Nature-Inspired 1-Phenylpyrrolo[2,1-a]isoquinoline Scaffold for Novel Antiproliferative Agents Circumventing P-Glycoprotein-Dependent Multidrug Resistance.

Previous studies have shown that some lamellarin-resembling annelated azaheterocyclic carbaldehydes and related imino adducts, sharing the 1-phenyl-5,6-dihydropyrrolo[2,1-a]isoquinoline (1-Ph-DHPIQ) scaffold, are cytotoxic in some tumor cells and may reverse multidrug resistance (MDR) mediated by P-glycoprotein (P-gp). Herein, several novel substituted 1-Ph-DHPIQ derivatives were synthesized which carry carboxylate groups (COOH, COOEt), nitrile (CN) and Mannich bases (namely, morpholinomethyl derivatives) in the C2 position, as replacements of the already reported aldehyde group. They were evaluated for antiproliferative activity in four tumor cell lines (RD, HCT116, HeLa, A549) and for the ability of selectively inhibiting P-gp-mediated MDR. Lipophilicity descriptors and molecular docking calculations helped us in rationalizing the structure-activity relationships in the P-gp inhibition potency of the investigated 1-Ph-DHPIQs. As a main outcome, a morpholinomethyl Mannich base (8c) was disclosed which proved to be cytotoxic to all the tested tumor cell lines in the low micromolar range (IC50 < 20 µM) and to inhibit in vitro the efflux pumps P-gp and MRP1 responsible for MDR, with IC50s of 0.45 and 12.1 µM, respectively.

Design, synthesis, and molecular docking of new phenothiazine incorporated N-Mannich bases as promising antimicrobial agents.

The present work aims to synthesize four series of phenothiazine incorporation Mannich bases. Therefore, 10-methyl-10H-phenothiazine-3-sulfonamide (4) which was subjected to react with some secondary amines and formaldehyde to give the Mannich bases 5a-f, and 6-13. Compound 13 was then subjected to react with some secondary amines and formaldehyde to give the corresponding Mannich bases 14a-f. In total, twenty-two new compounds were synthesized and evaluated for in vitro growth inhibition activity against P. aeruginosa, E. coli, and S. aureus. Among the tested compounds, compounds 3, 5a, 5c, 6, 12, 13, 14d, and 14e exhibited good activity with a MIC value (12.5 µg/mL), compounds 5b, 10, 11, 14a, and 14c exhibited strong activity against the growth of S. aureus with a MIC value (6.25 µg/mL), and compound 14b superior against S. aureus with a MIC value (3.125 µg/mL) compared to drug reference ciprofloxacin with MIC value (2 µg/mL). The molecular docking investigation revealed the presence of many derivatives with high binding affinities and distinct interaction patterns with the target protein. Derivatives 14a-e emerged as the most promising possibilities, displaying the greatest binding energies and a varied variety of interaction types, including hydrogen bonding and pi interactions, over different distances, with derivative 14b exhibiting the highest binding energy at S = -8.3093 kcal/mol. These derivatives displayed superior binding affinities and various interaction mechanisms with the target protein, suggesting that they have great promise as lead compounds for future development into therapeutic medicines.

Novel naphthoquinone-1H-1,2,3-triazole hybrids: Design, synthesis and evaluation as inductors of ROS-mediated apoptosis in the MCF-7 cells.

The search for novel anticancer drugs is essential to expand treatment options, overcome drug resistance, reduce toxicity, promote innovation, and tackle the economic impact. The importance of these studies lies in their contribution to advancing cancer research and enhancing patient outcomes in the battle against cancer. Here, we developed new asymmetric hybrids containing two different naphthoquinones linked by a 1,2,3-1H-triazole nucleus, which are potential new drugs for cancer treatment. The antitumor activity of the novel compounds was tested using the breast cancer cell lines MCF-7 and MDA-MB-231, using the non-cancer cell line MCF10A as control. Our results showed that two out of twenty-two substances tested presented potential antitumor activity against the breast cancer cell lines. These potential drugs, named here 12g and 12h were effective in reducing cell viability and promoting cell death of the tumor cell lines, exhibiting minimal effects on the control cell line. The mechanism of action of the novel drugs was assessed revealing that both drugs increased reactive oxygen species production with consequent activation of the AMPK pathway. Therefore, we concluded that 12g and 12h are novel AMPK activators presenting selective antitumor effects.

Synthesis, molecular modeling investigation, molecular dynamic and ADME prediction of some novel Mannich bases derived from 1,2,4-triazole, and assessment of their anticancer activity.

