9-aminoacridine Derivatives Research Articles

New biocidal hybrids bearing acridine and aminophosphonate Scaffolds against different bacterial pathogens

New hybrids containing acridine and α-amino phosphonate scaffolds 6a-h were synthesized by three one-pot reactions via Kabachnik–Fields reaction of 9-aminoacridine derivatives 3a-d, aldehydes 4a,b and triphenyl phosphite 5 in equimolar ratio under stirring at room temperature. The installation of the afforded hybrids was affirmed by different spectroscopic methods as IR, 1HNMR, 13CNMR, 31P NMR, MS and elemental analysis. The antibacterial activities of hybrids 6a-h were screened against both Gram-positive and Gram-negative bacteria of four pathogenic strains, comparable to ampicillin and chloramphenicol drugs. Most hybrids showed higher activity compared to the reference drugs. Notably, the antibacterial performance of 6c was more substantial than other analogues with best minimum inhibitory concentration (MIC) and highest zone of inhibition (ZOI) of 31, 34, 35, 38 mm, against Serratia marcescens, Streptococcus mutans, MRSA and Klebsiella pneumoniae clinical isolates respectively. In addition, Transmission Electron Microscopes (TEM) was carried out to study the mode of action of 6c with MRSA, the results confirmed that the titled hybrid caused the disruption of bacterial cell wall. Moreover, the time-dependent kill study revealed that the investigated compounds were time and dose-effective bactericidal agents and could be used as potential leads for further development and optimization of novel antibacterial agents.

A 9-aminoacridine derivative induces growth inhibition of Ehrlich ascites carcinoma cells and antinociceptive effect in mice.

Acridine derivatives have been found with anticancer and antinociceptive activities. Herein, we aimed to evaluate the toxicological, antitumor, and antinociceptive actions of N'-(6-chloro-2-methoxyacridin-9-yl)-2-cyanoacetohydrazide (ACS-AZ), a 9-aminoacridine derivative with antimalarial activity. The toxicity was assessed by acute toxicity and micronucleus tests in mice. The in vivo antitumor effect of ACS-AZ (12.5, 25, or 50mg/kg, intraperitoneally, i.p.) was determined using the Ehrlich tumor model, and toxicity. The antinociceptive efficacy of the compound (50mg/kg, i.p.) was investigated using formalin and hot plate assays in mice. The role of the opioid system was also investigated. In the acute toxicity test, the LD50 (lethal dose 50%) value was 500mg/kg (i.p.), and no detectable genotoxic effect was observed. After a 7-day treatment, ACS-AZ significantly (p < 0.05) reduced tumor cell viability and peritumoral microvessels density, suggesting antiangiogenic action. In addition, ACS-AZ reduced (p < 0.05) IL-1β and CCL-2 levels, which may be related to the antiangiogenic effect, while increasing (p < 0.05) TNF-α and IL-4 levels, which are related to its direct cytotoxicity. ACS-AZ also decreased (p < 0.05) oxidative stress and nitric oxide (NO) levels, both of which are crucial mediators in cancer known for their angiogenic action. Moreover, weak toxicological effects were recorded after a 7-day treatment (biochemical, hematological, and histological parameters). Concerning antinociceptive activity, ACS-AZ was effective on hotplate and formalin (early and late phases) tests (p < 0.05), characteristic of analgesic agents with central action. Through pretreatment with the non-selective (naloxone) and μ1-selective (naloxonazine) opioid antagonists, we observed that the antinociceptive effect of ACS-AZ is mediated mainly by μ1-opioid receptors (p < 0.05). In conclusion, ACS-AZ has low toxicity and antitumoral activity related to cytotoxic and antiangiogenic actions that involve the modulation of reactive oxygen species, NO, and cytokine levels, in addition to antinociceptive properties involving the opioid system.

