A Review of FDA-Approved Anti-HIV-1 Drugs, Anti-Gag Compounds, and Potential Strategies for HIV-1 Eradication.

Acquired immunodeficiency syndrome (AIDS) is an enormous global health threat stemming from human immunodeficiency virus (HIV-1) infection. Up to now, the tremendous advances in combination antiretroviral therapy (cART) have shifted HIV-1 infection from a fatal illness into a manageable chronic disorder. However, the presence of latent reservoirs, the multifaceted nature of HIV-1, drug resistance, severe off-target effects, poor adherence, and high cost restrict the efficacy of current cART targeting the distinct stages of the virus life cycle. Therefore, there is an unmet need for the discovery of new therapeutics that not only bypass the limitations of the current therapy but also protect the body's health at the same time. The main goal for complete HIV-1 eradication is purging latently infected cells from patients' bodies. A potential strategy called "lock-in and apoptosis" targets the budding phase of the life cycle of the virus and leads to susceptibility to apoptosis of HIV-1 infected cells for the elimination of HIV-1 reservoirs and, ultimately, for complete eradication. The current work intends to present the main advantages and disadvantages of United States Food and Drug Administration (FDA)-approved anti-HIV-1 drugs as well as plausible strategies for the design and development of more anti-HIV-1 compounds with better potency, favorable pharmacokinetic profiles, and improved safety issues.

Structural Characterization of TRAF6 N-Terminal for Therapeutic Uses and Computational Studies on New Derivatives.

Tumor necrosis factor receptor-associated factors (TRAFs) are a protein family with a wide variety of roles and binding partners. Among them, TRAF6, a ubiquitin ligase, possesses unique receptor binding specificity and shows diverse functions in immune system regulation, cellular signaling, central nervous system, and tumor formation. TRAF6 consists of an N-terminal Really Interesting New Gene (RING) domain, multiple zinc fingers, and a C-terminal TRAF domain. TRAF6 is an important therapeutic target for various disorders and structural studies of this protein are crucial for the development of next-generation therapeutics. Here, we presented a TRAF6 N-terminal structure determined at the Turkish light source "Turkish DeLight" to be 3.2 Å resolution at cryogenic temperature (PDB ID: 8HZ2). This structure offers insight into the domain organization and zinc-binding, which are critical for protein function. Since the RING domain and the zinc fingers are key targets for TRAF6 therapeutics, structural insights are crucial for future research. Separately, we rationally designed numerous new compounds and performed molecular docking studies using this template (PDB ID:8HZ2). According to the results, 10 new compounds formed key interactions with essential residues and zinc ion in the N-terminal region of TRAF6. Molecular dynamic (MD) simulations were performed for 300 ns to evaluate the stability of three docked complexes (compounds 256, 322, and 489). Compounds 256 and 489 was found to possess favorable bindings with TRAF6. These new compounds also showed moderate to good pharmacokinetic profiles, making them potential future drug candidates as TRAF6 inhibitors.

Discovery of Small Molecule COX-1 and Akt Inhibitors as Anti-NSCLC Agents Endowed with Anti-Inflammatory Action.

Targeted therapies have come into prominence in the ongoing battle against non-small cell lung cancer (NSCLC) because of the shortcomings of traditional chemotherapy. In this context, indole-based small molecules, which were synthesized efficiently, were subjected to an in vitro colorimetric assay to evaluate their cyclooxygenase (COX) inhibitory profiles. Compounds 3b and 4a were found to be the most selective COX-1 inhibitors in this series with IC50 values of 8.90 µM and 10.00 µM, respectively. In vitro and in vivo assays were performed to evaluate their anti-NSCLC and anti-inflammatory action, respectively. 2-(1H-Indol-3-yl)-N'-(4-morpholinobenzylidene)acetohydrazide (3b) showed selective cytotoxic activity against A549 human lung adenocarcinoma cells through apoptosis induction and Akt inhibition. The in vivo experimental data revealed that compound 3b decreased the serum myeloperoxidase and nitric oxide levels, pointing out its anti-inflammatory action. Moreover, compound 3b diminished the serum aminotransferase (particularly aspartate aminotransferase) levels. Based on the in vitro and in vivo experimental data, compound 3b stands out as a lead anti-NSCLC agent endowed with in vivo anti-inflammatory action, acting as a dual COX-1 and Akt inhibitor.

