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The present work demonstrates the design and synthesis of new indolo–pyrazole derivatives, their cytotoxic evaluation, tubulin polymerization inhibition, and molecular modeling studies.

The currently designed molecules demonstrated potential anti-cancer activity by the induction of apoptosis and tubulin polymerization inhibition.

Abstract: Cancer is a silent killer and remains to pose major health problems globally. Amongst the several biological targets, DNA is one of the most striking targets in cancer chemotherapy. Owing to its planar structure, phenanthrene and its derivatives exhibit potential cytotoxicity by intercalating between the DNA base pairs and by inhibiting the enzymes that are involved in the synthesis of DNA. However, due to the off-target effects and resistance, the development of novel chemotherapeutic agents would be meritorious. In this regard, we present a detailed review on the development of phenanthrene-based derivatives reported in the last quinquennial. This review mainly focuses on the synthetic aspects and strategies to procure the fused phenanthrene derivatives such as (i) phenanthroindolizidines, phenanthroquinolizidine, phenanthroimidazoles, podophyllotoxin-based phenanthrenes, and dihydrophenanthrodioxine derivatives, (ii) phenanthrene conjugates with other pharmacologically significant pharmacophores, and (iii) phenanthrene-metal complexes. This review also edifies their potential in vitro cytotoxicity evaluation against various carcinoma cell lines in submicromolar to nanomolar ranges. Additionally, computational studies and structure-activity relationships (SARs) have also been presented to highlight the essential features of the designed congeners. Thus, this review would aid in the development of novel derivatives in future as potential cytotoxic agents in the field of medicinal chemistry.

Abstract: Organic azides are in the interphase between chemistry, biology, medicine, and materials science. Their uses in peptide chemistry, combinatorial chemistry, and the synthesis of heterocycles are extensively explored. In this review, the focus is placed on the azido-reductive cyclization of azides and detailed its significant insights. The wide-ranging literature for synthesizing various heterocycles, employing chemoselective and straightforward protocols for azido-reduction with concomitant intramolecular cyclization, has been elaborated. In due course, the azido-reductive cyclization strategy witnessed the synthesis of essential heterocycles such as benzodiazepines, quinazolinones, piperidine, pyrrole and their derivatives. In addition, the review includes applications of azido-reductive cyclization strategies towards the synthesis of various iminosugars, drugs/APIs, and natural products embedding such heterocycles.

The protocol represents the efficiency of a C–H activation strategy in the construction of pharmacophoric and chromophoric structures employing cis-stilbene acids as directing groups.

Microwave-assisted dithiocarbamation of various imidazoheterocycles with in situ generated dithiocarbamates via a water-soluble Cu(i) catalyst using benign solvent, enabling catalyst recyclability, scalability, less reaction time and high yields.

In a quest for effective cancer targeted drug therapy, a series of new β-carboline tethered indole-3-glyoxylamide derivatives, conjoining salient pharmacophoric properties with prominent cytotoxicity, were synthesized. The in vitro cytotoxic ability of the compounds was established, and many of the compounds exhibited remarkable cytotoxicity (IC

Epigenetic enzyme-targeted therapy is a promising new development in the field of drug discovery. To date, histone deacetylases and DNA methyltransferases have been investigated as druggable epigenetic enzyme targets in cancer therapeutics. Histone methyltransferases and lysine demethylase inhibitors are the latest groups of epi-drugs being actively studied in clinical trials. KDM4s are JmjC domain-containing histone H3 lysine 9/36 demethylase enzymes, belonging to the 2-OG-dependent oxygenases, which are upregulated in multiple malignancies. In the recent years, these enzymes have captured much attention as a novel target in cancer therapy. Herein, we traverse the discovery path and current challenges in designing potent KDM4 inhibitors as potential anticancer agents. We discuss the considerable efforts and proposed future strategies to develop selective small molecule inhibitors of KDM4s, highlighting scaffold candidates and cyclic skeletons for which activity data, selectivity profiles and structure-activity relationships (SARs) have been studied.

