Filamentous temperature sensitive mutant Z: a putative target to combat antibacterial resistance.

In the pre-antibiotic era, common bacterial infections accounted for high mortality and morbidity. Moreover, the discovery of penicillin in 1928 marked the beginning of an antibiotic revolution, and this antibiotic era witnessed the discovery of many novel antibiotics, a golden era. However, the misuse or overuse of these antibiotics, natural resistance that existed even before the antibiotics were discovered, genetic variations in bacteria, natural selection, and acquisition of resistance from one species to another consistently increased the resistance to the existing antibacterial targets. Antibacterial resistance (ABR) is now becoming an ever-increasing concern jeopardizing global health. Henceforth, there is an urgent unmet need to discover novel compounds to combat ABR, which act through untapped pathways/mechanisms. Filamentous Temperature Sensitive mutant Z (FtsZ) is one such unique target, a tubulin homolog involved in developing a cytoskeletal framework for the cytokinetic ring. Additionally, its pivotal role in bacterial cell division and the lack of homologous structural protein in mammals makes it a potential antibacterial target for developing novel molecules. Approximately 2176 X-crystal structures of FtsZ were available, which initiated the research efforts to develop novel antibacterial agents. The literature has reported several natural, semisynthetic, peptides, and synthetic molecules as FtsZ inhibitors. This review provides valuable insights into the basic crystal structure of FtsZ, its inhibitors, and their inhibitory activities. This review also describes the available in vitro detection and quantification methods of FtsZ-drug complexes and the various approaches for determining drugs targeting FtsZ polymerization.

6-Shogaol Exhibits Anti-viral and Anti-inflammatory Activity in COVID-19-Associated Inflammation by Regulating NLRP3 Inflammasomes.

Recent global health concern motivated the exploration of natural medicinal plant resources as an alternative target for treating COVID-19 infection and associated inflammation. In the current study, a phytochemical, 6-shogaol [1-(4-hydroxy-3-methoxyphenyl)dec-4-en-3-one; 6-SHO] was investigated as a potential anti-inflammatory and anti-COVID-19 agent. In virus release assay, 6-SHO efficiently (94.5%) inhibited SARS-CoV2 replication. When tested in the inflammasome activation model, 6-SHO displayed mechanistic action by regulating the expression of the inflammasome pathway molecules. In comparison to the existing drugs, remdesivir and hydroxy-chloroquine, 6-SHO was not only found to be as effective as the standard anti-viral drugs but also much superior and safe in terms of predicted physicochemical properties and clinical toxicity. Comparative molecular dynamics simulation demonstrated a stable interaction of 6-SHO with NLRP3 (the key inflammasome regulator) in the explicit water environment. Overall, this study provides important cues for further development of 6-SHO as potential anti-inflammatory and anti-viral therapeutic agents.

Synthetic Imidazopyridine-Based Derivatives as Potential Inhibitors against Multi-Drug Resistant Bacterial Infections: A Review.

Fused pyridines are reported to display various pharmacological activities, such as antipyretic, analgesic, antiprotozoal, antibacterial, antitumor, antifungal, anti-inflammatory, and antiapoptotic. They are widely used in the field of medicinal chemistry. Imidazopyridines (IZPs) are crucial classes of fused heterocycles that are expansively reported on in the literature. Evidence suggests that IZPs, as fused scaffolds, possess more diverse profiles than individual imidazole and pyridine moieties. Bacterial infections and antibacterial resistance are ever-growing risks in the 21st century. Only one IZP, i.e., rifaximin, is available on the market as an antibiotic. In this review, the authors highlight strategies for preparing other IZPs. A particular focus is on the antibacterial profile and structure-activity relationship (SAR) of various synthesized IZP derivatives. This research provides a foundation for the tuning of available compounds to create novel, potent antibacterial agents with fewer side effects.

Synthesis and biological evaluation of coumarin-thiazole hybrids as selective carbonic anhydrase IX and XII inhibitors.

A series of coumarin-linked thiazoles (6a-p) was synthesized and the synthesized compounds were evaluated against human carbonic anhydrases (hCAs) IX and XII, which have been implicated in cancer. All the compounds exhibited selective inhibition of both isoforms. The designed compounds inhibited hCA IX in a moderate nanomolar to submicromolar range. The hCA XII was inhibited in a low to moderate nanomolar range. Compound 6o exhibited the best inhibition of hCA XII with a Ki value of 91.1 nM. The hydrolyzed form of compound 6o also exhibited favorable interactions as well as good docking scores with both the isoforms. Hence, this compound can be taken as a template for the design of selective and potent hCA XII inhibitors.

