Propanamide Derivatives Research Articles

Development of Novel Alaninamide Derivatives with Anticonvulsant Activity and Favorable Safety Profiles in Animal Models.

In our current study, we developed a focused series of original ((benzyloxy)benzyl)propanamide derivatives that demonstrated potent activity across in vivo mouse seizure models, specifically, maximal electroshock (MES) and 6 Hz (32 mA) seizures. Among these derivatives, compound 5 emerged as a lead molecule, exhibiting robust protection following intraperitoneal (i.p.) injection, as follows: ED50 = 48.0 mg/kg in the MES test, ED50 = 45.2 mg/kg in the 6 Hz (32 mA) test, and ED50 = 201.3 mg/kg in the 6 Hz (44 mA) model. Additionally, compound 5 displayed low potential for inducing motor impairment in the rotarod test (TD50 > 300 mg/kg), indicating a potentially favorable therapeutic window. In vitro toxicity assays further supported its promising safety profile. We also attempted to identify a plausible mechanism of action of compound 5 by applying both binding and functional in vitro studies. Overall, the data obtained for this lead molecule justifies the more comprehensive preclinical development of compound 5 as a candidate for a potentially broad-spectrum and safe anticonvulsant.

Synthesis of N-Alkyl-3-[2-oxoquinolin-1(2H)-yl]propanoic Acid Derivatives and Related Compounds: Cytotoxicity and EGFR Inhibition of Some Propanamide Derivatives.

A series of 20 new structure-modified quinolin-2-one derivatives were prepared for biological evaluation. This was successfully achieved based on chemoselective reactions of heterocyclic amides with acrylic acid derivatives, which gave 3-[2-oxoquinolin-1-(2H)-yl] propanoic acid derivatives (N-substitution via a unique behavior). The ester was reacted with hydrazine to afford the corresponding hydrazide. Both the corresponding ester and hydrazide were used as building blocks to modify the quinolone structure and give N-hydroxyl propanamides, oxadiazoles, and thiosemicarbazides. The corresponding carboxylic acid and hydrazide were used to prepare several amides: N-alkyl-3-[2-oxoquinolin-1(2H)-yl]propanamides via azide and dicyclohexyl carbodiimide coupling methods. Among derivatives, compound 9e exhibited potent cytotoxicity against MCF-7 cells with an IC50 value of 1.32 μM compared to doxorubicin with an IC50 value of 1.21 μM. Additionally, it caused potent EGFR inhibition by 97% with an IC50 value of 16.89 nM compared to Erlotinib with an IC50 value of 29.8 nM. Finally, the binding mode of compound interactions toward EGFR was highlighted using a molecular docking study; compound 9e exhibited good binding affinity with a binding energy of -17.89 kcal/mol, and it formed H-bond interactions with Met 769 as the key amino acid of interaction. Accordingly, compound 9e may be developed as an EGFR-oriented chemotherapeutic antibreast cancer agent.

Benzothiazole-Propanamide Linker Pyrrolidine (Morpholine) as Monoamine Oxidase-B and Butyrylcholinesterase Inhibitors.

According to the fusion technique create effective multi-target-directed ligands, in this study, we designed and synthesized a series of benzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl) or 3-(morph- olino-1-yl)propanamide derivatives, and evaluated their inhibitory potency against MAOs, AChE, BuChE by in vitro enzyme effect assays. Based on activity results, we found that derivatives N-(5-methylbenzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl)propanamide (2 c) and N-(6-bromobenzo[d]thiazol-2-yl)-3-(pyrrolidin-1-yl)propanamide (2 h) showed good inhibitory potency against BuChE with IC50 values of 15.12 μM and 12.33 μM, respectively. Besides, 2 c and 2 h also exhibited selective MAO-B inhibitory effects with inhibition rates of 60.10 % and 66.30 % at 100 μM, respectively. In contrast, all designed derivatives were poor active against AChE and MAO-A at a concentration of 100 μM. The toxicity analysis in vitro by MTT and AO/EB fluorescence staining confirmed that 2 c and 2 h were nontoxic up to 100 μM. Molecular modeling studies showed that 2 c and 2 h could bind to the active site of BuChE. This research paves the way for further study aimed at designing MAO-B and BuChE inhibitors for the treatment of neurodegenerative disorders.

