One-Stage Pathway from Hollongdione to C17-Alkyne and Vinyl Chloride Following Mannich Bases and Carboxylic Acid.

Hollongdione is the first recorded example of the occurrence of a dammarane hexanor-triterpene in nature possessing antiviral and cytotoxic activity. Its simple one-stage transformation into compounds with terminal alkyne and vinyl chloride fragments via the interaction with phosphorus halides is reported. The copper(I)-catalyzed Mannich reaction of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20(21)-in 3 led to a series of aminomethylated products, while 17-carboxylic acid was obtained by ozone oxidation of 3-oxo-22,23,24,25,26,27-hexanor-dammar-20-chloro-20(21)-en 4; the following direct amidation of the latter has been developed. The structures of all new molecules were established by spectroscopic studies that included 2D NMR correlation methods; the molecular structures of compounds 2-5 were determined by X-ray analysis.

Application of the Mannich reaction in the structural modification of natural products.

The Mannich reaction is commonly used to introduce N atoms into compound molecules and is thus widely applied in drug synthesis. The Mannich reaction accounts for a certain proportion of structural modifications of natural products. The introduction of Mannich bases can significantly improve the activity, hydrophilicity, and medicinal properties of compounds; therefore, the Mannich reaction is widely used for the structural modification of natural products. In this paper, the application of the Mannich reaction to the structural modification of natural products is reviewed, providing a method for the structural modification of natural products.

Design, Synthesis, Characterization and Computational Studies of Mannich Bases Oxadiazole Derivatives as New Class of Jack Bean Urease Inhibitors.

Mannich bases consisting of 1,3,4-oxadiazole-2-thione (3 a-3 l) bearing various substituents were synthesized and found potent jack bean urease inhibitors. The prepared compounds showed significantly good inhibitory activities with IC50 values from 9.45±0.05 to 267.42±0.23 µM. The compound 3 k containing 4-chlorophenyl (-R) and 4-hydroxyphenyl (-R') was most active with IC50 9.45±0.05 µM followed by 3 e (IC50 22.52±0.15 µM) in which -R was phenyl and -R' was isopropyl group. However, when both -R and -R' were either 4-chlorophenyl groups (3 l) or only -R' was 4-nitrophenyl (3 i), both compounds were found inactive. The detailed binding affinities of the produced compounds with protein were explored through molecular docking and data-supported in-vitro enzyme inhibition profiles. Drug likeness was confirmed by in silico ADME investigations and molecular orbital analysis (HOMO-LUMO) and electrostatic potential maps were got from DFT calculations. ESP maps exposed that there are two potential binding sites with the most positive and most negative parts.

Structure-Activity Relationship Prediction-Based Synthesis and Cytotoxicity Evaluation against the HEp-2 Laryngeal Carcinoma Cell of Isoflavone-Cytisine Mannich Bases.

QSAR analysis of previously synthesized and nature-inspired virtual isoflavone-cytisine hybrids against the HEp-2 laryngeal carcinoma cell lines was performed using the OCHEM web platform. The validation of the models using an external test set proved that the models can be used to predict the activity of newly designed compounds such as 8-cytisinylmethyl derivatives of 5,7- and 6,7-dihydroxyisoflavones. The synthetic procedure for selective aminomethylation of 5,7-dihydroxyisoflavones with cytisine was developed. In vitro testing identified compound 7 f with cisplatin-level cytotoxicity against HEp-2 cell lines and compound 10 which was twice active than cisplatin after 72 h of incubation.

Synthesis of Bioactive Aminomethylated 8-Hydroxyquinolines via the Modified Mannich Reaction.