Selectivity profile comparison for certain γ-butyrolactone and oxazolidinone-based ligands on a sigma 2 receptor over sigma 1: a molecular docking approach.

Sigma receptors (σ1 R and σ2 R) are pharmacologically characterized membrane-bound receptors that bind a wide range of chemical compounds. Alzheimer's disease, traumatic brain injury, schizophrenia, and neuropathic pain have all been associated with abnormal σ2 activity. The σ2 receptor has recently been identified as a potential therapeutic target for inhibiting the formation of amyloid plaques. Numerous laboratories are now investigating the potential of σ2 ligands. Small molecule discovery is the focus of current research, with the goal of using target-based action to treat a variety of illnesses and ailments. Functionalized γ-butyrolactone and oxazolidinone-based ligands, in particular, are pharmacologically important scaffolds in drug discovery research and have been thoroughly examined for σ2 receptor efficacy. The purpose of this study was to evaluate the pharmacophoric features of different σ2 receptor ligands using in silico techniques. This study used a library of 58 compounds having a γ-butyrolactone and oxazolidinone core. To investigate the binding characteristics of the ligands with the σ2 receptor, a 3D homology model was developed. To understand the binding pattern of the γ-butyrolactone and oxazolidinone based ligands, molecular docking studies were performed on both σ1 and σ2 receptors. Furthermore, MM/GBSA binding energy calculations were used to confirm the binding of ligands on the σ2 over σ1 receptor. These in silico findings will aid in the discovery of selective σ2 ligands with good pharmacophoric properties and potency in the future.

Design, synthesis of DNA-interactive 4-thiazolidinone-based indolo-/pyrroloazepinone conjugates as potential cytotoxic and topoisomerase I inhibitors.

With the rising cancer incidence and mortality globally, there is a prerequisite for effective design strategies towards the discovery of newer small molecular entities in chemotherapy. Hence, a series of new thiazolidinone-based indolo-/pyrroloazepinone conjugates was designed, synthesized via molecular hybridization, and evaluated for their in vitro cytotoxicity potential and DNA topoisomerase I and II inhibition. Among this series, conjugate 11g emerged as the most active compound with an IC50 value of 1.24 µM against A549 and 3.02-10.91 µM in the other tested cancer cell lines. Gratifyingly, 11g displayed 43-fold higher selectivity towards A549 cancer cells as compared to the non-cancer cells. Subsequently, conjugate 12g also demonstrated significant cytotoxicity against SK-MEL-28 cells. Basing the in vitro cytotoxicity results, SAR was established. Later, the conjugates 11g and 12g were further evaluated for their apoptosis-inducing ability, which was quantified by flow cytometric analysis, DNA-binding, Topo I inhibitory activity and IC50 value calculation. Molecular modeling studies provided profound insights about the binding nature of these compounds with DNA-Topo I complex. In silico ADME/T and prediction studies corroborated the drug-likeness of the two investigated compounds. TOPKAT toxicity profiling studies demonstrated the compounds' safety in many animal models with a minimal toxicological profile. Encouraging results obtained from in vitro and in silico studies could put this series of conjugates at the forefront of cancer drug discovery.

Exploration of mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives as DNA intercalative topo II inhibitors: Cytotoxicity and apoptosis induction.

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 IC50 value of 3.8 ± 0.02 µM. Moreover, 9p was found to be 25-fold more selective towards cancer cell lines than the non-cancerous (HEK) cell line. The target-based assay revealed the inhibition of the topoisomerase II enzyme by compound 9p. UV-visible spectroscopy, fluorescence, circular dichroism (CD), and viscosity studies inferred the intercalative property and effective binding of compound 9p with CT-DNA. Apoptosis induced by the compound 9p was observed by various morphological staining assays, i.e, DAPI, EtBr/AO. Further, the molecular modeling studies revealed the binding of compound 9p at the active site of the DNA-topoisomerase II complex while the physicochemical properties were in the recommended range. Finally, mercaptoacetamide-linked pyrimidine-1,3,4-oxadiazole derivatives can be considered as a promising scaffold for development as effective anticancer agents and topoisomerase II inhibitors.