A series of biologically active novel Mannich bases containing with a 1H-1,2,4-triazole-5-one ring were developed to evaluate the cytotoxic activity. For this purpose, the synthesized Schiff Bases (S1-5) were reacted with formaldehyde and morpholine, which is a secondary amine to yield novel N-Mannich bases (M1-5) via the Mannich reaction. The structures of the compounds (M1-5) were determined structurally employing 1H/13C-NMR, IR and elemental analysis. In this study, we evaluated the cytotoxic potential of the compounds (M1-5) on the human hypopharyngeal carcinoma FaDu cells. We found that the compound (M3) possesses a significant anticancer feature against FaDu cells that might be evaluated with further in vitro and in vivo studies to understand its anticancer potential better. Lastly, comparisons were made using molecular docking calculations to find the theoretical activities of the compounds (M1-5). The docking score parameter of the compound (M3) against the 2DO4 protein is -5.67, the docking score parameter against the 5JPZ protein is -5.72, and finally, the docking score parameter against the 2H80 protein is -5.50. Molecular dynamic calculations are made for 0-100 ns. The ADME/T calculations were performed to find the drug potential of the compounds (M1-5). The results suggest that our drug candidate compound exhibits strong potential for co-administration with the antigen structures, owing to the low rate of interactions that decreased over time.Communicated by Ramaswamy H. Sarma.

Combining eugenol and dihydroeugenol with a piperazine moiety to create new antimicrobial agents that are effective against resistant species.

Historically, the piperazine moiety has been demonstrated to possess pharmacophoric properties, and has subsequently been incorporated in many drugs that have antitumor, antimalarial, antiviral, antibacterial and antifungal properties. Derivatives of eugenol and dihydroeugenol have also been reported as being bioactive compounds. This study reports the synthesis of a range of eugenol/dihydroeugenol - piperazine derivatives which have been tested as antimicrobial compounds against Gram positive, Gram negative and rapid-growing mycobacteria (RGM). The rationale employed in the design of the structural pattern of these new derivatives, provides useful insights into the structure-activity relationships (SAR) of the series. Antimicrobial activity tests were extremely encouraging, with the majority of the synthesised compounds being more active than eugenol and dihydroeugenol starting materials. The antimicrobial potential was most notable against the Gram-negative species K. pneumoniae and P. aeruginosa, but there was also significant performance against the Gram-positive strains S. epidermidis and S. aureus and the Rapidly Growing Mycobacteria (RGM) strains tested. Tests using the synthesised compounds against multidrug-resistance clinical (MDR) isolates also showed high activity. The biofilm inhibition tests using M. fortuitum showed that all evaluated derivatives were able to inhibit biofilm formation even at low concentrations. In terms of structural-activity relationships; the results generated by this study demonstrate that the compounds with bulky substituents on the piperazine subunit were much more active than those with less bulky groups, or no groups. Importantly, the derivatives with a sulfonamide side chain were the most potent compounds. A further observation was that those compounds with a para-substituted benzenesulfonamide ring stand out, regardless of whether this substituent is a donor or an electron-withdrawing group.

Current Pharmaceutical Research on the Significant Pharmacophore Mannich bases in Drug Design.

A multitude of distinct Mannich bases have been synthesized and evaluated as potential therapeutics for a wide variety of diseases and medical conditions, either in the form of prodrugs or as molecules that trigger a biological response from specific targets. The Mannich reaction has been utilized to enhance the biological activity of numerous compounds, resulting in notable progress in various areas such as anticonvulsant, antimalarial, anticancer, anti-inflammatory, antiproliferative, antibacterial, antimicrobial, antitubercular, antiprotozoal, topoisomerases I and II inhibition, α-glucosidase inhibition, carbonic anhydrase inhibition, as well as research related to anti-Alzheimer's disease and anti-Parkinson's disease. Bioactive semisynthetic Mannich bases derived from natural compounds such as chalcone, curcumin, and thymol have also been identified. Pharmaceutical compounds characterized by low solubility may encounter challenges related to their oral bioavailability, half-life, distribution within tissues, rapid metabolism, toxicity, and various other relevant variables. Mannich bases have the ability to undergo protonation under physiological circumstances, facilitating interactions between ligands and receptors, and enhancing their solubility in water. The experimental findings indicate that the solubility of Mannich base prodrugs is higher compared to that of the parent compound. The use of the multicomponent Mannich reaction has been established as a valuable synthetic methodology for the construction of multifunctional compounds through the application of diverse synthetic strategies under varying reaction conditions. The continuous investigation of synthetic techniques for Mannich reactions involves several approaches, such as employing protocols in aquatic environments, utilizing catalysts that are both biodegradable and reusable, exploring the use of ionic liquids, investigating solvent-free and/or catalyst-free media, and exploring reaction conditions involving microwave and ultrasound irradiation. Consequently, the Mannich reaction has emerged as a powerful technique in the field of medicinal chemistry. It is utilized for the creation of new chemical compounds that possess diverse and attractive biologic features. Additionally, this reaction is employed to alter the physicochemical properties of a potential drug candidate, thereby influencing its bioavailability, efficacy, and pharmacological activity. Due to their favorable bioactivities and synthesis techniques, Mannich bases remain a subject of ongoing attention in the field of medicinal/pharmaceutical chemistry.