8-hydroxyquinoline (oxine) is a widely known and frequently used chelating agent, and the pharmacological effects of the core molecule and its derivatives have been studied since the 19th century. There are several synthetic methods to modify this core. The Mannich reaction is one of the most easily implementable examples, which requires mild reaction conditions and simple chemical reagents. The three components of the Mannich reaction are a primary or secondary amine, an aldehyde and a compound having a hydrogen with pronounced activity. In the modified Mannich reaction, naphthol or a nitrogen-containing naphthol analogue (e.g., 8-hydroxyquinoline) is utilised as the active hydrogen provider compound, thus affording the formation of aminoalkylated products. The amine component can be ammonia and primary or secondary amines. The aldehyde component is highly variable, including aliphatic and aromatic aldehydes. Based on the pharmacological relevance of aminomethylated 8-hydroxyquinolines, this review summarises their syntheses via the modified Mannich reaction starting from 8-hydroxyquinoline, formaldehyde and various amines.

Investigations of Electronic, Structural, and In Silico Anticancer Potential of Persuasive Phytoestrogenic Isoflavene-Based Mannich Bases.

Isoflavenes have received the greatest research attention among the many groups of phytoestrogens. In this study, various isoflavene-based Mannich bases were selected for their theoretical studies. The purpose of this research was to discover the binding potential of all the designated Mannich bases acting as inhibitors against cancerous proteins EGFR, cMet, hTrkA, and HER2 (PDB codes: 5GTY, 3RHK, 6PL2, and 7JXH, respectively). For their virtual screening, DFT calculations and molecular docking studies were undertaken using in silico software. Docking studies predicted that ligands 5 and 15 exhibited the highest docking score by forming hydrogen bonds within the active pocket of protein 6PL2, ligands 1 and 15 both with protein 3RHK, and 7JXH, 12, and 17 with protein 5GTY. Rendering to the trends in polarizability and dipole moment, the energy gap values (0.2175 eV, 0.2106 eV) for the firm conformers of Mannich bases (1 and 4) replicate the increase in bioactivity and chemical reactivity. The energy gap values (0.2214 eV and 0.2172 eV) of benzoxazine-substituted isoflavene-based Mannich bases (9 and 10) reflect the increase in chemical potential due to the most stable conformational arrangements. The energy gap values (0.2188 eV and 0.2181 eV) of isoflavenes with tertiary amine-based Mannich bases (14 and 17) reflect the increase in chemical reactivity and bioactivity due to the most stable conformational arrangements. ADME was also employed to explore the pharmacokinetic properties of targeted moieties. This study revealed that these ligands have a strong potential to be used as drugs for cancer treatment.

Synthesis and Antimicrobial Activity of New Mannich Bases with Piperazine Moiety.

A series of novel Mannich bases were designed, synthesized, and screened for their antimicrobial activity. The target compounds were synthesized from 4-(3-chlorophenyl)-5-(3-fluorophenyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione and different piperazine derivatives. The structures of the products were confirmed by 1H and 13C NMR and elemental analysis. The activity of piperazine derivatives against bacteria (Gram-positive: Staphylococcus epidermidis, Staphylococcus aureus, Micrococcus luteus, Bacillus cereus, and Bacillus subtilis; Gram-negative: Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, and Proteus mirabilis) and yeasts (Candida glabrata, Candida krusei, and Candida parapsilosis) was determined by the minimum inhibitory concentration and minimum bactericidal concentration values. Significant activity was observed against Gram-positive bacteria, mainly staphylococci (PG7-PG8) and bacteria of the genes of Micrococcus and Bacillus (PG1-3), as well as selected strains of Gram-negative bacteria, including bacteria of the Enterobacteriaceae family (PG7), while all tested compounds showed high fungistatic activity against Candida spp. yeasts, especially C. parapsilosis, with MICs ranging from 0.49 µg/mL (PG7) to 0.98 µg/mL (PG8) and 62.5 µg/mL (PG1-3). In conclusion, the results obtained confirm the multidirectional antimicrobial activity of the newly synthesized piperazine derivatives. Furthermore, in silico studies suggest that the tested compounds are likely to have good oral bioavailability. The results obtained will provide valuable data for further research into this interesting group of compounds. The library of compounds obtained is still the subject of pharmacological research aimed at finding new interesting biologically active compounds.

In Vitro Anticancer Activity of Novel Ciprofloxacin Mannich Base in Lung Adenocarcinoma and High-Grade Serous Ovarian Cancer Cell Lines via Attenuating MAPK Signaling Pathway.