Objective:To synthesize a series of phenanthrene-thiazolidinedione hybrids and explore their cytotoxic potential against human cancer cell lines of A-549 (lung cancer), HCT-116 and HT-29 (colon cancer), MDA MB-231 (triple negative breast cancer), BT-474 (breast cancer) and (mouse melanoma) B16F10 cells.Methods:A new series of phenanthrene-thiazolidinedione hybrids was synthesized via Knoevenagel condensation of phenanthrene-9-carbaldehyde and N-alkylated thiazolidinediones. The cytotoxicity (IC50) of the synthesized compounds was determined by MTT assay. Apoptotic assays like (AO/EB) and DAPI staining, cell cycle analysis, JC-1 staining and Annexin V binding assay studies were performed for the most active compound (Z)- 3-(4-bromobenzyl)-5-((2,3,6,7-tetramethoxyphenanthren-9-yl)methylene)thiazolidine-2,4-dione (17b). Molecular docking, dynamics and evaluation of pharmacokinetic (ADME/T) properties were also carried out by using Schrödinger.Results and Discussion:From the series of tested compounds, 17b unveiled promising cytotoxic action with an IC50value of 0.985±0.02μM on HCT-116 human colon cancer cells. The treatment of HCT-116 cells with 17b demonstrated distinctive apoptotic morphology like shrinkage of cells, horseshoe-shaped nuclei formation and chromatin condensation. The flow-cytometry analysis revealed the G0/G1 phase cell cycle arrest in a dosedependent fashion. The AO/EB, DAPI, DCFDA, Annexin-V and JC-1 staining studies were performed in order to determine the effect of the compound on cell viability. Computational studies were performed by using Schrödinger to determine the stability of the ligand with the DNA.Conclusion:The current study provides an insight on developing a series of phenanthrene thiazolidinedione derivatives as potential DNA interactive agents which might aid in colon cancer therapy.

Sulphonamides and N-sulphonyl ketimines/aldimines have turned out to be versatile motifs in the field of synthetic and medicinal chemistry. The field of C-H activation/functionalization flourished remarkably due to their synthetic applicability and directing group plays a remarkable role to achieve regioselectivity in these reactions. The current review summarizes recent tactics by utilizing sulphonamides and N-sulphonyl ketimines/aldimines as directing groups for C-H activation or functionalization. As a directing group, they also facilitate site selectivity and late-stage functionalization of drug molecules in order to construct complex scaffolds of therapeutic importance by C-H activation.

An efficient Ru(ii)-catalyzed carbene insertion strategy has been developed with β-carbolines and isoquinolines as effective directing groups. The protocol enabled the construction of various pharmacophores and chromophores.

Nitrogen-containing heterocyclic scaffolds constitute nearly 75% of small molecules which favorably act as drug candidates. For the past few decades, numerous natural and synthetic indole-based scaffolds have been reported for their diverse pharmacological profiles. In particular, indole-fused azepines, termed azepinoindolones, have come under the radar of medicinal chemists owing to their synthetic and pharmacological importance. A plethora of literature reports has been generated thereof, which calls for the need for the compilation of information to understand their current status in drug discovery. Accumulating reports of evidence suggest that compounds containing this privileged scaffold display their cytotoxic effects via inhibition of kinase, topoisomerase I, mitochondrial malate dehydrogenase (mMDH), and tubulin polymerization and as DNA minor groove binding agents. Herein, we endeavor to present a closer look at the advancements of various synthetic and derivatization methods of azepinoindolone-based compounds. We have further extended our efforts to discuss the pharmacological effects of azepinoindolones in the whole range of medicinal chemistry as anti-Alzheimer, anticancer, anti-inflammatory, antidiabetic, antileishmanial, and antipyranosomal agents and as drug delivery vectors. Our analysis of recent advances reveals that azepinoindolones will continue to serve as potential pharmaceutical modalities in the years to come and their substantial pool of synthetic methods will be ever expanding.

The discovery of a series of combretastatin A-4 inspired novel molecular hybrids of 4-thiazolidinone–umbelliferone as prominent cytotoxic agents is reported. Representative compounds exhibited potent anti-proliferative activities against four human cancer cell lines (A549, MDA-MB-231, THP-1 and HL-60). Amongst the compounds tested, 7q showed the highest potency against A549 cells with an IC50 value of 0.96 ± 1.09 μM and a selectivity index of 51.7. The flow cytometric analysis of compound 7q treated A549 cells showed apoptosis induction by the annexin-v/PI dual staining assay and the effect of 7q on different phases of the cell cycle was also analyzed. Target based studies demonstrated inhibition of tubulin polymerization by 7q at an IC50 value of 2.65 ± 0.47 μM and its effective binding with CT-DNA. Further, molecular modelling studies revealed that 7q has a prominent binding affinity towards the α/β-tubulin receptor with remarkable protein–ligand interactions and binding energy.