Synthesis and evaluation of multitarget new 2-aminothiazole derivatives as potential anti-Alzheimer's agents.

In this study, two diverse series of 2-aminothiazole-based multitarget compounds, one propenamide and the other propanamide derivatives, were designed and synthesized. Subsequently, their anticholinesterease and antioxidant (ORAC) activities were tested. Among them, compound 3e was the most potent acetylcholinesterase (AChE) inhibitor (AChE IC50 = 0.5 μM, butyrylcholinesterase [BChE] IC50 = 14.7 μM) and compound 9e was the most potent BChE inhibitor (AChE IC50 = 3.13 μM, BChE IC50 = 0.9 μM). Kinetic experiments showed that both compounds were mixed-type inhibitors. According to the anticholinesterease activity results, five compounds (3e, 4e, 5e, 9d, and 9e) were selected for further activity studies, all of which are dual cholinesterase inhibitors. Then, selected compounds were investigated in terms of their metal chelation activity. Moreover, their neuroprotective effects against H2 O2 -induced damage in the PC12 cell line were evaluated at 10 μM and the results showed that the neuroprotective effect of 3e was 53% compared with the reference ferulic acid (77%). 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) results of selected compounds revealed that the compounds were noncytotoxic. Additionally, 3e was more effective in reducing lipopolysaccharides-induced interleukin-1β (IL-1β), IL-6, tumor necrosis factor-α (TNF-α), and nitric oxide (NO) production in the human monocyte derived from patient with acute monocytic leukemia cell line compared with other selected compounds. Finally, a molecular docking study was also performed.

Synthesis of new thiazole derivatives and evaluation of their antimicrobial and cytotoxic activities

Novel 2-heteroaryl-N-[4-(substituted aryl)thiazol-2-yl]propanamide derivatives (7a–7o) were synthesized and investigated for their antimicrobial activity. Among the tested compounds, 2-[(1H-Benzimidazol-2-yl)thio]-N-[4-(naphthalen-2-yl)thiazol-2-yl]propanamide (7e) and N-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(1-methyl-1H-tetrazol-5-yl)thio]propanamide (7f) showed the highest antibacterial activity, whereas 2-[Benzothiazol-2-ylthio]-N-[4-(4-chlorophenyl)thiazol-2-yl]propanamide (7i) and 2-[(1H-Benzimidazol-2-yl)thio]-N-[4-(4-chlorophenyl)thiazol-2-yl]propanamide (7j) displayed anticandidal effect against C. parapsilosis and C. glabrata. The cytotoxic activity of the compounds (7a–7o) was also tested against HL-60 human leukemia cells, THP-1 human monocytic leukemia cells, and NIH/3T3 mouse embryonic fibroblast cells. Compound N-[4-(4-Chlorophenyl)thiazol-2-yl]-2-[(1-methyl-1H-imidazol-2-yl)thio]propanamide (7 g) and compound 7j exhibited high cytotoxicity against HL-60; and compounds 2-[(1-Methyl-1H-imidazol-2-yl)thio]-N-[4-(naphthalen-2-yl)thiazol-2-yl]propanamide (7b), 7 g and N-[4-(4-Methoxyphenyl)thiazol-2-yl]-2-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]propanamide (7 m) also had cytotoxic activity against THP-1 compared with standard drug with selective profile. Additionally, in silico physicochemical properties of the compounds were described.

Exploration and Biological Evaluation of Basic Heteromonocyclic Propanamide Derivatives as SARDs for the Treatment of Enzalutamide-Resistant Prostate Cancer.