Evaluation of anti-glioma effects of benzothiazoles as efficient apoptosis inducers and DNA cleaving agents.

Glioma is the fast-growing, aggressive, and prevalent brain cancer with a great level of morbidity and mortality. Current therapy is usually found insufficient for glioma treatment. In the course of our research attempting to identify effective anti-glioma agents, three benzothiazole derivatives (1-3) were examined on U251 glioma cells. Among these derivatives, compound 3 was found to have the strongest cytotoxic effect on glioma cells with an IC50 value of 9.84 ± 0.64 µM in reference to cisplatin (IC50 = 8.41 ± 1.27 µM). Further mechanism of anti-glioma effects of compound 3 was characterized by the determination of its apoptotic effects in glioma cells and DNA cleaving capacity. Compound 3 caused a significant apoptotic death of U251 cell line. Besides, this compound cleaved DNA with FeSO4, H2O2 and ascorbic acid system. Molecular docking results also showed that compound 3 possessed a significant binding potential to DNA via important π-π stacking interaction with DG-16. Some pharmacokinetic determinants of compound 3 complied with standard limits making it as an efficient bioavailable anti-glioma drug candidate for upcoming exploration.

Scaffold Hopping and Structural Modification of NSC 663284: Discovery of Potent (Non)Halogenated Aminobenzoquinones.

The development of new anticancer drugs is still ongoing as a solution to the unsatisfactory results obtained by chemotherapy patients. Our previous studies on natural product-based anticancer agents led us to synthesize a new series of Plastoquinone (PQ) analogs and study their anticancer effects. Four members of PQ analogs (PQ1-4) were designed based on the scaffold hopping strategy; the design was later completed with structural modification. The obtained PQ analogs were synthesized and biologically evaluated against different cancer genotypes according to NCI-60 screening in vitro. According to the NCI results, bromo and iodo-substituted PQ analogs (PQ2 and PQ3) showed remarkable anticancer activities with a wide-spectrum profile. Among the two selected analogs (PQ2 and PQ3), PQ2 showed promising anticancer activity, in particular against leukemia cell lines, at both single- and five-dose NCI screenings. This compound was also detected by MTT assay to reveal significant selectivity between Jurkat cells and PBMC (healthy) compared to imatinib. Further in silico studies indicated that PQ2 was able to occupy the ATP-binding cleft of Abl TK, one of the main targets of leukemia, through key interactions similar to dasatinib and imatinib. PQ2 is also bound to the minor groove of the double helix of DNA. Based on computational pharmacokinetic studies, PQ2 possessed a remarkable drug-like profile, making it a potential anti-leukemia drug candidate for future studies.

Identification of New L-Heptanoylphosphatidyl Inositol Pentakisphosphate Derivatives Targeting the Interaction with HIV-1 Gag by Molecular Modelling Studies.

The HIV-1 Gag protein binds to the host cell membrane and assembles into immature particles. Then, in the course of immature virion budding, activated protease cleaves Gag into its main components: MA, CA, NC, and p6 proteins. The highly basic residues of MA predominantly interact with the acidic head of phosphatidyl-inositol-4,5-bisphosphate (PI(4,5)P2) inserted into the membrane. Our research group developed L-Heptanoylphosphatidyl Inositol Pentakisphosphate (L-HIPPO) and previously confirmed that this compound bound to the MA more strongly than PI(4,5)P2 and inositol hexakisphosphate (IP6) did. Therefore, herein we rationally designed eight new L-HIPPO derivatives based on the fact that the most changeable parts of L-HIPPO were two acyl chains. After that, we employed molecular docking for eight compounds via Maestro software using high-resolution crystal structures of MA in complex with IP6 (PDB IDs: 7E1I, 7E1J, and 7E1K), which were recently elucidated by our research group. The most promising docking scores were obtained with benzene-inserted compounds. Thus, we generated a library containing 213 new aromatic group-inserted L-HIPPO derivatives and performed the same molecular docking procedure. According to the results, we determined the nine new L-HIPPO derivatives most effectively binding to the MA with the most favorable scoring functions and pharmacokinetic properties for further exploration.