DFT calculation, molecular docking, and molecular dynamics simulation study on substituted phenylacetamide and benzohydrazide derivatives.

The atomic and molecular properties of the title compounds were calculated by Jaguar using a basis set B3LYP/6-31G**++ with hybrid DFT in the gas phase, to determine the chemical reactivity. Analysis of quantum chemical features such as HOMO and LUMO explained that the electronic charge transfer occurred within the system through conjugated paths of the selected compounds. The nucleophilic and electrophilic reactive sites are recognized from the molecular electrostatic potential plot. Electrophilic and nucleophilic attack-prone molecular sites were predicted by mapping ALIE value to the molecular surface. The bond dissociation energy of the high active compound 15 (2-chloro-N-(2-(2-(2-(2-chlorobenzoyl)hydrazineyl)-2-oxoethoxy)phenyl)acetamide) was calculated to assess the probability of compound autoxidation or degradation. Further, molecular docking, binding free energy calculations, and ADMET profile of the degradation products (DPs) of compound 15 was carried out to determine the binding affinity and toxicity profile of the formed DPs compared with the parent compound. A 150-ns molecular dynamics (MD) simulation was performed to evaluate the binding stability of the compound 15/4URL complex using Desmond. Binding free energy and binding affinity of the complex were computed for 100 trajectory frames using the MM-GBSA approach.

Synthesis and biological evaluation of novel imidazo[1,2-a]pyridine-oxadiazole hybrids as anti-proliferative agents: Study of microtubule polymerization inhibition and DNA binding.

Efforts towards the development of potential anticancer agents, a new series of imidazo[1,2-a]pyridine-oxadiazole hybrids were synthesized and evaluated for their in vitro anticancer activity against lung cancer (A549) and prostate cancer (PC-3, DU-145) cell lines. Amongst the compounds tested, 6d showed the highest potency on A549 cells with an IC50 value of 2.8 ± 0.02 µM. Flow cytometric analysis of compound 6d treated A549 cells showed apoptosis induction by annexin-v/PI dual staining assay and the effect of 6d on different phases of cell cycle was also analyzed. Target based studies demonstrated the inhibition of tubulin polymerization by 6d at an IC50 value of 3.45 ± 0.51 µM and its effective binding with CT-DNA. Further, the molecular modelling studies revealed that 6d has a prominent binding affinity towards α/ß-tubulin receptor with admirable physico-chemical properties.

Syntheses and medicinal chemistry of azepinoindolones: a look back to leap forward.

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.

Development of ß-carboline-benzothiazole hybrids via carboxamide formation as cytotoxic agents: DNA intercalative topoisomerase IIα inhibition and apoptosis induction.

In quest of promising anticancer agents, the pharmacophores of natural (ß-carboline) and synthetic origin (benzothiazole) were adjoined by a carboxamide bridge and three-point diversification was accomplished. The in vitro cytotoxic ability of the compounds was established on adherent and suspension human cancer cell lines and compounds 8u and 8f advanced as pre-eminent molecules with IC50 values of 1.46 and 1.81 µM respectively in A549 cell line. The cytospecificity was entrenched for potent compounds 8u and 8f by evaluating against normal human lung epithelial cells and selectivity index was calculated. Furthermore, EtBr displacement, relative viscosity and gel-based topoisomerase II target assays unveiled the intercalative topo-II inhibitory capability and DNA binding studies (absorbance) revealed the dissociation constant (Kd) for compounds 8u and 8f as 98 and 103 µM respectively. Additionally, cell-based flow cytometric assays like Annexin-V/PI dual staining aids in the quantification of apoptosis induced and JC-1 staining disclosed the depolarization of mitochondrial membrane potential by compound 8u in A549 cells in a dose-dependent manner. Moreover, wound healing assay established the inhibition of in vitro cell migration by compound 8u on A549 cells. In addition, molecular docking studies proved the binding of compounds 8u and 8f in the active site of DNA complexed with topo IIα and stabilized by interactions with DNA base pairs and amino acid residues. Remarkably, the compounds 8u and 8f follow Lipinski's rule of five and are in the recommended range for Jorgensen's rule of three with a minimal violation and other pharmacokinetic parameters revealing druggability of the synthesized hybrids.

Synthesis, biological evaluation, and molecular docking analysis of phenstatin based indole linked chalcones as anticancer agents and tubulin polymerization inhibitors.