A A new matrix of MALDI-TOF MS derivative of 9-aminoacridine for lipid identification in positive ions mode

Matrix-assisted laser desorption/ionization (MALDI) has evolved to become a well- established technique during the last decades. Because of matrix peak interference in the low molecular-weight region, however, new matrices are often studied with the purpose of improving the spectral quality under m/z 500. Herein, we present the substance 2,4,5,7-tetranitro-9-aminoacridine (TNA) as a suitable alternative matrix for lipid detection in the positive-ion mode. TNA is obtained from 9-aminoacridine, a matrix commonly used to analyze lipids in negative-ion mode, with the addition of 4 nitro groups through a synthetic path. The procedure results in a highly conjugated system that presents a bigger electronic dispersion and therefore higher UV absorption. First, we demonstrated the high sensitivity of TNA for retinol. Second, TNA was applied to detect lipids in the liver of the water rat Nectomys squamipes. By using this natural model of hepatic steatosis (fat liver), a condition in which there is excessive accumulation of lipids, TNA provided a clearer identification of three species of polyunsaturated fatty acids (PUFAs) compared to other matrices. TNA presents better sensitivity and spectral resolution, little or no interference from matrix ions, high intensity of signal and low cost with high yield of matrix production.

Effects of Quinacrine on Expression of Hippo signaling Pathway Components (LATS1, LATS2, and YAP) in Human Breast Cancer Stem Cells.

Objective:The Hippo signaling pathway has important role in the pathogenesis of some tumors. Breast cancer is the most prevalent cancer among females in the world. In recent years, various articles referred to inhibiting effect of quinacrine, a derivative of 9-aminoacridine, on the growth of several types of cancer cells. In this study, we evaluated the effect of quinacrine on expression of LATS1, LATS2, and YAP genes of the Hippo signaling pathway and YAP level in human breast cancer stem cells (MDA-MB 231 cell line). This cell line of breast cancer expresses the triple negative characteristics. Methods:MDA-MB 231 cells was treated with 0.5 µM of quinacrine for 3 days. The dose was selected using MTT assays. The expression of genes was quantified by Real-time PCR. The protein expression was performed by Western blotting. Significance of observations were checked by means of Mann-Whitney test using p<0.05 as the level of significance. Results:The present study demonstrated that expression of YAP gene in MDA-MB 231 cell line significantly down regulated by quinacrine. Quinacrine significantly decreased the amount of YAP protein. Moreover, quinacrine did not have meaningful effect on LATS1 and LATS2 genes expression. Conclusion: YAP gene is an oncogene and inhibition of its expression by quinacrine could effect on breast cancer cell progression.

Anti-Cancer Stem Cells Potentiality of an Anti-Malarial Agent Quinacrine: An Old Wine in a New Bottle.

Quinacrine (QC) is a tricyclic compound and a derivative of 9-aminoacridine. It has been widely used to treat malaria and other parasitic diseases since the last century. Interestingly, studies have revealed that it also displays anti-cancer activities. Here, we have discussed the anti-cancer mechanism of QC along with its potentiality to specifically target cancer stem cells. The anti-cancer action of this drug includes DNA intercalation, inhibition of DNA repair mechanism, prevention of cellular growth, cell cycle arrest, inhibition of DNA and RNA polymerase activity, induction of autophagy, promotion of apoptosis, deregulation of cell signaling in cancer cells and cancer stem cells, inhibition of metastasis and angiogenesis. In addition, we have also emphasized on the synergistic effect of this drug with other potent chemotherapeutic agents and mentioned its different applications in anti-cancer therapy.