A series of propanamide derivatives were designed, synthesized, and pharmacologically characterized as selective androgen receptor degraders (SARDs) and pan-antagonists that exert a broad-scope androgen receptor (AR) antagonism. Incorporating different basic heteromonocyclic B-ring structural elements in the common A-ring-linkage-B-ring nonsteroidal antiandrogen general pharmacophore contributed to a novel scaffold of small molecules with SARD and pan-antagonist activities even compared to our recently published AF-1 binding SARDs such as UT-69 (11), UT-155 (12), and UT-34 (13). Compound 26f exhibited inhibitory and degradation effects in vitro in a wide array of wtAR, point mutant, and truncation mutant-driven prostate cancers (PCs). Further, 26f inhibited tumor cell growth in a xenograft model composed of enzalutamide-resistant (EnzR) LNCaP cells. These results demonstrate an advancement toward the development of novel SARDs and pan-antagonists with efficacy against EnzR prostate cancers.

Computational Fragment-Based Design Facilitates Discovery of Potent and Selective Monoamine Oxidase-B (MAO-B) Inhibitor.

Parkinson's disease (PD) is one of the most common age-related neurodegenerative diseases. Inhibition of monoamine oxidase-B (MAO-B), which is mainly found in the glial cells of the brain, may lead to an elevated level of dopamine (DA) in patients. MAO-B inhibitors have been used extensively for patients with PD. However, the discovery of the selective MAO-B inhibitor is still a challenge. In this study, a computational strategy was designed for the rapid discovery of selective MAO-B inhibitors. A series of (S)-2-(benzylamino)propanamide derivatives were designed. In vitro biological evaluations revealed that (S)-1-(4-((3-fluorobenzyl)oxy)benzyl)azetidine-2-carboxamide (C3) was more potent and selective than safinamide, a promising drug for regulating MAO-B. Further studies revealed that the selectivity mechanism of C3 was due to the steric clash caused by the residue difference of Phe208 (MAO-A) and Ile199 (MAO-B). Animal studies showed that compound C3 could inhibit cerebral MAO-B activity and alleviate 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neuronal loss.

Uses of ethyl benzoyl acetate for the synthesis of thiophene, pyran, and pyridine derivatives with antitumor activities

AbstractThe N‐(arly)propanamide derivatives 3a,b were used for a series of heterocyclization reactions to give thiophene, pyran, and pyridine derivatives. Thus, these compounds underwent the Gewald's thiophene synthesis through their reactions with either malononitrile or ethyl cyanoacetate and elemental sulfur to afford compounds 6a‐f, respectively. In addition, they were subjected through a series of multicomponent reactions (MCRs) to give pyran and fused derivatives. The reactions of 3a,b with either malononitrile or ethyl cyanoacetate gave pyridine derivatives 14a‐d, respectively. The latter compounds afforded arylhydrazone derivatives 15a‐m through their reactions with any of the aromatic diazonium salts 15a‐c. The antitumor of the synthesized compounds against A549 (nonsmall cell lung cancer), H460 (human lung cancer), HT‐29 (human colon cancer), and MKN‐45 (human gastric cancer cancer) cancer cell lines together with foretinib as the positive control by a MTT assay was measured, and the results obtained showed that many compounds exhibited high potency against the six cancer cell lines.

Identification of highly potent and selective inhibitor, TIPTP, of the p22phox-Rubicon axis as a therapeutic agent for rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease linked to oxidative stress, which is associated with significant morbidity. The NADPH oxidase complex (NOX) produces reactive oxygen species (ROS) that are among the key markers for determining RA’s pathophysiology. Therefore, understanding ROS-regulated molecular pathways and their interaction is necessary for developing novel therapeutic approaches for RA. Here, by combining mouse genetics and biochemistry with clinical tissue analysis, we reveal that in vivo Rubicon interacts with the p22phox subunit of NOX, which is necessary for increased ROS-mediated RA pathogenesis. Furthermore, we developed a series of new aryl propanamide derivatives consisting of tetrahydroindazole and thiadiazole as p22phox inhibitors and selected 2-(tetrahydroindazolyl)phenoxy-N-(thiadiazolyl)propanamide 2 (TIPTP, M.W. 437.44), which showed considerably improved potency, reaching an IC50 value up to 100-fold lower than an inhibitor that we previously synthesized reported N8 peptide-mimetic small molecule (blocking p22phox–Rubicon interaction). Notably, TIPTP treatment showed significant therapeutic effects a mouse model for RA. Furthermore, TIPTP had anti-inflammatory effects ex vivo in monocytes from healthy individuals and synovial fluid cells from RA patients. These findings may have clinical applications for the development of TIPTP as a small molecule inhibitor of the p22phox-Rubicon axis for the treatment of ROS-driven diseases such as RA.