A library of new phenstatin based indole linked chalcone compounds (9a-z and 9aa-ad) were designed and synthesized. Of these, compound 9a with 1-methyl, 2- and 3-methoxy substituents in the aromatic ring was efficacious against the human oral cancer cell line SCC-29B, spheroids, and in a mouse xenograft model of oral cancer AW13516. Compound 9a exhibited anti-cancer activity through disrupting cellular integrity and affecting glucose metabolism-which is a hallmark of cancer. The cellular architecture was affected by inhibition of tubulin polymerization as observed by an immunofluorescence assay on 9a-treated SCC-29B cells. An in vitro tubulin polymerization kinetics assay provided evidence of direct interaction of 9a with tubulin. This physical interaction between tubulin and compound 9a was further confirmed by Surface Plasmon Resonance (SPR) analysis. Molecular docking experiments and validations revealed that compound 9a interacts and binds at the colchicine binding site of tubulin and at active sites of key enzymes in the glucose metabolism pathway. Based on in silico modeling, biophysical interactions, and pre-clinical observations, 9a consisting of phenstatin based indole-chalcone scaffolds, can be considered as an attractive tubulin polymerization inhibitor candidate for developing anti-cancer therapeutics.

Design and synthesis of thiadiazolo-carboxamide bridged ß-carboline-indole hybrids: DNA intercalative topo-IIα inhibition with promising antiproliferative activity.

The conjoining of salient pharmacophoric properties directing the development of prominent cytotoxic agents was executed by constructing thiadiazolo-carboxamide bridged ß-carboline-indole hybrids. On the evaluation of in vitro cytotoxic potential, 12c exhibited prodigious cytotoxicity among the synthesized new molecules 12a-k, with an IC50 < 5 µM in all the tested cancer cell lines (A549, MDA-MB-231, BT-474, HCT-116, THP-1) and the best cytotoxic potential was expressed in lung cancer cell line (A549) with an IC50 value of 2.82 ± 0.10 µM. Besides, another compound 12a also displayed impressive cytotoxicity against A549 cell line (IC50: 3.00 ± 1.40 µM). Further target-based assay of these two compounds 12c and 12a revealed their potential as DNA intercalative topoisomerase-IIα inhibitors. Additionally, the antiproliferative activity of compound 12c was measured in A549 cells by traditional apoptosis assays revealing the nuclear, morphological alterations, and depolarization of membrane potential in mitochondria and externalization of phosphatidylserine in a concentration-dependent manner. Cell cycle analysis unveiled the G0/G1 phase inhibition and wound healing assay inferred the inhibition of in vitro cell migration by compound 12c in lung cancer cells. Remarkably, the safety profile of compound 12c was disclosed by screening against normal human lung epithelial cell line (BEAS-2B: IC50: 71.2 ± 7.95 µM) with a selectivity index range of 14.9-25.26. Moreover, Molecular modeling studies affirm the intercalative binding of compound 12c and 12a in the active pocket of topo-IIα. Furthermore, in silico prediction of physico-chemical parameters divulged the propitious drug-like properties of the synthesized derivatives.

Design and synthesis of ß-carboline linked aryl sulfonyl piperazine derivatives: DNA topoisomerase II inhibition with DNA binding and apoptosis inducing ability.

A series of new ß-carboline linked aryl sulfonyl piperazine congeners have been synthesized by coupling various ß-carboline acids with substituted aryl sulfonyl piperazines. Evaluation of their anticancer activity against a panel of human cancer cell lines such as colon (HT-29), breast (MDA-MB-231), bone osteosarcoma (MG-63), brain (U87 MG), prostate (PC- 3) and normal monkey kidney (Vero) cell line has been done. Among the series, compound 8ec and 8ed has shown most potent cytotoxicity with an IC50 values of 2.80 ± 0.10 µM and 0.59 ± 0.28 µM respectively against MG-63 cell line and also potent on other cell lines tested. Compounds 8ec and 8ed was found to inhibit Topo II that is confirmed by specific Topo II inhibition assay. DNA binding studies, cell cycle analysis, Annexin V study indicate that these compounds has potential anticancer activity. Molecular docking studies for compound 8ec and 8ed are incorporated to understand the nature of interaction with topoisomerase IIα and dsDNA.

Synthesis and carbonic anhydrase inhibition studies of sulfonamide based indole-1,2,3-triazole chalcone hybrids.