In Vitro Cytotoxicity Evaluation of Plastoquinone Analogues against Colorectal and Breast Cancers along with In Silico Insights.

Colorectal cancer (CRC) and breast cancer are leading causes of death globally, due to significant challenges in detection and management. The late-stage diagnosis and treatment failures require the discovery of potential anticancer agents to achieve a satisfactory therapeutic effect. We have previously reported a series of plastoquinone analogues to understand their cytotoxic profile. Among these derivatives, three of them (AQ-11, AQ-12, and AQ-15) were selected by the National Cancer Institute (NCI) to evaluate their in vitro antiproliferative activity against a panel of 60 human tumor cell lines. AQ-12 exhibited significant antiproliferative activity against HCT-116 CRC and MCF-7 breast cancer cells at a single dose and further five doses. MTT assay was also performed for AQ-12 at different concentrations against these two cells, implying that AQ-12 exerted notable cytotoxicity toward HCT-116 (IC50 = 5.11 ± 2.14 µM) and MCF-7 (IC50 = 6.06 ± 3.09 µM) cells in comparison with cisplatin (IC50 = 23.68 ± 6.81 µM and 19.67 ± 5.94 µM, respectively). This compound also augmented apoptosis in HCT-116 (62.30%) and MCF-7 (64.60%) cells comparable to cisplatin (67.30% and 78.80%, respectively). Molecular docking studies showed that AQ-12 bound to DNA, forming hydrogen bonding through the quinone scaffold. In silico pharmacokinetic determinants indicated that AQ-12 demonstrated drug-likeness with a remarkable pharmacokinetic profile for future mechanistic anti-CRC and anti-breast cancer activity studies.

Design, semi-synthesis and examination of new gypsogenin derivatives against leukemia via Abl tyrosine kinase inhibition and apoptosis induction.

Chronic myelogenous leukemia (CML) is characterized by Philadelphia translocation arising from Bcr-Abl fusion gene, which encodes abnormal oncoprotein showing tyrosine kinase (TK) function. Certain mutations in kinase domain, off-target effects and resistance problems of current TK inhibitors require the discovery of novel Abl TK inhibitors. For this purpose, herein, we synthesized new gypsogenin derivatives (6a-l) and evaluated their anticancer effects towards CML cells along with healthy cell line and different leukemic cells. Among these compounds, compound 6l was found as the most active anti-leukemic agent against K562 CML cells compared to imatinib exerting less cytotoxicity towards PBMCs (healthy). This compound also revealed significant anti-leukemic effects against Jurkat cell line. Besides, compound 6l enhanced apoptosis in CML cells with 52.4 % when compared with imatinib (61.8 %) and inhibited Abl TK significantly with an IC50 value of 13.04 ± 2.48 µM in a large panel of kinases accentuating Abl TK-mediated apoptosis of compound 6l in CML cells. Molecular docking outcomes showed that compound 6l formed mainly crucial interactions in the ATP-binding cleft of Abl TK similar to that of imatinib. Ultimately, in silico pharmacokinetic evaluation of compound 6l indicated that this compound was endowed with anti-leukemic drug candidate features.

Design, synthesis and biological evaluation of a new series of arylidene indanones as small molecules for targeted therapy of non-small cell lung carcinoma and prostate cancer.