Synthesis of novel N-(naphthalen-1-yl)propanamide derivatives and evaluation their antimicrobial activity

New N-(naphthalen-1-yl)propanamide was synthesized and studied for their antimicrobial activity. The final compounds were procured by reacting N-(naphthalen-1-yl)propanamide with some 2-mercapto aryl or dithiocarbamate salt derivatives. Their structures were determined by 1H-NMR and 13C-NMR spectroscopy and LC-MS/MS spectral data. The synthesized compounds were investigated for their antimicrobial activities against 10 bacteria and 10 fungi species. All compounds showed notable activity. Especially, compounds 2-[(5-methyl-1,3,4-thiadiazol-2-yl)thio]-N-(naphthalen-1-yl)propanamide (2a), 2-(benzothiazol-2-ylthio)-N-(naphthalen-1-yl)propenamide (2b), 2-[(1-methyl-1H-imidazol-2-yl)thio]-N-(naphthalen-1-yl)propanamide (2c), and N-(naphthalen-1-yl)-2-[(5-nitro-1H-benzimidazol-2-yl)thio]propanamide (2e) exhibited antifungal activity against at least one fungus at the half potency of ketoconazole. Also, 2-[(1-methyl-1H-imidazol-2-yl)thio]-N-(naphthalen-1-yl)propanamide (2c), N-(naphthalen-1-yl)-2-[(5-nitro-1H-benzimidazol-2-yl)thio]propanamide (2e) and 2-[(4-methyl-4H-1,2,4-triazol-3-yl)thio]-N-(naphthalen-1-yl)propanamide (2f) showed anti-gram-positive bacterial activity at the half potency of chloramphenicol. Only one compound, 2-(benzothiazol-2-ylthio)-N-(naphthalen-1-yl)propanamide (2b) displayed anti-gram-negative bacterial activity against Yersinia enterocolitica (Y53).

Base Metal Catalysis in Directed C(sp3)−H Functionalisation

AbstractDirected C(sp3)−H functionalisation has made enormous progress in recent years, but has largely been restricted to catalysis using noble metals, particularly palladium. However, since 2013, there have been prominent advances that exploit the reactivity of abundant first row transition metals for a multitude of new bond formations. The use of base metal catalysis for C−H functionalisation can provide huge advantages in terms of cost and sustainability compared to methods using noble metals. This review covers all examples, to the end 2018, of auxiliary‐assisted, base metal‐catalysed C(sp3)−H functionalisation reactions. Successful examples are reported for Fe, Co, Ni and Cu catalysis with monodentate or bidentate directing groups for C−N, C−O, C−S and C−C bond forming reactions. This review aims to highlight the current state of this field and potential for expansion and so scope and limitations are highlighted. Notably, examples to date have required sterically activated α‐disubstituted substrates, particularly propanamide derivatives with bidentate directing groups, such as 8‐aminoquinoline amides. Monodentate quinoline and thioamide directing groups have also been used with Co catalysis for C−N and C−C bond formations. Mechanistic details are provided to outline the nature of the proposed organometallic intermediates and potential reaction pathways. We hope this review will stimulate further developments in this growing and important field.magnified image

SYNTHESIS AND INVESTIGATION OF ANTHELMINTIC, ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY OF 3,3-DIPHENYL PROPANAMIDE DERIVATIVES