Sulfonamide is one of the most promising classes of classical carbonic anhydrase (CA, EC 4.2.1.1) inhibitors. A novel series of indolylchalcones incorporating benzenesulfonamide-1,2,3-triazole (6a-q) has been synthesized by click chemistry reaction and investigated for hCA inhibitory activity against a panel of human carbonic anhydrases (hCAs). Most of these newly synthesized compounds exhibited interesting inhibition constants, in the nanomolar range, with some derivatives being more potent than the standard drug acetazolamide (AAZ) on hCA I isoform. Among the tested compounds, the compounds 6d (18.8 nM), 6q (38.3 nM) and 6e (50.4 nM) were 13, 6 and 5 times more potent than AAZ against hCA I isoform, respectively. Compounds 6o, 6m and 6f efficiently inhibited isoform hCA XII, with KIs in the range of 10-41.9 nM. Several compounds were also active against isoforms hCA II and hCA IX, with KIs under 100 nM. These indolylchalcone-benzenesulfonamide-1,2,3-triazole hybrids may be considered as potential leads for hCA I-selective inhibitors.

Novel diindoloazepinone derivatives as DNA minor groove binding agents with selective topoisomerase I inhibition: Design, synthesis, biological evaluation and docking studies.

We present here-in the molecular design and chemical synthesis of a novel series of diindoloazepinone derivatives as DNA minor groove binding agents with selective topoisomerase I inhibition. The in vitro cytotoxicity of the synthesized compounds was evaluated against four human cancer cell lines including DU143, HEPG2, RKO and A549 in addition to non-cancerous immortalized human embryonic kidney cells (HEK-293). Compound 11 showed significant cytotoxicity against all the four human cancer cell lines with IC50 values ranging from 4.2 to 6.59 µM. 11 was also found to display 13-fold selective cytotoxicity towards A549 cancerous cells compared to the non-cancerous cell lines (HEK-293). The decatenation, DNA relaxation and intercalation assays revealed that the investigational compounds 10 and 11 act as highly selective inhibitors of Topo-I with DNA minor groove binding ability which was also supported by the results obtained from circular dichroism (CD), UV-visible spectroscopy and viscosity studies. Apoptosis induced by the lead 11 was observed using morphological observations, AO/EB and DAPI staining procedures. Further, dose-dependent increase in the depolarization of mitochondrial membrane was also observed through JC-1 staining. Annexin V-FITC/PI assay confirmed that 11 induced early apoptosis. Additionally, cell cycle analysis indicated that the cells were arrested at sub-G1 phase. Gratifyingly, in silico studies demonstrated promising interactions of 11 with the DNA and Topo I, thus supporting their potential DNA minor groove binding property with relatively selective Topo I inhibition compared to Topo II.

Piperlongumine regulates epigenetic modulation and alleviates psoriasis-like skin inflammation via inhibition of hyperproliferation and inflammation.

Psoriasis is an autoimmune skin disease, where chronic immune responses due to exaggerated cytokine signaling, abnormal differentiation, and evasion of keratinocytes apoptosis plays a crucial role in mediating abnormal keratinocytes hyperproliferation. From the therapeutic perspective, the molecules with strong anti-proliferative and anti-inflammatory properties could have tremendous relevance. In this study, we demonstrated that piperlongumine (PPL) treatment effectively abrogated the hyperproliferation and differentiation of keratinocytes by inducing ROS-mediated late apoptosis with loss of mitochondrial membrane potential. Besides, the arrest of cell cycle was found at Sub-G1 phase as a result of DNA fragmentation. Molecularly, inhibition of STAT3 and Akt signaling was observed with a decrease in proliferative markers such as PCNA, ki67, and Cyclin D1 along with anti-apoptotic Bcl-2 protein expression. Keratin 17 is a critical regulator of keratinocyte differentiation, and it was found to be downregulated with PPL significantly. Furthermore, prominent anti-inflammatory effects were observed by inhibition of lipopolysaccharide (LPS)/Imiquimod (IMQ)-induced p65 NF-κB signaling cascade and strongly inhibited the production of cytokine storm involved in psoriasis-like skin inflammation, thus led to the restoration of normal epidermal architecture with reduction of epidermal hyperplasia and splenomegaly. In addition, PPL epigenetically inhibited histone-modifying enzymes, which include histone deacetylases (HDACs) of class I (HDAC1-4) and class II (HDAC6) evaluated by immunoblotting and HDAC enzyme assay kit. In addition, our results show that PPL effectively inhibits the nuclear translocation of p65 and a histone modulator HDAC3, thus sequestered in the cytoplasm of macrophages. Furthermore, PPL effectively enhanced the protein-protein interactions of HDAC3 and p65 with IκBα, which was disrupted by LPS stimulation and were evaluated by Co-IP and molecular modeling. Collectively, our findings indicate that piperlongumine may serve as an anti-proliferative and anti-inflammatory agent and could serve as a potential therapeutic option in treating psoriasis.