Novel drugs are desperately needed in order to combat a significant challenge due to chemo-therapeutic resistance and bad prognosis. This research aimed to assess the anticancer activity of a newly synthesized ciprofloxacin Mannich base (CMB) on ovarian cancer (OVCAR-3) and lung cancer (A-549) cell lines and to investigate probable involved molecular mechanisms. The cytotoxic and pro-apoptotic impact of CMB on both cell lines was investigated using MTT assay, Annexin V assay, and cell cycle analysis, as well as caspase-3 activation. Western blotting was carried out to evaluate downstream targets of the MAPK pathway, while qRT PCR was used to evaluate the gene expression pattern of the p53/Bax/Bcl2 pathway. CMB treatment showed significantly reduced cell proliferation in both OVCAR-3 and A-549 cells with half maximum inhibitory concentration (IC50) = 11.60 and 16.22 µg/mL, respectively. CMB also induced apoptosis, S phase cell cycle arrest, and up-regulated expression of p53, p21, and Bax while down-regulated Bcl2 expression. CMB also halted cell proliferation by deactivating the MAPK pathway. In conclusion, CMB may be regarded as a potential antiproliferative agent for lung and ovarian cancers due to anti-proliferative and pro-apoptotic actions via inhibition of the MAPK pathway and p53/Bax/Bcl2.

Discovery of novel 3-butyl-6-benzyloxyphthalide Mannich base derivatives as multifunctional agents against Alzheimer's disease.

Based on the multitarget-directed ligands strategy, a series of 3-butyl-6-benzyloxyphthalide Mannich base derivatives were designed, synthesized and identified for Alzheimer's disease (AD). Biological activity studies demonstrated that the designed hybrids showed multitarget activities toward AD. Among them, compound 7d was the most potent agent with excellent inhibitory activities on EeAChE (IC50 = 0.087 µM), HuAChE (IC50 = 0.041 µM) and MAO-B (IC50 = 0.30 µM). Furthermore, molecular docking studies were conducted to investigate the interaction mode with enzymes. Besides, 7d also possessed good effects of Cu2+ chelation, ameliorate oxidative stress, and anti-neuroinflammation, desirable BBB permeability and eligible drug-like properties. Altogether, the multifunctional profiles of 7d prove that it deserves further investigation as a novel drug candidate for AD treatment.

Synthesis of Indole-Coupled KYNA Derivatives via C-N Bond Cleavage of Mannich Bases.

KYNAs, a compound with endogenous neuroprotective functions and an indole that is a building block of many biologically active compounds, such as a variety of neurotransmitters, are reacted in a transformation building upon Mannich bases. The reaction yields triarylmethane derivatives containing two biologically potent skeletons, and it may contribute to the synthesis of new, specialised neuroprotective compounds. The synthesis has been investigated via two procedures and the results were compared to those of previous studies. A possible alternative reaction route through acid catalysis has been established.

Fine-Tuned Reactivity of N-Containing Naphthol Analogues.

6-Hydroxyquinoline and 3-hydroxyisoquinoline as N-containing naphthol analogues were tested in modified Mannich reactions (mMr's). In the case of 6-hydroxyquinoline, the outcomes of the attempted Mannich reactions were strongly influenced by the amine components. Aminoalkylation of this substrate with reagents 1-naphthaldehyde and N-benzylmethylamine led to the isolation of a diol regarded as a stabilised water adduct of an ortho-quinone methide (o-QM), of which formation can be ascribed to the presence of a hydroxide ion in a relatively higher concentration generated by the bulky and basic amine component with decreased nucleophilicity. The classical Mannich base was isolated as a single product when the amine component was replaced for morpholine, featuring nucleophilicity rather than basic character under the applied reaction conditions. Starting from the isomer substrate 3-hydroxyisoquinoline, independently on the nucleophile (methanol or morpholine) besides the formation of the classical Mannich base, the nucleophilic attack at position one of the heterocyclic substrate was also observed. The DFT analysis of the acceptor molecular orbitals of the potential electrophilic components and the thermodynamics of the assumed-possible transformations demonstrated that this regioselective addition is a feasible process on the investigated heterocyclic skeleton. DFT modelling studies also suggest that besides the steric bulk, the orbital-controlled electronic properties of the aryl group, originating from the aldehyde components, have a strong influence on the ratios and the NMR-monitored interconversions of the C-1-substituted 3-hydroxyisoquinolines and the classical Mannich bases formed in multistep reaction sequences. On the basis of the DFT analysis of the thermodynamics of alternative pathways, a reaction mechanism was proposed for the rationalization of these characteristic substrate-controlled interconversions.