Objective: A novel series of substituted 3,3-diphenyl propanamide derivatives (I-VIII) were synthesized by reacting 3,3-diphenyl propanoyl chloride with different amines/amino acids, and all the derivatives were investigated for anthelmintic, antibacterial, and antifungal activity.Methods: All the compounds were characterized by infrared (IR) and1H- nuclear magnetic resonance spectrometry data. The synthesized derivatives were investigated for their anthelmintic activity employing housefly worms method and earthworm species model. The antibacterial and antifungal activity was performed employing cup plate method.Results: The synthesized compounds (VII and VIII) exhibited maximum anthelmintic activity as compared with standard drug albendazole at doses of 50 and 100 mg/mL, due to minimal paralyzing and death time in both housefly and earthworm models. The compounds (IV, VII, and VIII) at 50 μg/mL exhibited maximum activity against Gram-negative bacterial strains, namely, Escherichia coli, Pseudomonas aeruginosa as compared with ciprofloxacin and same compounds exhibited maximum antifungal activity against Candida albicans and Aspergillus niger in comparison with standard drug griseofulvin at 50 μg/mL.Conclusion: The synthesized compounds bearing amino acid moiety in their structure (VII-VIII) exhibited impressive anthelmintic activity in comparison with albendazole. This suggests that amino acid/peptide derivative of diphenyl propanamides can act as great anthelmintic agents. Further, the research can be performed to design potent antimicrobial diphenyl propanamide derivatives.

SYNTHESIS AND INVESTIGATION OF ANTHELMINTIC, ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY OF 3,3-DIPHENYL PROPANAMIDE DERIVATIVES

Objective: A novel series of substituted 3,3-diphenyl propanamide derivatives (I-VIII) were synthesized by reacting 3,3-diphenyl propanoyl chloride with different amines/amino acids, and all the derivatives were investigated for anthelmintic, antibacterial, and antifungal activity.Methods: All the compounds were characterized by infrared (IR) and1H- nuclear magnetic resonance spectrometry data. The synthesized derivatives were investigated for their anthelmintic activity employing housefly worms method and earthworm species model. The antibacterial and antifungal activity was performed employing cup plate method.Results: The synthesized compounds (VII and VIII) exhibited maximum anthelmintic activity as compared with standard drug albendazole at doses of 50 and 100 mg/mL, due to minimal paralyzing and death time in both housefly and earthworm models. The compounds (IV, VII, and VIII) at 50 μg/mL exhibited maximum activity against Gram-negative bacterial strains, namely, Escherichia coli, Pseudomonas aeruginosa as compared with ciprofloxacin and same compounds exhibited maximum antifungal activity against Candida albicans and Aspergillus niger in comparison with standard drug griseofulvin at 50 μg/mL.Conclusion: The synthesized compounds bearing amino acid moiety in their structure (VII-VIII) exhibited impressive anthelmintic activity in comparison with albendazole. This suggests that amino acid/peptide derivative of diphenyl propanamides can act as great anthelmintic agents. Further, the research can be performed to design potent antimicrobial diphenyl propanamide derivatives.

4-Aminophenyl acetamides and propanamides as potent transient receptor potential vanilloid 1 (TRPV1) ligands

A series of 2-(3,5-substituted 4-aminophenyl)acetamide and propanamide derivatives were investigated as human TRPV1 antagonists. The analysis of the structure-activity relationship indicated that 2-(3,5-dihalo 4-aminophenyl)acetamide analogues displayed excellent antagonism of hTRPV1 activation by capsaicin and showed improved potency compared to the corresponding propanamides. The most potent antagonist (36) exhibited potent and selective antagonism for hTRPV1 not only to capsaicin but also to NADA and elevated temperature; however, it only displayed weak antagonism to low pH. Further studies indicated that oral administration of antagonist 36 blocked the hypothermic effect of capsaicin in vivo but demonstrated hyperthermia at that dose. A docking study of 36 was performed in our established hTRPV1 homology model to understand its binding interactions with the receptor and to compare with that of previous antagonist 1.

Synthesis of some new propanamide derivatives bearing 4- piperidinyl-1,3,4-oxadiazole, and their evaluation as promising anticancer agents