Evaluation of the Gene Expression of Hedgehog Signaling Pathway Components in Response to Quinacrine in MDA-MB 231 Cells

Background: Hedgehog signaling pathway abnormality plays an important role in the development of various cancers. PTCH1 and SMO proteins are essential receptors in the hedgehog signaling pathway. Quinacrine as a derivative of 9-aminoacridine revealed an inhibitory effect on the growth of some cancer cells. Triple-negative breast cancer with stem cell-like characteristics remains a poor prognostic type. Objectives: In this study, the effect of quinacrine on patched1 protein receptor (PTCH1) and smoothened protein receptor (SMO) gene expression in the hedgehog signaling pathway was evaluated in MDA-MB 231 breast cancer cell line. Methods: Toxicity of quinacrine was determined based on the MTT assay results. MDA-MB 231 breast cancer cells were treated with 0.5 µM quinacrine for 72 hours. The alteration of the hedgehog signaling pathway was studied by quantitative assessment of PTCH1 and SMO gene expression. Results were evaluated using t-test and were analyzed based on P < 0.05. Results: This study showed that 0.5 µM quinacrine decreases SMO gene expression involved in the hedgehog signaling pathway (-2.1 fold) in MDA-MB 231 breast cancer cell line (P = 0.007). Quinacrine had no significant effect on PTCH1 gene expression (P = 0.059). Conclusions: The SMO gene inhibition by quinacrine could affect breast cancer cells growth with respect to its oncogenic role.

In-silico Design, ADMET Screening, MM-GBSA Binding Free Energy of Some Novel Isoxazole Substituted 9-Anilinoacridines as HER2 Inhibitors Targeting Breast Cancer.

Human Epidermal development factor Receptor-2 (HER2) is a membrane tyrosine kinase which is overexpressed and gene amplified in human breast cancers. HER2 amplification and overexpression have been linked to important tumor cell proliferation and survival pathways for 20% of instances of breast cancer. 9-aminoacridines are significant DNA-intercalating agents because of their antiproliferative properties. Some novel isoxazole substituted 9-anilinoacridines(1a-z) were designed by in-silico technique for their HER2 inhibitory activity. Docking investigations of compounds 1a-z are performed against HER2 (PDB id-3PP0) by using Schrodinger suit 2016-2. Molecular docking study for the designed molecules 1a-z are performed by Glide module, in-silico ADMET screening by QikProp module and binding free energy by Prime-MMGBSA module of Schrodinger suit. The binding affinity of designed molecules 1a-z towards HER2 was chosen based on GLIDE score. Many compounds showed good hydrophobic communications and hydrogen bonding associations to hinder HER2. The compounds 1a-z, aside from 1z have significant Glide scores in the scope of - 4.91 to - 10.59 when compared with the standard Ethacridine (- 4.23) and Tamoxifen (- 3.78). The in-silico ADMET properties are inside the suggested about drug likeness. MM-GBSA binding of the most intense inhibitor is positive. The outcomes reveal that this study provides evidence for the consideration of isoxazole substituted 9-aminoacridine derivatives as potential HER2 inhibitors. The compounds, 1s,x,v,a,j,r with significant Glide scores may produce significant anti breast cancer activity and further in vitro and in vivo investigations may prove their therapeutic potential.

Interaction of fatty acid-containing 9-aminoacridine derivative with surfactants and bio-surfactants: Synthesis and photophysical studies

The present work describes the synthesis and photophysical studies of two 9-aminoacridine derivatives (N-(acridine-9-yl)palmitamide (AC-PA) and N-(acridine-9-yl)acetamide (AC-ACYL)). For AC-PA and AC-ACYL, the -NH2 group of 9-aminoacridine is acylated by a long hydrophobic tail (palmitic acid, a saturated fatty acid), and a short hydrophobic tail (acetic acid), respectively. The steady-state and time-resolved fluorescence of AC-PA are sensitive towards the micellization of sodium deoxycholate and sodium cholate bile salts. Fluorescence of AC-PA is also senstive to microenviornment of different type of suffactants and is used to monitor the anionic, cationic and neutral surfactants. The critical micellar concentration determined from the fluorescene studies of AC-PA in the bile salts and surfactants are consistent with the values reported in the literatur. In contrast, steady-state and time-resolved fluorescence of AC-ACYL are insenstive to towards the micellization process of bile-salts and surfactants. The comparative study presented here shows the importance of a hydrophobic long tail, attached to a fluorophore, to make its fluorescence properties sensitive towards microenvironment and, in the process, make such molecules suitable for investigation of structure and dynamics of various organized systems.