Synthesis, Anticancer Activity and Molecular Docking Studies of Novel N-Mannich Bases of 1,3,4-Oxadiazole Based on 4,6-Dimethylpyridine Scaffold.

Cancer is one of the greatest challenges in modern medicine today. Difficult and long-term treatment, the many side effects of the drugs used and the growing resistance to treatment of neoplastic cells necessitate new approaches to therapy. A very promising targeted therapy is based on direct impact only on cancer cells. As a continuation of our research on new biologically active molecules, we report herein the design, synthesis and anticancer evaluation of a new series of N-Mannich-base-type hybrid compounds containing morfoline or different substituted piperazines moieties, a 1,3,4-oxadiazole ring and a 4,6-dimethylpyridine core. All compounds were tested for their potential cytotoxicity against five human cancer cell lines, A375, C32, SNB-19, MCF-7/WT and MCF-7/DX. Two of the active N-Mannich bases (compounds 5 and 6) were further evaluated for growth inhibition effects in melanoma (A375 and C32), and normal (HaCaT) cell lines using clonogenic assay and a population doubling time test. The apoptosis was determined with the neutral version of comet assay. The confocal microscopy method enabled the visualization of F-actin reorganization. The obtained results demonstrated that compounds 5 and 6 have cytotoxic and proapoptotic effects on melanoma cells and are capable of inducing F-actin depolarization in a dose-dependent manner. Moreover, computational chemistry approaches, molecular docking and electrostatic potential were employed to study non-covalent interactions of the investigated compounds with four receptors. It was found that all the examined molecules exhibit a similar binding affinity with respect to the chosen reference drugs.

Weak Noncovalent Interactions in Three Closely Related Adamantane-Linked 1,2,4-Triazole N-Mannich Bases: Insights from Energy Frameworks, Hirshfeld Surface Analysis, In Silico 11ß-HSD1 Molecular Docking and ADMET Prediction.

Structural analysis and docking studies of three adamantane-linked 1,2,4-triazole N-Mannich bases (1-3) are presented. Compounds 1, 2 and 3 crystallized in the monoclinic P21/c, P21 and P21/n space groups, respectively. Crystal packing of 1 was stabilized by intermolecular C-H⋯O interactions, whereas compounds 2 and 3 were stabilized through intermolecular C-H⋯N, C-H⋯S and C-H⋯π interactions. The energy frameworks for crystal structures of 1-3 were described. The substituent effect on the intermolecular interactions and their contributions were described on the basis of Hirshfeld surface analyses. The 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) inhibition potential, pharmacokinetic and toxicity profiles of compounds 1-3 were determined using in silico techniques. Molecular docking of the compounds into the 11ß-HSD1 active site showed comparable binding affinity scores (-7.50 to -8.92 kcal/mol) to the 11ß-HSD1 co-crystallized ligand 4YQ (-8.48 kcal/mol, 11ß-HSD1 IC50 = 9.9 nM). The compounds interacted with key active site residues, namely Ser170 and Tyr183, via strong hydrogen bond interactions. The predicted pharmacokinetic and toxicity profiles of the compounds were assessed, and were found to exhibit excellent ADMET potential.

Novel 3-benzylidene/benzylphthalide Mannich base derivatives as potential multifunctional agents for the treatment of Alzheimer's disease.