Design and synthesis of substituted (1-(benzyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone conjugates: study on their apoptosis inducing ability and tubulin polymerization inhibition.

A library of substituted (1-(benzyl)-1H-1,2,3-triazol-4-yl)(piperazin-1-yl)methanone derivatives were designed, synthesized and screened for their in vitro cytotoxic activity against BT-474, HeLa, MCF-7, NCI-H460 and HaCaT cells by employing 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Among all the synthesized analogues, compound 10ec displayed the highest cytotoxicity with the IC50 value of 0.99 ± 0.01 µM towards BT-474 cancer cell line. The target compound (10ec) was also evaluated for its tubulin polymerization inhibition study. Detailed biological studies such as acridine orange/ethidium bromide (AO/EB), DAPI and annexin V-FITC/propidium iodide staining assay suggested that compound 10ec induced the apoptosis of BT-474 cells. The clonogenic assay revealed that the inhibition of colony formation in BT-474 cells by 10ec in concentration-dependent manner. Moreover, the flow cytometric analysis revealed that 10ec induced apoptosis via cell cycle arrest at the sub-G1 and G2/M phase. In silico studies of sulfonyl piperazine-integrated triazole conjugates unveil that they possess drug-like properties. According to the molecular modelling studies, compound 10ec binds to the colchicine binding site of the tubulin.

Novel huperzine A based NMDA antagonists: insights from molecular docking, ADME/T and molecular dynamics simulation studies.

Huperzine A (HupA) is an alkaloidal natural product and drug isolated from Chinese herb Huperzia serrata, which is a potent selective anticholinesterase inhibitor. HupA has symptomatic, cognitive-enhancing and protective effect on neurons against amyloid beta-induced oxidative injury and antagonizing N-methyl-d-aspartate receptors by blocking the ion channels. The present study aimed to identify the docking, ADME/T and molecular dynamics simulation parameters of a library of 40 analogues which can correlate the binding affinity, conformational stability and selectivity of the ligands towards NMDA receptor through in silico approach. Glide molecular docking analysis was performed for the designed analogues to understand the binding mode and interactions. MD simulations were performed to explain the conformational stability and natural dynamics of the interaction in physiological environmental condition of protein-ligand complex affording a better understanding of chemical-scale interactions between HupA and its analogues with NMDA channel that could potentially benefit the development of new drugs for neurodegenerative diseases involving NMDA receptors.

Discovery of certain benzyl/phenethyl thiazolidinone-indole hybrids as potential anti-proliferative agents: Synthesis, molecular modeling and tubulin polymerization inhibition study.

A series of certain benzyl/phenethyl thiazolidinone-indole hybrids were synthesized for the study of anti-proliferative activity against A549, NCI-H460 (lung cancer), MDA-MB-231 (breast cancer), HCT-29 and HCT-15 (colon cancer) cell lines by using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). We found that compound G37 displayed highest cytotoxicity with IC50 value of 0.92 ±â€¯0.12 µM towards HCT-15 cancer cell line among all the synthesized compounds. Moreover, compound G37 was also tested on normal human lung epithelial cells (L132) and was found to be safe in contrast to HCT-15 cells. The lead compound G37 showed significant G2/M phase arrest in HCT-15 cells. Additionally, compound G37 significantly inhibited tubulin polymerization with IC50 value of 2.92 ±â€¯0.23 µM. Mechanistic studies such as acridine orange/ethidium bromide (AO/EB) dual staining, DAPI nuclear staining, annexinV/propidium iodide dual staining, clonogenic growth inhibition assays inferred that compound G37 induced apoptotic cell death in HCT-15 cells. Moreover, loss of mitochondrial membrane potential with elevated intracellular ROS levels was observed by compound G37. These compounds bind at the active pocket of the α/ß-tubulin with higher number of stable hydrogen bonds, hydrophobic and arene-cation interactions confirmed by molecular modeling studies.