Binding interaction of N-acetylated acridine conjugate with ct-DNA and β-cyclodextrin: Synthesis and photophysical studies

In the present work we are reporting the synthesis and binding interaction of a saturated fatty acid containing 9-aminoacridine derivative (AC-PA) with ct-DNA and β-cyclodextrin (β-CD). From Steady-state fluorescence experiments this newly synthesized 9-aminoacridine derivative, AC-PA, shows more efficient binding interaction with ct-DNA as compared to the 9-aminoacridine (AC). The extent of interaction of AC-PA and AC with ct-DNA was found out by calculating the fluorescence quenching by using Stern–Volmer quenching equation. The calculated quenching constants of AC-PA and AC are (4.5 ± 0.5) × 103M−1 (3.7 ± 0.5) × 103M−1 respectively. The mechanism of fluorescence quenching of AC-PA and AC, were understand by using Stern–Volmer plots as well as time-resolved fluorescence experiments. The fluorescence quenching of AC-PA and AC by ct-DNA are static in nature and take place by formation of ground state complexes. The binding mode between AC-PA and AC were understood by DNA melting analysis experiment. The DNA melting analysis experiments were reveals that the binding interactions between fluorophores (AC-PA and AC) with ct-DNA are intercalative in nature. The melting temperature and mode of binding intercalative mode of binding between AC-PA and AC were further confirmed by DSC and CD experiments. The steady-state and time-resolved fluorescence parameters of AC-PA are quite sensitive towards the formation of inclusion complexes between AC-PA and β-CD. Long hydrophobic tail containing acridine conjugate (AC-PA) shows more efficient binding interactions with the β-CD and the calculated binding constants value of AC-PA is 0.51 × 102M−1. Whereas, the parent molecule, AC not showing any binding interactions with β-CD.

Molecular Docking studies and in-silico ADMET Screening of Some novel Oxazine substituted 9-Anilinoacridines as Topoisomerase II Inhibitors

The derivatives of 9-aminoacridine are generally inhibiting DNA Topoisomerase II (topo II), because of the ability of acridine nucleus to intercalate into DNA base pair. In the present study, an attempt is made to identify potent ligands from heterocyclic substituted 9-anilinoacridines which target against Topoisomerase II (1ZXM) by molecular modelling and docking studies using Schrodinger suite-2011 Maestro 9.2 version. The binding affinity of the designed compounds towards Topoisomerase II (1ZXM) was calculated based on the GLIDE score due to various interactions. Many of the designed compounds have good Glide score due to strong hydrogen bonding interactions, hydrophobic interactions and other parameters.. The N-Phenyl pyrazole substituted 9-anilino acridine derivatives 1a- 1x have good binding affinity with topo II with Glide score in the range of -5.58 to -7.78 when compared with the standard ledacrine (-5.24). The in silico ADMET screening of these compounds also performed by qikprop module of Schrodinger suite and the values of all the properties are within the recommended values. So it is worthwhile to synthesis the designed compounds for their antibacterial and cytotoxic activities against Topoisomerase II.

New 9-Aminoacridine Derivative: Synthesis, Study and Potential Application as pH Indicator in Organic Solvents

In this work, we describe the synthesis of a novel 9-aminoacridine derivative that presents surprisingly different colors when exposed to neutral, acidic or basic mediums with potential application as pH indicator in organic solvents. Furthermore, pKa and molar absorptivity values were determined and theoretical studies supported by density functional theory (DFT) calculations were performed to elucidate the different structures of this compound.

Amsacrine-induced apoptosis of human leukemia U937 cells is mediated by the inhibition of AKT- and ERK-induced stabilization of MCL1.