To discover novel multifunctional agents for the treatment of Alzheimer's disease, a series of 3-benzylidene/benzylphthalide Mannich base derivatives were designed, synthesized and evaluated. The biological screening results indicated that most of these derivatives exhibited good multifunctional activities. Among them, compound (Z)-13c raised particular interest because of its excellent multifunctional bioactivities. It displayed excellent EeAChE and HuAChE inhibition (IC50 = 9.18 × 10-5 and 6.16 × 10-4 µM, respectively), good MAO-B inhibitory activity (IC50 = 5.88 µM) and high antioxidant activity (ORAC = 2.05 Trolox equivalents). Additionally, it also exhibited good antiplatelet aggregation activity, moderate self- and Cu2+-induced Aß1-42 aggregation inhibitory potency, disaggregation ability on Aß1-42 fibrils, biometal chelating ability, appropriate BBB permeability and significant neuroprotective effect. Furthermore, (Z)-13c can also ameliorate the learning and memory impairment induced by scopolamine in mice. These multifunctional properties highlight compound (Z)-13c as a promising candidate for further development of multifunctional drug against AD.

Synthesis, design, and assessment of novel morpholine-derived Mannich bases as multifunctional agents for the potential enzyme inhibitory properties including docking study.

The synthesized Schiff Bases were reacted with formaldehyde and secondary amine such as 2,6-dimethylmorpholine to afford N-Mannich bases through the Mannich reaction. 3-Substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4) were treated with 2,6-dimethylmorpholine in the presence of formaldehyde to synthesize eight new 1-(2,6-dimethylmorpholino-4-yl-methyl)-3-substitued-4-(4-hydroxybenzylidenamino)-4,5-dihydro-1H-1,2,4-triazol-5-ones (4a-h). The structures of the synthesized eight new compounds were characterized using IR, 1H NMR, 13C NMR, and HR-MS spectroscopic methods. Synthesized compounds inhibitory activity determined against the acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and glutathione S-transferase (GST) enzymes with Ki values in the range 25.23-42.19 µM for AChE, 19.37-34.22 µM for BChE, and 21.84-41.14 µM for GST, respectively. Binding scores of most active inhibitors against AChE, BChE, and GST enzymes were detected as -10.294 kcal/mol, -9.562 kcal/mol, and -7.112 kcal/mol, respectively. The hydroxybenzylidene moiety of the most active inhibitors caused to inhibition of the enzymes through hydrophobic interaction and hydrogen bond.

Novel Mannich bases of ciprofloxacin with improved physicochemical properties, antibacterial, anticancer activities and caspase-3 mediated apoptosis.

The design, synthesis and identification of a novel series of Mannich bases of ciprofloxacin was reported. Naphthol derivatives 2a and 2b showed highly potent cytotoxic activity among the tested compounds. Compound 2a showed broad spectrum antiproliferative activity with GI50 of 2.5-6.79 µM with remarkable selectivity towards renal and prostate cancers with selectivity ratios ranging from 0.17 to 6.79. Independently, 2a showed outstanding activity against colon cancer HOP-92 cell lines with IC50 of 6.66 µM while 2b showed highly potent activity against ovarian cancer cell lines with IC50 of 0.97 µM. Results showed that 2b induced cell cycle arrest at G2/M phase and apoptosis; compound 2b showed over-expression of caspase-3 protein level (449.2 ± 7.95) compared to doxorubicin (578.7 ± 14.4 pg/mL). Meanwhile, compounds 2a and 2b experienced outstanding activity against both Gram-positive and Gram-negative microorganisms. Interestingly, compound 2j experienced high activity against Escherichia coli and Pseudomonas aeruginosa with MIC of 0.036 and 0.043, respectively. Compound 2d revealed 27 folds and 22 folds, respectively increasing of activity over ciprofloxacin against Staphylococcus aureus and MRSA(reference strain). Compound 2d showed high activity against Staphylococcus aureus, MRSA (reference strain) and MRSA (clinical strain) with MIC of 0.57, 0.52, 0.082 µg/mL, respectively. Interestingly, the most active tested compounds were found to have promising physicochemical and drug likeness properties. The Mannich bases 2j, 2d and 2g showed promising antibacterial activities, while naphthols 2a and 2b showed promising antiproliferative and antibacterial activities that require further optimization.

Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation.

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC50 and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2-5.6-fold) and suppressed cyclin D expression (0.8-0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC50 concentrations. 15 (IC50 = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC50 = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria.

1,3,4-Oxadiazole N-Mannich Bases: Synthesis, Antimicrobial, and Anti-Proliferative Activities.

The reaction of 5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thione 3 with formaldehyde solution and primary aromatic amines or 1-substituted piperazines, in ethanol at room temperature yielded the corresponding N-Mannich bases 3-arylaminomethyl-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 4a-l or 3-[(4-substituted piperazin-1-yl)methyl]-5-(3,4-dimethoxyphenyl)-1,3,4-oxadiazole-2(3H)-thiones 5a-d, respectively. The in vitro inhibitory activity of compounds 4a-l and 5a-d was assessed against pathogenic Gram-positive, Gram-negative bacteria, and the yeast-like pathogenic fungus Candida albicans. The piperazinomethyl derivatives 5c and 5d displayed broad-spectrum antibacterial activities the minimal inhibitory concentration (MIC) 0.5-8 µg/mL) and compounds 4j, 4l, 5a, and 5b showed potent activity against the tested Gram-positive bacteria. In addition, the anti-proliferative activity of the compounds was evaluated against prostate cancer (PC3), human colorectal cancer (HCT-116), human hepatocellular carcinoma (HePG-2), human epithelioid carcinoma (HeLa), and human breast cancer (MCF7) cell lines. The optimum anti-proliferative activity was attained by compounds 4l, 5a, 5c, and 5d.

Novel Mannich base 3FB3FA8H induces apoptosis by upregulating P53 pathway in neuroblastoma cells.

P53 plays an important role in maintaining genetic stability and development of resistance against tumors. Dysregulation of P53 gene is one of the key factors contributing to the etiology of neuroblastoma which causes cells to evade apoptosis. Activating P53 pathway can be a therapeutic alternative to the currently available medicinal strategies. Mannich bases have been known to possess various biological activities including the anticancer activity. In this study, we have targeted the P53 pathway by novel Mannich base (3FB3FA8H) which can be a future prospect to cure neuroblastoma. 3FB3FA8H has shown modulation of P53 pathway leading to apoptosis of neuroblastoma cells. Mitochondrial membrane permeability is also increased by 3FB3FA8H which may be a consequence of P53 pathway modulation. 3FB3FA8H increases the mRNA levels of P53 leading to activation of BAX. Inclining BAX/BCL2 ratio towards apoptotic BAX leads to cleavage of caspase 3, ultimately, causing apoptosis. Series of experiments provide the evidence that Mannich base 3FB3FA8H leads to P53-mediated apoptosis. Inducing apoptosis by this mechanism could be of central importance in reducing tumor burden which can be a good prospect for neuroblastoma patients.

In vitro and in vivo evaluation of the antimalarial MMV665831 and structural analogs.

Antimalarial candidates possessing novel mechanisms of action are needed to control drug resistant Plasmodium falciparum. We were drawn to Malaria Box compound 1 (MMV665831) by virtue of its excellent in vitro potency, and twelve analogs were prepared to probe its structure-activity relationship. Modulation of the diethyl amino group was fruitful, producing compound 25, which was twice as potent as 1 against cultured parasites. Efforts were made to modify the phenolic Mannich base functionality of 1, to prevent formation of a reactive quinone methide. Homologated analog 28 had reduced potency relative to 1, but still inhibited growth with EC50 ≤ 200 nM. Thus, the antimalarial activity of 1 does not derive from quinone methide formation. Chemical stability studies on dimethyl analog 2 showed remarkable hydrolytic stability of both the phenolic Mannich base and ethyl ester moieties, and 1 was evaluated for in vivo efficacy in P. berghei-infected mice (40 mg/kg, oral). Unfortunately, no reduction in parasitemia was seen relative to control. These results are discussed in the context of measured plasma and hepatocyte stabilities, with reference to structurally-related, orally-efficacious antimalarials.