Purpose : To sequentially synthesize piperidine-4-carboxylic acid ethyl ester-appended 1,3,4-oxadiazole hybrids and to evaluate them as anticancer agents. Methods : Ethyl 1-[(4-methylphenyl)sulfonyl]-4-piperidinecarboxylate (1) was synthesized from 4- methylbenzenesulfonylchloride (a) and ethyl 4-piperidinecarboxylate (b). Compound (1) was converted into ethyl 1-[(4-methylphenyl)sulfonyl]-4-piperidine carbohydrazides (2) and 5-{1-[(4- methylphenyl)sulfonyl]-4-piperidinyl}-1,3,4-oxadiazole-2-thiol (3) respectively. A variety of aryl amine (4a-l) were treated with 2-bromopropionylbromide to synthesize an array of propanamide (5a-l). Finally, 5-{1-[(4-methylphenyl)sulfonyl]-4-piperidinyl}-1,3,4-oxadiazole-2-thiol (3) and propanamides (5a-l) were reacted to synthesize target compounds (6a-l). Purity compounds 6a-l was confirmed by spectroscopic techniques like ( 1 H-NMR), ( 13 C-NMR) and EI-MS. To determine their anticancer potential, the change in absorbance of mixture and cell line before and after incubation was determined. Results : All the compounds 6a-l were successfully synthesized in 73-85 % yield. Compounds 6h, 6j and 6e have low IC 50 (±SD) values of 20.12 ± 6.20, 10.84 ± 4.2 and 24.57 ± 1.62 μM to act as strong anticancer agents relative to doxorubicin (0.92 ± 0.1 μM) used as a reference. Conclusion : The synthesized propanamide derivatives bearing 4-piperidinyl-1,3,4-oxadiazole are potential anticancer agents, but further studies, especially in vivo, are required to ascertain their therapeutic usefulness. Keywords : Ethyl isonipecotate, Propanamides, 1,3,4-Oxadiazole, Anti-cancer activity

Design and synthesis of some new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring and the investigation of their inhibitory potential on in-vitro acetylcholinesterase and butyrylcholinesterase

A series of new carboxamide and propanamide derivatives bearing phenylpyridazine as a core ring were designed, synthesized and evaluated for their ability to inhibit both cholinesterase enzymes. In addition, a series of carboxamide and propanamide derivatives bearing biphenyl instead of phenylpyridazine were also synthesized to examine the inhibitory effect of pyridazine moiety on both cholinesterase enzymes. The inhibitory activity results revealed that compounds 5b, 5f, 5h, 5j, 5l pyridazine-3-carboxamide derivative, exhibited selective acetylcholinesterase (AChE) inhibition with IC50 values ranging from 0.11 to 2.69 µM. Among them, compound 5h was the most active one (IC50 = 0.11 µM) without cytotoxic effect at its effective concentration against AChE. Additionally, pyridazine-3-carboxamide derivative 5d (IC50 for AChE = 0.16 µM and IC50 for BChE = 9.80 µM) and biphenyl-4-carboxamide derivative 6d (IC50 for AChE = 0.59 µM and IC50 for BChE = 1.48 µM) displayed dual cholinesterase inhibitory activity. Besides, active compounds were also tested for their ability to inhibit Aβ aggregation. Theoretical physicochemical properties of the compounds were calculated by using Molinspiration Program as well. The Lineweaver-Burk plot and docking study showed that compound 5 h targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE.

Optimization of the anticonvulsant activity of 2-acetamido-N-benzyl-2-(5-methylfuran-2-yl) acetamide using QSAR modeling and molecular docking techniques

Chemometric descriptors were used to analyze quantitatively the anticonvulsant activity of ninety propanamide derivatives. Molecular geometries of the data set were optimized with B3LYP/6-31G∗∗ quantum mechanical method and chemometric descriptors were calculated from the optimized structure. Linear QSAR models were developed using genetic function algorithm. Predictive capabilities of the models were evaluated using various internal and external validation techniques. The best three models proposed were octa-parametric equation with good statistical quality: R2 (0.898–0.918); Q2 (0.865–0.893); R2pred (0.746–0.772) and F (66.657–88.036). 2-acetamido-N-benzyl-2-(5-methylfuran-2-yl) acetamide a member of the data set was chosen as scaffold for in silico design. Using the information afforded by the models, several attempts were made to optimize the scaffold by introducing various modifications. Potential derivatives with higher predicted activity values than the template were identified and a detailed analysis on the models applicability domain defined the designed compounds, whose estimations can be accepted with confidence. Some of the designed compounds docked with γ-aminobutyrate aminotransferase (PBD: 1OHV) (target) showed better binding affinity for the target when compare with 4-aminohex-5-enoic acid (vigabatrin) (a known inhibitor of the target).