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.

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.

Synthesis of fusidane triterpenoid Mannich bases as potential antibacterial and antitumor agents.

Mannich bases (8 examples) were synthesized via aminomethylation of fusidane propargyl esters. In vitro antimicrobial screening against key ESKAPE pathogens showed that the fusidic acid based Mannich products exhibit a high antimicrobial effect against Gram-positive bacteria Staphylococcus aureus and the fungus Cryptococcus neoformans. Moreover, the cytotoxic effect of fusidic acid and its analogs, which showed high antibacterial activity, was determined by MTT assay on cancer HepG2, HCT-116, SH-SY5Y, MCF-7, A549 and conditionally normal cells HEK293. A remarkable cytotoxic activity of fusidic acid propargyl ester and its aminomethylene derivatives against cancer and nontumoral HEK293 cells with IC50 values within 4.2-25 µM was found.

Mannich bases derivatives of 2-Phenyl-5-Benzimidazole sulfonic acid; Synthesis, Characterization, Computational studies and Biological evaluation

Abstract A new series of N-Mannich bases of 2-Phenyl-5-benzimidazole sulfonic acid have been synthesized through amino methylation reaction with secondary amines. The two moieties were held together through a methylene bridge, which comes from formaldehyde (Formalin Solution 37%) used in the reaction. Chemical structures of the newly synthesized compounds have been confirmed using FT-IR, 1HNMR and 13CNMR. Different in vitro assays including Anti-oxidant, Enzyme inhibition, Anti-microbial and Cytotoxicity assay were performed to evaluate the biological potential with reference to the standard drug. Among the synthesized library, compound 3a shows maximum alpha-glucosidase inhibition with an IC50 value of 66.66 µg/ml, compound 3d was found most toxic with LC50 value of 10.17 µg/ml. ADME evaluation studies were performed with the help of Molinspiration online software. Docking calculations were also performed. Given the importance of the nucleus involved, the synthesized compound might find extensive medicinal applications as reported in the literature.

Evaluation of antiviral activity of terpenophenols and some of their N- and O-derivatives.

A comparative evaluation of the antiviral activity of a number of new and previously synthesized terpenophenols and their N- or O-containing derivatives against the A/Puerto Rico/8/34 (H1N1) virus strain was carried out. 2-Isobornylphenol, 1,2-dihydroxy-6-isobornyl-4-methylbenzene, 2-isobornyl-1,4-benzoquinone, and N-butyl-4-hydroxy-3,5-diisobornylbenzamide showed the highest activity.

Synthesis and evaluation of diterpenic Mannich bases as antiviral agents against influenza A and SARS-CoV-2.

A chemical library was constructed based on the resin acids (abietic, dehydroabietic, and 12-formylabietic) and its diene adducts (maleopimaric and quinopimaric acid derivatives). The one-pot three-component CuCl-catalyzed aminomethylation of the abietane diterpenoid propargyl derivatives was carried out by formaldehyde and secondary amines (diethylamine, pyrrolidine, morpholine, and homopiperazine). All compounds were tested for cytotoxicity and antiviral activity against influenza virus A/Puerto Rico/8/34 (H1N1) in MDCK cells and SARS-CoV-2 pseudovirus in BHK-21-hACE2 cells. Among 21 tested compounds, six derivatives demonstrated a selectivity index (SI) higher than 10, and their IC50 values ranged from 0.19 to 5.0 µM. Moreover, two derivatives exhibited potent anti-SARS-CoV-2 infection activity. The antiviral activity and toxicity strongly depended on the nature of the diterpene core and heterocyclic substituent. Compounds 12 and 21 bearing pyrrolidine moieties demonstrated the highest virus-inhibiting activity with SIs of 128.6 and 146.8, respectively, and appeared to be most effective when added at the time points 0-10 and 1-10 h of the viral life cycle. Molecular docking and dynamics modeling were adopted to investigate the binding mode of compound 12 into the binding pocket of influenza A virus M2 protein. Compound 9 with a pyrrolidine group at C20 of 17-formylabietic acid was a promising anti-SARS-CoV-2 agent with an EC50 of 10.97 µM and a good SI value > 18.2. Collectively, our data suggested the potency of diterpenic Mannich bases as effective anti-influenza and anti-COVID-19 compounds.