In an attempt to identify small molecules for targeted therapy of non-small cell lung carcinoma (NSCLC) and prostate cancer (PCa), new arylidene indanones (1-10) were synthesized via the Claisen-Schmidt condensation of 5,6-methylenedioxy-1-indanone with p-substituted benzaldehyde. Compounds 1-10 were assessed for their cytotoxic effects on human lung adenocarcinoma (A549) and human pancreatic ductal carcinoma (PANC-1) cells as well as human normal lung fibroblast (CCD-19Lu) and human normal pancreatic ductal epithelial (hTERT-HPNE) cells. Among them, compounds 2, 4 and 10 were more effective on A549 and PANC-1 cells than cisplatin. Compounds 1 and 9 also showed more potent cytotoxic activity towards PANC-1 cells than cisplatin. In vitro assays were performed to assess their effects on DNA synthesis, apoptosis, caspase-3, mitochondrial membrane potential, intracellular calcium levels, morphological changes in cancer cells. Furthermore, all compounds were investigated for their inhibitory effects on cathepsin L (CatL) and cathepsin D (CatD). Compounds 2 and 4 exerted potent anti-NSCLC action through caspase-independent apoptosis induced by an increase in intracellular calcium level and correspondingly the disruption of the ΔΨm. These compounds also caused apoptotic morphological alterations in A549 cells. Compound 4 also inhibited both cathepsins but its inhibitory potency on CatL was more significant. Based on in vitro mechanistic assays, compound 4 was identified as a promising anticancer agent for targeted therapy of NSCLC. On the other hand, the marked anti- PCa activity of compound 1 mediated by apoptotic cell death is also noteworthy, but further enzymatic assays are required to elucidate its main mechanism of action.

An investigation of bacteriocin nisin anti-cancer effects and FZD7 protein interactions in liver cancer cells.

The bacteriocin, nisin, produced by Lactococcus and Streptococcus species during fermentation, is widely used for bio preservatives in a wide variety of foods. Liver cancer has a high mortality rate and is the fourth leading cause of cancer-related deaths worldwide. Recently, researchers have shown the anti-cancer effects of nisin through in vitro and in vivo studies. This study aimed to investigate the effect of nisin on liver cancer cell lines, which represented two subgroups of the disease model. Nisin exhibited significant growth inhibition and apoptosis in both cell lines, HuH-7, and SNU182. Drug resistance is the main problem in liver cancer and the epithelial-to-mesenchymal transition has a role in the development of drug resistance in hepatocellular carcinoma. The expression of EMT transcription factors ZEB1, SNAI1, and TWIST1 were analyzed depending on nisin treatment, TWIST1 expression was down-regulated after nisin treatment compared to the untreated SNU182 and HuH-7 cell lines. Besides, due to the reported correlation between the overexpression of Frizzled (FZD) proteins, specifically FZD7, in primary hepatocellular carcinomas (HCCs), molecular docking was assessed for Nisin A in the binding site of FZD7. Results confirmed that Nisin A was able to form important hydrogen bonding with key residues. This research not only determined the role of nisin in different liver cancer cell models but it also provided the first result of FZD7 and nisin interaction.

A new series of thiosemicarbazone-based anti-inflammatory agents exerting their action through cyclooxygenase inhibition.

In an endeavor to identify potent anti-inflammatory agents, new thiosemicarbazones (TSCs) incorporated into a diaryl ether framework (2a-2l) were prepared and screened for their in vitro inhibitory effects on cyclooxygenases (COXs). 4-[4-(Piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-cyanophenoxy)benzylidene]thiosemicarbazide (2c) was the most potent and selective COX-1 inhibitor in this series, with an IC50 value of 1.89 ± 0.04 µM. On the other hand, 4-[4-(piperidin-1-ylsulfonyl)phenyl]-1-[4-(4-nitrophenoxy)benzylidene]thiosemicarbazide (2b) was identified as a nonselective COX inhibitor (COX-1 IC50 = 13.44 ± 0.65 µM, COX-2 IC50 = 12.60 ± 0.78 µM). Based on molecular docking studies, the diaryl ether and the TSC groups serve as crucial moieties for interactions with pivotal amino acid residues in the active sites of COXs. According to MTT test, compounds 2b and 2c showed low cytotoxic activity toward NIH/3T3 cells. Their in vivo anti-inflammatory and antioxidant potencies were also assessed using the lipopolysaccharide-induced sepsis model. Compounds 2b and 2c diminished high-sensitivity C-reactive protein, myeloperoxidase, nitric oxide, and malondialdehyde levels. Both compounds also caused a significant decrease in aspartate aminotransferase levels as well as alanine aminotransferase levels. In silico pharmacokinetic studies suggest that compounds 2b and 2c possess favorable drug-likeness and oral bioavailability. It can be concluded that these compounds may act as orally bioavailable anti-inflammatory and antioxidant agents.

