductase. Compound 22 was depicted as the most active compound for the inhibition of dihydrofolate reductase with IC50 value of 2.0nM. DNA binding studies were also revealed strong interacting properties of triazine derivatives towards calf thymus-DNA.

Benzimidazole-Based Quinazolines: In Vitro Evaluation, Quantitative Structure-Activity Relationship, and Molecular Modeling as Aurora Kinase Inhibitors.

A series of benzimidazole-based quinazoline derivatives with different substitutions of primary and secondary amines at the C2 position (1-12) were evaluated for their Aurora kinase inhibitory activities. All compounds except for 3 and 6 showed good activity against Aurora kinase inhibitors, with IC50 values in the range of 0.035-0.532 µM. The ligand efficiency (LE) of the compounds with Aurora A kinase was also determined. The structure-activity relationship and the quantitative structure-activity relationship revealed that the Aurora inhibitory activities of these derivatives primarily depend on the different substitutions of the amine present at the C2 position of the quinazoline core. Molecular docking studies in the active binding site also provided theoretical support for the experimental biological data acquired. The current study identifies a novel class of Aurora kinase inhibitors, which can further be used for the treatment of cancer.

Recent advances in development of imidazo[1,2-a]pyrazines: synthesis, reactivity and their biological applications.

Imidazo[1,2-a]pyrazine acts as a versatile scaffold in organic synthesis and drug development. This review article is an effort to compile the progress made in synthetic methods and to illustrate its reactivity and multifarious biological activity. This review is mainly based on the pattern and position of the substitution, and should help the scientific community to bring about future developments.

Triazine-benzimidazole hybrids: anticancer activity, DNA interaction and dihydrofolate reductase inhibitors.

A new series of triazine-benzimidazole hybrids has been synthesized with different substitution of primary and secondary amines at one of the position of triazine in moderate to good yields. These compounds were evaluated for their inhibitory activities over 60 human tumor cell lines at one dose and five dose concentrations. Compounds 6b, 8 and 9 showed broad spectrum of antitumor activities with GI50 values of 9.79, 2.58 and 3.81µM, respectively. DNA binding studies also indicated strong interaction properties of these compounds. These synthesized compounds also showed inhibition of mammalian dihydrofolate reductase (DHFR). Compound 6b was depicted as the most active member of DHFR inhibitor with IC50 value of 1.05µM. Molecular modelling studies were used to identify the stabilized interactions of Compound 6b within the active site of enzyme for DHFR.

Synthesis and in vitro antitumor evaluation of primary amine substituted quinazoline linked benzimidazole.

By combining the structural features of quinazoline and benzimidazole, new hybrid regioisomeric molecules with substituted primary amines have been synthesized. Evaluation of these molecules over 60 cancer cell line panel has identified three molecules as most potent anticancer agents. Compound 10 showed ten and eleven folds more activity than respective quinazoline and benzimidazole class of compounds with GI50 value of 1.64 µM. Compound 11 (GI50 value of 0.81 µM) showed almost twenty and twenty-two fold more activity than quinazoline and benzimidazole analogue, respectively while compound 12 (GI50 value of 4.52 µM) has four fold more activity than quinazoline and benzimidazole analogue. In vitro evaluation of compound 11 exhibited remarkable anticancer activity towards colon cancer cell lines and prostate cancer cell lines at five dose concentrations with GI50 values of 0.34 and 0.31 µM, respectively.

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.

Synthesis, single crystal and antitumor activities of benzimidazole-quinazoline hybrids.

A series of novel regioisomeric hybrids of quinazoline/benzimidazole viz. (3-allyl-2-methyl-3H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine and (1-allyl-2-methyl-1H-benzimidazol-5-yl)-(2-substituted-quinazolin-4-yl)-amine of biological interest were synthesized. All the synthesized compounds were well characterized by (1)H and (13)C NMR as well as mass spectroscopy. The newly synthesized compounds were screened for in vitro antitumor activities against 60 tumor cell lines panel assay. A significant inhibition for cancer cells were observed with compound 9 and also more active against known drug 5-fluorouracil (5-FU) in some tumor cell lines. Compound 9 displayed appreciable anticancer activity against leukemia, colon, melanoma, renal and breast cancer cell lines.

Synthesis of new conjugated coumarin-benzimidazole hybrids and their anticancer activity.

A series of novel coumarin-benzimidazole hybrids, 3-(1H-benzo[d]imidazol-2-yl)-7-(substituted amino)-2H-chromen-2-one derivatives of biological interest were synthesized. Six out of the newly synthesized compounds were screened for in vitro antitumor activity against preliminary 60 tumor cell lines panel assay. A significant inhibition for cancer cells was observed with compound 8 (more than 50% inhibition) compared with other compounds and active known drug 5-fluorouracil (in some cell lines) as positive control. Compound 8 displayed appreciable anticancer activities against leukemia, colon cancer and breast cancer cell lines.

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.

FRET-based ratiometric detection of Hg2+ and biothiols using naphthalimide-rhodamine dyads.

A new naphthalimide-rhodamine-based dyad in CH(3)CN-HEPES (1 : 1) buffer solution exhibits fluorescence resonance energy transfer (FRET) from naphthalimide to the rhodamine moiety on addition of only Hg(2+) ions and allows ratiometric absorption and fluorimetric estimation of Hg(2+) ions between 50 nM (10 ppb) to 2 µM (0.4 ppm). FRET-induced fluorescence changes were recovered again by the subsequent addition of thiol amino acids via reverse FRET. The interconversion of probe and via the complexation/decomplexation by the modulation of Hg(2+)/Cys exhibited a selective probe for biothiols in real samples.

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.