Newly Synthesized Morpholinyl Mannich Bases as Corrosion Inhibitors for N80 Steel in Acid Environment.

New Mannich bases, 3-morpholino-1-phenylpropan-1-one (MPO) and 3-morpholino-1-phenyl-3-(pyridin-4-yl) propan-1-one (MPPO), were synthesized, characterized, and studied as corrosion inhibitors for N80 steel in 1 M hydrochloric acid (HCl) solution using weight loss, potentiodynamic polarization, electrochemical impedance spectroscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, and FT-IR spectroscopy. The inhibition efficiency increases with increasing inhibitor concentrations, and the corrosion inhibition efficiency of the MPO and MPPO could reach 90.3% and 91.4%, respectively, at a concentration of 300 ppm at 305 K. The effect of the temperature on the corrosion inhibition behavior of inhibitors was discussed. Electrochemical tests showed that the synthesized inhibitors are mixed. The EIS test results showed that the presence of MPO and MPPO reduced the double-layer capacitance in the corrosion process, thereby reducing the charge transfer resistance. The SEM and EDX results showed that the MPO and MPPO formed a uniform adsorption film on the surface of the N80 steel. The adsorption mechanism of the inhibitors was simulated with different adsorption models and the results showed that the inhibitors were the chemisorbed type. The results of the FT-IR spectroscopy proved that the inhibitor interacted with metal atoms on the steel surface.

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.

Design, synthesis, in vitro antiproliferative evaluation and in silico studies of new VEGFR-2 inhibitors based on 4-piperazinylquinolin-2(1H)-one scaffold.

Angiogenesis is essential in the growth of solid tumors which need oxygen and nutrients supply to grow in size. The VEGF/VEGFR-2 signaling pathway plays an important role in tumor angiogenesis. Sorafenib is an FDA approved cancer therapeutic with activity against many protein kinases, including VEGFR. We designed 4-piperazinylquinolin-2(1H)-ones with variable aromatic moieties and Mannich bases as Sorafenib analogues as potential inhibitors of angiogenesis. In this study, we investigated the impact of replacing the linker aromatic ring with cyclic tertiary amines and the effect of incorporation of variably substituted distal rings. We hypothesized that cyclic tertiary amines would improve pharmacokinetic properties and contribute to enzyme interactions. Two series of piperazinylquinolinone-based compounds were synthesized, characterized, and evaluated for bioactivity against adenocarcinoma EKVX NSCLC and T-47D breast cancer cells. Ability to inhibit VEGFR-2 and apoptosis were investigated and molecular docking into the enzyme active site and theoretical ADME properties were determined. Notably, amongst series I three compounds exhibited higher anticancer activity than Staurosporine against EKVX NSCLC adenocarcinoma cell line. In series II, nine compounds exhibited higher antiproliferative activity than Staurosporine against T-47D breast cancer cell line. Two compounds; 5d and 7z exhibited lower toxicity against normal cell line (MCF 10A) than Staurosporine. Compound 7z was the most potent agent with IC50 38.76 nM. Moreover, 7z showed VEGFR-2 inhibitory activity higher than sorafenib and induced remarkable levels of both early and late apoptosis (2.82% and 21.30%, respectively). Hence, 5d and 7z are considered promising VEGFR-2 inhibitors with high efficacy against adenocarcinoma EKVX and T-47D breast cancer cells. The target compounds also possessed favorable physicochemical properties and pharmacokinetic parameters These studies further suggested that the 4-piperazinylquinolin-2(1H)-one derivatives developed in this study play a critical role in modulating VEGFR, and guide the design of innovative anticancer therapies.

Mannich Bases: Centrality in Cytotoxic Drug Design.