Cycloaddition reactions are of great interest due to their potential and rapid construction of optically enriched spiro-cyclic products. 3-Methyleneindolinones have been proven to be a valuable precursor in cycloaddition reactions for the construction of diverse 3,3'-spirocyclic oxindoles. Their versatile reactivity has provided a new forum for the development of a variety of building blocks and synthetic compounds, including bioactive molecules. Herein, significant accomplishments in the cycloaddition reactions of 3-methyleneindolinones for the synthesis of spirooxindoles have been summarised and elaborated. The review is outlined according to the type of cycloaddition such as [2 + 1], [2 + 2], [3 + 2], [4 + 2] and [5 + 2] cycloaddition reactions.

Multi-component reactions (MCRs) are considered to be an important methodological arsenal in synthetic and medicinal chemistry. These reactions have been strategically employed in various synthetic transformations where classical methods usually involve many steps with tedious procedures. The MCR approach provides high yields, atom-/step economy, reduced reaction time, is eco-friendly, and acts as an amenable tool for the generation of a library of new chemical entities (NCEs), especially in the drug discovery process. Extensive research has led to copious developments in the field of MCRs. The developments have emerged with different synthetic approaches, including C–H activation, coupling, and cycloaddition, and eventually, such an amalgamation has enabled access to a broad spectrum of organic frameworks. The present review summarizes recent advancements in MCRs and their mechanistic insights from the last triennium (2017–2020).

The unprecedented efficiency, reliability and adaptability in drug discovery, with the growing number of applications and impact, have made Click Chemistry fascinating to the scientific community. The specificity, biocompatibility along with other principles of click chemistry offers a reliable platform for the synthesis of drug-like molecules that can expedite the drug discovery process. This account summarizes such successes of versatile click reactions from our research group towards the development of functional molecules.

Knoevenagel condensation is an entrenched, prevailing, prominent arsenal following greener principles in the generation of α, β-unsaturated ketones/carboxylic acids by involving carbonyl functionalities and active methylenes. This reaction has proved to be a major driving force in many multicomponent reactions indicating the prolific utility toward the development of biologically fascinating molecules. This eminent reaction was acclimatised on different pharmacophoric aldehydes (benzimidazole, β-carboline, phenanthrene, indole, imidazothiadiazole, pyrazole etc.) and active methylenes (oxindole, barbituric acid, Meldrum's acid, thiazolidinedione etc.) to generate the library of chemical compounds. Their potential was also explicit to understand the significance of functionalities involved, which thereby evoke further developments in drug discovery. Furthermore, most of these reaction products exhibited remarkable anticancer activity in nanomolar to micromolar ranges by targeting different cancer targets like DNA, microtubules, Topo-I/II, and kinases (PIM, PARP, NMP, p300/CBP) etc. This review underscores the efficiency of the Knoevenagel condensation explored in the past six-year to generate molecules of pharmacological interest, predominantly toward cancer. The present review also provides the aspects of structure-activity relationships, mode of action and docking study with possible interaction with the target protein.

The design and synthesis of a new series of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole hybrids was accomplished. The in vitro cytotoxic potential of these new compounds was evaluated against lung cancer (A549), prostate cancer (PC-3, DU-145) and human embryonic kidney (HEK) cell lines. Compound 9p showed the highest potency on A549 cells with an IC

A β-carboline directed regioselective C-H activation protocol for hydroxylation has been developed by employing Cu(OAc)2, a cost-effective 3d metal. This fastidious reaction proceeds under microwave irradiation and furnishes exclusively ortho-hydroxylated products with moderate to good yields under greener reaction conditions. Gratifyingly, this approach retains considerable functional group tolerance and is feasible on both electron-rich and electron-deficient substrates. This protocol signifies monohydroxylation on β-carboline via C-H functionalization which leads into development of biologically relevant molecules. The reaction mechanism was confirmed by intercepting and characterizing all the proposed intermediates by ESI-QTOF-MS.

Spiro-epoxy/aziridine oxindole frameworks are considered as an efficient structural toolbox to obtain C3-functionalised oxindole derivatives. These 3,3'-spiro-cyclic precursors are highly susceptible towards nucleophiles owing to their inherent ring strain. Their versatile reactivity has opened many potential synthetic transformations, allowing access to bioactive molecules as well as natural products. The present review aims to elaborate various enabling strategies applied in the successful synthesis of strained spiro-cyclic oxindole scaffolds. Furthermore, the nucleophilic ring-opening/expansion and cycloaddition reactions of spiro-epoxy/aziridine oxindole are well discussed. Moreover, mechanistic insights to define the regio- and stereo-chemical outcome of the products have also been highlighted briefly.