Previous studies have attributed the anticancer activity of amsacrine to its inhibitory effect on topoisomerase II. However, 9-aminoacridine derivatives, which have the same structural scaffold as amsacrine, induce cancer cell apoptosis by altering the expression of BCL2 family proteins. Therefore, in the present study, we assessed whether BCL2 family proteins mediated the cytotoxic effects of amsacrine on human leukemia U937 cells. Amsacrine-induced apoptosis of U937 cells was characterized by caspase-9 and caspase-3 activation, increased intracellular Ca2+ concentration, mitochondrial depolarization, and MCL1 down-regulation. Amsacrine induced MCL1 down-regulation by decreasing its stability. Further, amsacrine-treated U937 cells showed AKT degradation and Ca2+-mediated ERK inactivation. Blockade of ERK-mediated phosphorylation of MCL1 inhibited the effect of Pin1 on the stabilization of MCL1, and AKT degradation promoted GSK3β-mediated degradation of MCL1. Restoration of ERK phosphorylation and AKT expression abrogated amsacrine-induced MCL1 down-regulation. Moreover, MCL1 over-expression inhibited amsacrine-induced depolarization of mitochondria membrane and increased the viability of amsacrine-treated cells. Taken together, our data indicate that amsacrine abolishes ERK- and Pin1-mediated stabilization of MCL1 and promotes GSK3β-mediated degradation of MCL1, leading to activate mitochondria-mediated apoptosis pathway in U937 cells.

Determinants of action of hydrophobic amines on ASIC1a and ASIC2a

Acid-sensing ion channels (ASICs) are involved in numerous physiological and pathological processes in the central nervous system. Development of pharmacological tools capable to inhibit or potentiate these channels is important for our knowledge about roles of ASICs in the neuronal network and can be promising for treatment of some disorders. Recently we described four hydrophobic monoamines that potentiate and inhibit ASICs depending on subunit composition of the channel and peculiarities of the drug structure. In the present work we performed structure-activity relationship analysis using derivatives of adamantane, phenylcyclohexyl and 9-aminoacridine to reveal the main determinants of action of amine-containing compounds on recombinant ASIC1a and ASIC2a homomers expressed in CHO cells. We found that the most active compounds are monocations with protonatable aminogroup. In general, potentiators and inhibitors of ASIC1a we found, but only potentiators for ASIC2a. Flat aromatic structure of the headgroup determines inhibition of ASIC1a while “V-shape” structure of the hydrophobic moiety favors potentiation of ASIC2a. Moreover, for some series of monoamines there was a correlation between action on ASIC1a and ASIC2a, the weaker ASIC1a inhibition, the stronger ASIC2a potentiation. Decay of response was accelerated by ASIC1a inhibitors as well as by potentiators. All compounds potentiating ASIC2a slowed down desensitization. Our results suggest that hydrophobic amines cause complex action on ASICs.

Synthesis of 9-Aminoacridine Derivatives as Anti-Alzheimer Agents.

In the present study, some 9-aminoacridine derivatives have been synthesized by condensation of 9-aminoacridine with substituted phenacyl, benzoyl, and benzyl halides (RM1-RM6). Compounds were investigated for acetylcholinesterase and butyrylcholinesterase inhibition potential, considering these enzymes playing a key role in Alzheimer's disease. All derivatives showed better inhibition of enzymes than the standard galantamine, whereas except RM4, all exhibit better results than tacrine, a well-known acridine derivative used for the treatment of Alzheimer's disease.