Mannich bases identified by Professor Carl Mannich have been the most extensively explored scaffolds for more than 100 years now. The versatile biological roles that they play have promoted their applications in many clinical conditions. The present review highlights the application of Mannich bases as cytotoxic agents, categorizing them into synthetic, semisynthetic, and prodrugs classes, and gives an exhaustive account of the work reported in the last two decades. The methods of synthesis of these cytotoxic agents, their anti-cancer potential in various cell lines, and promising leads for future drug development have also been discussed. Structure-activity relationships, along with the targets on which these cytotoxic Mannich bases act, have been included as well.

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.

In Vitro and In Silico Evaluation of New 1,3,4-Oxadiazole Derivatives of Pyrrolo[3,4-d]pyridazinone as Promising Cyclooxygenase Inhibitors.

Since long-term use of classic NSAIDs can cause severe side effects related mainly to the gastroduodenal tract, discovery of novel cyclooxygenase inhibitors with a safe gastric profile still remains a crucial challenge. Based on the most recent literature data and previous own studies, we decided to modify the structure of already reported 1,3,4-oxadiazole based derivatives of pyrrolo[3,4-d]pyridazinone in order to obtain effective COX inhibitors. Herein we present the synthesis, biological evaluation and molecular docking studies of 12 novel compounds with disubstituted arylpiperazine pharmacophore linked in a different way with 1,3,4-oxadiazole ring. None of the obtained molecules show cytotoxicity on NHDF and THP-1 cell lines and, therefore, all were qualified for further investigation. In vitro cyclooxygenase inhibition assay revealed almost equal activity of new derivatives towards both COX-1 and COX-2 isoenzymes. Moreover, all compounds inhibit COX-2 isoform better than Meloxicam which was used as reference. Anti-inflammatory activity was confirmed in biological assays according to which title molecules are able to reduce induced inflammation within cells. Molecular docking studies were performed to describe the binding mode of new structures to cyclooxygenase. Investigated derivatives take place in the active site of COX, very similar to Meloxicam. For some compounds, promising druglikeness was calculated using in silico predictions.

Novel Mannich bases with strong carbonic anhydrases and acetylcholinesterase inhibition effects: 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2(3H)-benzoxazolones.

In this study, a new series of Mannich bases, 3-(aminomethyl)-6-{3-[4-(trifluoromethyl)phenyl]acryloyl}-2( 3H )-benzoxazolones ( 1a-g ), were synthesized by the Mannich reaction. Inhibitory effects of the newly synthesized compounds towards carbonic anhydrases (CAs) and acetylcholinesterase (AChE) enzymes were evaluated to find out new potential drug candidate compounds. According to the inhibitory activity results, Ki values of the compounds 1 and 1a-g were in the range of 12.3 ± 1.2 to 154.0 ± 9.3 nM against hCA I, and they were in the range of 8.6 ± 1.9 to 41.0 ± 5.5 nM against hCA II. Ki values of acetazolamide (AZA) that was used as a reference compound were 84.4 ± 8.4 nM towards hCA I and 59.2 ± 4.8 nM towards hCA II. Ki values of the compounds 1 and 1a-g were in the range of 35.2 ± 2.0 to 158.9 ± 33.5 nM towards AChE. Ki value of Tacrine (TAC), the reference compound, was 68.6 ± 3.8 nM towards AChE. Furthermore, docking studies were done with the most potent compounds 1d , 1g , and 1f (in terms of hCA I, hCA II, and AChE inhibition effects, respectively) to determine the binding profiles of the series with these enzymes. Additionally, the prediction of ADME profiles of the compounds pointed out that the newly synthesized compounds had desirable physicochemical properties as lead compounds for further studies.

Design and synthesis of Mannich base-type derivatives containing imidazole and benzimidazole as lead compounds for drug discovery in Chagas Disease.

The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas disease, the most important parasitic infection in Latin America. The only treatments currently available are nitro-derivative drugs that are characterised by high toxicity and limited efficacy. Therefore, there is an urgent need for more effective, less toxic therapeutic agents. We have previously identified the potential for Mannich base derivatives as novel inhibitors of this parasite. To further explore this family of compounds, we synthesised a panel of 69 new analogues, based on multi-parametric structure-activity relationships, which allowed optimization of both anti-parasitic activity, physicochemical parameters and ADME properties. Additionally, we optimized our in vitro screening approaches against all three developmental forms of the parasite, allowing us to discard the least effective and trypanostatic derivatives at an early stage. We ultimately identified derivative 3c, which demonstrated excellent trypanocidal properties, and a synergistic mode of action against trypomastigotes in combination with the reference drug benznidazole. Both its druggability and low-cost production make this derivative a promising candidate for the preclinical, in vivo assays of the Chagas disease drug-discovery pipeline.