Molecular hybridization approach is a promising structural modification tool to design new chemical entities (NCEs) by mimicking two different pharmacophoric units into one scaffold to enhance the biological properties. With this aim, combretastatin-A4 acids were integrated with sulfonyl piperazine scaffolds as a one molecular platform and evaluated for their in vitro antiproliferative activity against a panel of human cancer lines cell lines namely, lung (A549), mouse melanoma (B16F10), breast (MDA MB-231and MCF-7) and colon (HCT-15) by MTT assay. Amongst which the compound (E)-3-(4-Chlorophenyl)-1-(4-((4-chlorophenyl)sulfonyl)piperazin-1-yl)-2-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (5 ab) displayed significant IC50 values in the range of 0.36 to 7.08 μm against the selected cancer cell lines. Moreover, 5 ab was found to be the most potent member of this series with IC50 0.36±0.02 μm. Further investigations revealed that the compound 5 ab displayed significant inhibition of tubulin assembly with IC50 5.24±0.06 μm and molecular docking studies also disclosed the binding of 5 ab effectively in CA4 binding space at the colchicine binding site. The flow cytometric analysis demonstrated that the compound 5 ab caused cell cycle arrest at G2/M phase in A549 cells. Compound 5 ab induced apoptosis in A549 cells which was further evaluated by different staining assays such as DAPI and AO which undoubtedly speculated, the induction of apoptosis. To study the anti-migration with 5 ab, cell migration/scratch wound assay was performed and the extent of apoptosis was studied by Annexin-V, including mitochondrial potential by JC-1 staining.

A new series of biphenyl methylene indolinones has been designed, synthesized and evaluated for their in vitro antiproliferative activity against various cancer cell lines like DU-145 (prostate cancer cell line), 4T1 (mouse breast cancer cell line), MDA-MB-231 (human breast cancer cell line), BT-549 (human breast cancer cell line), T24 (human urinary bladder carcinoma cell line), and HeLa (cervical cancer cell line). Among the series, compound 10e showed potent in vitro cytotoxic activity against HeLa and DU-145 cancer cell lines with IC50 value of 1.74 ± 0.69 µM and 1.68 ± 1.06 µM respectively. To understand the underlying mechanism of most potent cytotoxic compound 10e, various mechanistic studies were carried out on DU-145 cell lines. Cell cycle analysis results revealed that these conjugates affect both G0/G1 and G2/M phase of the cycle, tubulin binding assay resulted that compound 10e interrupting microtubule network formation by inhibiting tubulin polymerization with IC50 value of 4.96 ± 0.05 μM. Moreover, molecular docking of 10e on colchicine binding site of the tubulin explains the interaction of 10e with tubulin. Clonogenic assay indicated inhibition of colony formation by compound 10e in a dose dependent manner. In addition, morphological changes were clearly observed by AO/EB and DAPI staining studies. Moreover, ROS detection using DCFDA, JC-1, and annexin V-FITC assays demonstrated the significant apoptosis induction by 10e.

This review article proposes a comprehensive report of the design strategies engaged in the development of various sulfur-bearing cytotoxic agents. The outcomes of various studies depict that the sulfur heterocyclic framework is a fundamental structure in diverse synthetic analogs representing a myriad scope of therapeutic activities. A number of five-, six- and seven-membered sulfur-containing heterocyclic scaffolds, such as thiazoles, thiadiazoles, thiazolidinediones, thiophenes, thiopyrans, benzothiazoles, benzothiophenes, thienopyrimidines, simple and modified phenothiazines, and thiazepines have been discussed. The subsequent studies of the derivatives unveiled their cytotoxic effects through multiple mechanisms (viz. inhibition of tyrosine kinases, topoisomerase I and II, tubulin, COX, DNA synthesis, and PI3K/Akt and Raf/MEK/ERK signaling pathways), and several others. Thus, our concise illustration explains the design strategy and anticancer potential of these five- and six-membered sulfur-containing heterocyclic molecules along with a brief outline on seven-membered sulfur heterocycles. The thorough assessment of antiproliferative activities with the reference drug allows a proficient assessment of the structure-activity relationships (SARs) of the diversely synthesized molecules of the series.