Synthesis of acridine cyclic imide hybrid molecules and their evaluation for anticancer activity

9-Amino acridine derivatives (1a–e) on condensation with dihydrofuran-2,5-dione, hexahydroisobenzofuran-1,3-dione and isochroman-1,3-dione under microwave irradiation gave corresponding condensation products 2a–e, 3a–e and 4a–e, respectively, in good yields. All these compounds were screened in vitro for anticancer activity against five human cancer cell lines, i.e., breast (T47D), lung (NCl H-522), colon (HCT-15), ovary (PA-1) and liver (Hep G2). Compounds 1-(3-methoxyacridine-9-yl) pyrrolidine-2,5-dione (2d) (ovary PA-1), 2-(2-methylacridine-9-yl)hexahydro-1H-isoindole-1,3(2H)-dione (3b) (lung NCl H-522), 2-(4-methylacridine-9-yl)hexahydro-1H-isoindole-1,3(2H)-dione (3c) (ovary PA-1), 2-(4-methoxyacridine-9-yl)hexahydro-1H-isoindole-1,3(2H)-dione (3e) (ovary PA-1) and 2-(2-methylacridine-9-yl)isoquinoline-1,3(2H,4H)-dione (4b) (ovary PA-1) exhibited IC50 values 7.1, 8.0, 5.4, 10.0 and 6.56 µM, respectively, and hence possess good anticancer activity.

Synthesis and anticancer activity evaluation of some acridine derivatives

9-Amino acridine derivatives (1a–1h) on condensation with 9, 10-dihydroanthracene-9, 10-α, β-succinic anhydride (2) at room temperature gave condensation products (3a–3h). Microwave-assisted condensation of 9-amino acridine derivatives (1a–1d) with phthalic anhydride, cis 1,2,3,6-tetrahydrophthalimide, and 2,5-pyrroledione gave corresponding condensation products 4a–4d, 5a–5d & 6a–6d, respectively, in good yields. All these compounds were screened for in vitro anticancer activity against five human cancer cell lines i.e., breast (T47D), lung (NCl H-522), colon (HCT-15), ovary (PA-1), and liver (Hep G2). Compounds 3a (breast T47D), 3 g (lung NCl H-522), 4a (liver Hep G2), and 6b (colon HCT-15) exhibited IC50 values 5.4, 4.2, 4.5, and 2.4 µM, respectively, and hence possess good anticancer activity.

Enhanced antitumor activity of erlotinib in combination with quinacrine in EGFR WT and L858R/T790M mutant NSCLC.

e22153 Background: Non-small cell lung cancer (NSCLC) cell lines with epidermal growth factor receptor (EGFR) mutations are very sensitive to EGFR inhibitors such as erlotinib (E). However, the efficacy of E is limited in NSCLC cells harboring wild-type (WT) EGFR or second-site mutation EGFR-L858R/T790M. Various mechanisms of resistance have been described including activation of alternate signaling pathways through activation of MET, PI3K and NF-κB. Quinacrine (Q) is member of a group of small molecules called curaxins, which are 9-aminoacridine derivative and known to suppresses NF-κB activity by causing chromatin trapping of the FACT (facilitates chromatin transcription) complex. We evaluated utility of NF-κB inhibition by Q in overcoming the resistance to E in NSCLC cell lines Methods: E resistant NSCLC cell lines, A549 (EGFR WT), H1975 (EGFR-L858R/T790M) and H1993 (Met amplification) were used for drug synergy experiments. MTT assay, flow cytometry, Annexin V/PI staining, western blot and NF-κB lucif...

Abstract A263: Combination of quinacrine and erlotinib overcomes resistance to erlotinib in non-small cell lung cancer.