Comprehensive Research on Past and Future Therapeutic Strategies Devoted to Treatment of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly debilitating fatal neurodegenerative disorder, causing muscle atrophy and weakness, which leads to paralysis and eventual death. ALS has a multifaceted nature affected by many pathological mechanisms, including oxidative stress (also via protein aggregation), mitochondrial dysfunction, glutamate-induced excitotoxicity, apoptosis, neuroinflammation, axonal degeneration, skeletal muscle deterioration and viruses. This complexity is a major obstacle in defeating ALS. At present, riluzole and edaravone are the only drugs that have passed clinical trials for the treatment of ALS, notwithstanding that they showed modest benefits in a limited population of ALS. A dextromethorphan hydrobromide and quinidine sulfate combination was also approved to treat pseudobulbar affect (PBA) in the course of ALS. Globally, there is a struggle to prevent or alleviate the symptoms of this neurodegenerative disease, including implementation of antisense oligonucleotides (ASOs), induced pluripotent stem cells (iPSCs), CRISPR-9/Cas technique, non-invasive brain stimulation (NIBS) or ALS-on-a-chip technology. Additionally, researchers have synthesized and screened new compounds to be effective in ALS beyond the drug repurposing strategy. Despite all these efforts, ALS treatment is largely limited to palliative care, and there is a strong need for new therapeutics to be developed. This review focuses on and discusses which therapeutic strategies have been followed so far and what can be done in the future for the treatment of ALS.

In Vitro and In Silico Study of Analogs of Plant Product Plastoquinone to Be Effective in Colorectal Cancer Treatment.

Plants have paved the way for the attainment of molecules with a wide-range of biological activities. However, plant products occasionally show low biological activities and/or poor pharmacokinetic properties. In that case, development of their derivatives as drugs from the plant world has been actively performed. As plant products, plastoquinones (PQs) have been of high importance in anticancer drug design and discovery; we have previously evaluated and reported the potential cytotoxic effects of a series of PQ analogs. Among these analogs, PQ2, PQ3 and PQ10 were selected for National Cancer Institute (NCI) for in vitro screening of anticancer activity against a wide range of cancer cell lines. The apparent superior anticancer potency of PQ2 on the HCT-116 colorectal cancer cell line than that of PQ3 and PQ10 compared to other tested cell lines has encouraged us to perform further mechanistic studies to enlighten the mode of anti-colorectal cancer action of PQ2. For this purpose, its apoptotic effects on the HCT-116 cell line, DNA binding capacity and several crucial pharmacokinetic properties were investigated. Initially, MTT assay was conducted for PQ2 at different concentrations against HCT-116 cells. Results indicated that PQ2 exhibited significant cytotoxicity in HCT-116 cells with an IC50 value of 4.97 ± 1.93 µM compared to cisplatin (IC50 = 26.65 ± 7.85 µM). Moreover, apoptotic effects of PQ2 on HCT-116 cells were investigated by the annexin V/ethidium homodimer III staining method and PQ2 significantly induced apoptosis in HCT-116 cells compared to cisplatin. Based on the potent DNA cleavage capacity of PQ2, molecular docking studies were conducted in the minor groove of the double helix of DNA and PQ2 presented a key hydrogen bonding through its methoxy moiety. Overall, both in vitro and in silico studies indicated that effective, orally bioavailable drug-like PQ2 attracted attention for colorectal cancer treatment. The most important point to emerge from this study is that appropriate derivatization of a plant product leads to unique biologically active compounds.

A New Series of Indeno[1,2-c]pyrazoles as EGFR TK Inhibitors for NSCLC Therapy.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death throughout the world. Due to the shortcomings of traditional chemotherapy, targeted therapies have come into prominence for the management of NSCLC. In particular, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) therapy has emerged as a first-line therapy for NSCLC patients with EGFR-activating mutations. In this context, new indenopyrazoles, which were prepared by an efficient microwave-assisted method, were subjected to in silico and in vitro assays to evaluate their potency as EGFR TK-targeted anti-NSCLC agents. Compound 4 was the most promising antitumor agent towards A549 human lung adenocarcinoma cells, with an IC50 value of 6.13 µM compared to erlotinib (IC50 = 19.67 µM). Based on its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), it can be concluded that compound 4 exerts selective antitumor action. This compound also inhibited EGFR TK with an IC50 value of 17.58 µM compared to erlotinib (IC50 = 0.04 µM) and induced apoptosis (56.30%). Taking into account in silico and in vitro data, compound 4 stands out as a potential EGFR TKI for the treatment of NSCLC.

Studies on 1,4-Quinone Derivatives Exhibiting Anti-Leukemic Activity along with Anti-Colorectal and Anti-Breast Cancer Effects.

Colorectal cancer (CRC), breast cancer, and chronic myeloid leukemia (CML) are life-threatening malignancies worldwide. Although potent therapeutic and screening strategies have been developed so far, these cancer types are still major public health problems. Therefore, the exploration of more potent and selective new agents is urgently required for the treatment of these cancers. Quinones represent one of the most important structures in anticancer drug discovery. We have previously identified a series of quinone-based compounds (ABQ-1-17) as anti-CML agents. In the current work, ABQ-3 was taken to the National Cancer Institute (NCI) for screening to determine its in vitro antiproliferative effects against a large panel of human tumor cell lines at five doses. ABQ-3 revealed significant growth inhibition against HCT-116 CRC and MCF-7 breast cancer cells with 2.00 µM and 2.35 µM GI50 values, respectively. The MTT test also showed that ABQ-3 possessed anticancer effects towards HCT-116 and MCF-7 cells with IC50 values of 5.22 ± 2.41 µM and 7.46 ± 2.76 µM, respectively. Further experiments indicated that ABQ-3 induced apoptosis in both cell lines, and molecular docking studies explicitly suggested that ABQ-3 exhibited DNA binding in a similar fashion to previously reported compounds. Based on in silico pharmacokinetic prediction, ABQ-3 might display drug-like features enabling this compound to become a lead molecule for future studies.

EGFR-Targeted Pentacyclic Triterpene Analogues for Glioma Therapy.

Glioma, particularly its most malignant form, glioblastoma multiforme (GBM), is the most common and aggressive malignant central nervous system tumor. The drawbacks of the current chemotherapy for GBM have aroused curiosity in the search for targeted therapies. Aberrantly overexpressed epidermal growth factor receptor (EGFR) in GBM results in poor prognosis, low survival rates, poor responses to therapy and recurrence, and therefore EGFR-targeted therapy stands out as a promising approach for the treatment of gliomas. In this context, a series of pentacyclic triterpene analogues were subjected to in vitro and in silico assays, which were conducted to assess their potency as EGFR-targeted anti-glioma agents. In particular, compound 10 was the most potent anti-glioma agent with an IC50 value of 5.82 µM towards U251 human glioblastoma cells. Taking into account its low cytotoxicity to peripheral blood mononuclear cells (PBMCs), compound 10 exerts selective antitumor action towards Jurkat human leukemic T-cells. This compound also induced apoptosis and inhibited EGFR with an IC50 value of 9.43 µM compared to erlotinib (IC50 = 0.06 µM). Based on in vitro and in silico data, compound 10 stands out as a potential orally bioavailable EGFR-targeted anti-glioma agent endowed with the ability to cross the blood-brain barrier (BBB).

Novel metabolic enzyme inhibitors designed through the molecular hybridization of thiazole and pyrazoline scaffolds.

New hybrid thiazolyl-pyrazoline derivatives (4a-k) were obtained through a facile and versatile synthetic procedure, and their inhibitory effects on the human carbonic anhydrase (hCA) isoforms I and II as well as on acetylcholinesterase (AChE) were determined. All new thiazolyl-pyrazolines showed activity at nanomolar levels as hCA I, hCA II, and AChE inhibitors, with KI values in the range of 13.35-63.79, 7.01-115.80, and 17.89-48.05 nM, respectively. 1-[4-(4-Cyanophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4f) and 1-(4-phenylthiazol-2-yl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4a) against hCAs and 1-[4-(4-chlorophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4d) and 1-[4-(4-nitrophenyl)thiazol-2-yl]-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (4b) against AChE were identified as highly potent inhibitors, superior to the standard drugs, acetazolamide and tacrine, respectively. Compounds 4a-k were also evaluated for their cytotoxic effects on the L929 mouse fibroblast (normal) cell line. Moreover, a comprehensive ligand-receptor interaction prediction was performed using the ADME-Tox, Glide XP, and MM-GBSA modules of the Schrödinger Small-Molecule Drug Discovery Suite to elucidate the potential binding modes of the new hybrid inhibitors against these metabolic enzymes.