Abstract The epidermal growth factor receptor (EGFR) inhibitor erlotinib is highly effective in non-small cell lung cancer (NSCLC) patients whose tumors express EGFR mutations, e.g., EGFR-L858R or EGFR exon 19 del. However, the efficacy of erlotinib is limited by either primary or secondary resistance, i.e., in patients whose tumors express wild-type EGFR (wtEGFR), or in initially sensitive patients whose tumors develop the second-site mutation EGFR-L858R/T790M or Met amplification after 10-14 months of erlotinib treatment. To improve treatment with erlotinib, we combined it with quinacrine in several erlotinib-resistant NSCLC cells. Quinacrine is a 9-aminoacridine derivative that suppresses nuclear factor-kappa B (NF-κB) by causing chromatin trapping of the FACT (facilitates chromatin transcription) complex. In A549 (wtEGFR), H1975 (EGFR-L858R/T790M), and H1993 (Met amplification) cells, the combination of erlotinib and quinacrine at 5 to 1 or 10 to 1 fixed ratios was highly synergistic, as quantified by the Chou-Talalay combination indices [ED50: 0.61 (0.42-0.81); ED75: 0.53 (0.40-0.67); ED90: 0.63 (0.54-0.71)]. Addition of quinacrine to erlotinib treatment inhibited colony formation and induced significant cell cycle arrest and apoptosis in A549 and H1975 cells. Upon quinacrine treatment, the FACT subunit SSRP1 disappeared from the soluble protein fraction, and NF-κB-dependent luciferase activity was decreased. Knockdown of SSRP1 decreased cell viability and colony formation, and sensitized the cells to erlotinib treatment. Moreover, microarray analysis of A549 and H1975 cells treated with erlotinib only, quinacrine only, or both, showed that quinacrine or combination treatment significantly affected genes involved in cell cycle progression or nucleotide metabolism, and many of these genes contain binding sites for transcription factors that regulate SSRP1-enriched genes. These data support a Phase I/II clinical trial (NCT01839955) that is just beginning, combining erlotinib and quinacrine in wtEGFR NSCLC patients after first-line chemotherapy. To assess synergistic effects in this clinical trial, we identified genes from the microarray analysis that were more significantly suppressed by combination treatment than by either single treatment. We further narrowed them down to those whose increased expression is associated with poorer survival in lung adenocarcinoma patients (HR ranges from 1.58-2.92) as potential biomarkers of drug synergy for the clinical trial. These genes, most of which are involved in various cell cycle processes, included BIRC5, DLGAP5, FOSL1, FOXM1, HIST1H2AK, HIST1H2BM, KIFC1, MKI67, PBK, PLK1, TOP2A, and ZWILCH. We conclude that the combination of quinacrine and erlotinib helps overcome erlotinib resistance in NSCLC, potentially by targeting FACT and suppressing cell cycle progression. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A263. Citation Format: Josephine Kam Tai Dermawan, Katerina Gurova, John Pink, Afshin Dowlati, Sarmishtha De, Goutham Narla, Neelesh Sharma, George Stark. Combination of quinacrine and erlotinib overcomes resistance to erlotinib in non-small cell lung cancer. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A263.

New 9-aminoacridine derivatives as inhibitors of Botulinum neurotoxins and P. falciparum malaria

Steroidal and adamantane aminoacridine derivatives were prepared and tested as both botulinum neurotoxin (BoNT) inhibitors and antimalarials. Steroid-bound acridines provided good potency against both the BoNT/A and BoNT/B light chains (LCs). The observed inhibition of the BoNT/B LC by ca. 50% is the highest attained inhibitory activity against this serotype by acridine-based compounds to date. With respect to antimalarial activity, adamantane acridines were the most potent derivatives (IC50 = 6-9 nM, SI &gt; 326), indicating that an adamantyl group is a better carries than a steroidal motif for this indication.

In vitro efficiency of 9-(N-cinnamoylbutyl)aminoacridines against blood- and liver-stage malaria parasites

Novel 9-aminoacridine derivatives were synthesized by linking the heteroaromatic core to different cinnamic acids through an aminobutyl chain. The test compounds demonstrated mid-nanomolar in vitro activity against erythrocytic stages of the chloroquine-resistant W2 strain of the human malaria parasite Plasmodium falciparum. Two of the most active derivatives also showed in vitro activity against liver-stage Plasmodium berghei, with activity greater than that of the reference liver-stage antimalarial primaquine. The compounds were not toxic to human hepatoma cells at concentrations up to 5μM. Hence, 9-(N-cinnamoylbutyl)aminoacridines are a new class of leads for prevention and treatment of malaria.