Design, synthesis and investigation of the mechanism of action underlying anti-leukemic effects of the quinolinequinones as LY83583 analogs.

Literature conclusively shows that one of the quinolinequinone analogs (6-anilino-5,8-quinolinequinone), referred to as LY83583 hereafter, an inhibitor of guanylyl cyclase, was used as the inhibitor of the cell proliferation in cancer cells. In the present work, a series of analogs of the LY83583 containing alkoxy group(s) in aminophenyl ring (AQQ1-15) were designed and synthesized via a two-step route and evaluated for their in vitro cytotoxic activity against four different cancer cell lines (K562, Jurkat, MT-2, and HeLa) and human peripheral blood mononuclear cells (PBMCs) by MTT assay. The analog (AQQ13) was identified to possess the most potent cytotoxic activity against K562 human chronic myelogenous (CML) cell line (IC50 = 0.59 ± 0.07 µM) with significant selectivity (SI = 4.51) compared to imatinib (IC50 = 5.46 ± 0.85 µM; SI = 4.60). Based on its superior cytotoxic activity, the analog AQQ13 was selected for further mechanistic studies including determination of its apoptotic effects on K562 cell line via annexin V/ethidium homodimer III staining potency, ABL1 kinase inhibitory activity, and DNA cleaving capacity. Results ascertained that the analog AQQ13 induced apoptosis in K562 cell line with notable DNA-cleaving activity. However, AQQ13 demonstrated weak ABL1 inhibition indicating the correlation between anti-K562 and anti-ABL1 activities. In continuance, respectively conducted in silico molecular docking and Absorption, Distribution, Metabolism, and Excretion (ADME) studies drew attention to enhanced binding interactions of AQQ13 towards DNA and its high compatibility with the potential limits of specified pharmacokinetic parameters making it as a potential anti-leukemic drug candidate. Our findings may provide a new insight for further development of novel quinolinequinone-based anticancer analogs against CML.

Identification of a new class of potent aldose reductase inhibitors: Design, microwave-assisted synthesis, in vitro and in silico evaluation of 2-pyrazolines.

Aldose reductase (AR) acts as a multi-disease target for the design and development of therapeutic agents for the management of diabetic complications as well as non-diabetic diseases. In the search for potent AR inhibitors, the microwave-assisted synthesis of twenty new compounds with a 1,3-diaryl-5-(4-fluorophenyl)-2-pyrazoline moiety as a common fragment in their structure (1-20) was carried out efficiently. Compounds 1-20 were subjected to in vitro studies, which were conducted to assess their AR inhibitory effects and cytotoxicity towards L929 mouse fibroblast (normal) cells. Among these compounds, 1-(3-bromophenyl)-3-(4-piperidinophenyl)-5-(4-fluorophenyl)-2-pyrazoline (20) was identified as the most promising AR inhibitor with an IC50 value of 0.160 ± 0.005 µM exerting competitive inhibition with a Ki value of 0.019 ± 0.001 µM as compared to epalrestat (IC50 = 0.279 ± 0.001 µM; Ki = 0.801 ± 0.023 µM) and quercetin (IC50 = 4.120 ± 0.123 µM; Ki = 6.082 ± 0.272 µM). Compound 20 displayed cytotoxicity towards L929 cells with an IC50 value of 18.75 ± 1.06 µM highlighting its safety as an AR inhibitor. Molecular docking studies suggested that π-π stacking interactions occurred between the m-bromophenyl moiety of compound 20 and Trp21. Based on in silico pharmacokinetic studies, compound 20 was found to possess favorable oral bioavailability and drug-like properties. It can be concluded that compound 20 is a potential orally bioavailable AR inhibitor for the management of diabetic complications as well as non-diabetic diseases.