Design, synthesis, 3D pharmacophore, QSAR, and docking studies of some new (6-methoxy-2-naphthyl) propanamide derivatives with expected anti-bacterial activity as FABI inhibitor

Antibiotic resistance is a major health problem; so there is a emerging need for developing new antibiotic agents. A novel series of (6-methoxy-2-naphthyl) propanamide derivatives were synthesized and evaluated for their potential antibacterial activity. The minimum inhibitory concentration of these compounds were determined by microdilution technique against five known strains of bacteria. Test strains included three Gram-positive strains (Streptococcus pneumonia, Bacillus subtilis and Staphylococcus aureus) and two Gram-negative strains (Escherichia coli and Salmonella typhimurium). According to the observed antibacterial activity results showed that compounds N-(4-(2-(5-bromo-2-hydroxybenzylidene)hydrazine carbonyl) phenyl)-2-(6-meth oxynaphthalen-2-yl)propanamide 2d and N-(4-(2-(2,4-dichlorobenzylidene)hydrazine carbonyl)phenyl)-2-(6-methoxy-naphthalen-2-yl)propanamide 2j has potent antibacterial activity against B. subtilis (minimal inhibitory concentrations 1.95 µg/ml). Also 2-(6-methoxynaphthalen-2-yl)-N-(4-(2-(4-oxopentan-2-ylidene)hydrazinecarbonnyl)phenyl) propanamide 6 showed potent antibacterial activity against S. pneumonia (minimal inhibitory concentrations 1.95 µg/ml) compared to Naproxen (7.81, 15.63 µg/ml) and the reference drug Ampicillin (7.81 µg/ml). Two of the synthesized compounds, namely, 2j and 2k exhibited more potent antibacterial activity than the reference drugs (Gentamicin and Ampicillin) against all the test strains of bacteria. Molecular docking simulation was also carried out for Enoyl-aceyl carrier protein reductase enzyme, which is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. In addition, generation of 3D pharmacophore model and quantitative structure–activity relationship models were combined to explore the structural requirements controlling the observed antibacterial properties.

In Silico Design, Synthesis and Bioactivity of N-(2, 4-Dinitrophenyl)-3-oxo- 3-phenyl-N-(aryl) Phenyl Propanamide Derivatives as Breast Cancer Inhibitors.

Breast cancer is a systemic disease which has challenged physicians worldwide as it is the most predominant cancer in women often leading to fatality. One of the types of treatment is chemotherapy which includes targeted oral or intravenous cancer-killing drugs. Treatment options are often limited to surgery and/or chemotherapy. The discovery and design of new small molecule estrogen inhibitors is necessitated in order to circumvent the problem of drug-induced resistance in chemotherapy resulting in disease relapse. Chemoinformatics facilitates the design, selection and synthesis of new drug candidates for breast cancer by providing efficient in silico techniques for prediction of favourable ADMET properties, and structural descriptors to profile druggability of a compound. Several molecules selected from docking studies were synthesized and evaluated for their biological activities on the MCF-7 (human breast cancer) cell line. These estrogen inhibitors displayed good inhibitory activity with high selectivity and hence can be further progressed as drug candidates effective against breast cancer. It is for the first time that N-(2, 4-dinitrophenyl)-3-oxo-3-phenyl-N-(aryl) phenylpropanamide derivatives were reported to be biological active as potential breast cancer inhibitors.

ANTIMICROBIAL AND IN SILICO ADMET SCREENING OF NOVEL (E)-N-(2-(1H-INDOL-3-YL-AMINO) VINYL)-3-(1-METHYL-1H-INDOL-3-YL)-3-PHENYLPROPANAMIDE DERIVATIVES

<p><strong>Objective: </strong>Synthesis, <em>in silico</em> absorption, distribution, metabolism, excretion, toxicity (ADMET) and <em>in vitro</em> antimicrobial screening of (<em>E</em>)-<em>N</em>-(2-(1<em>H</em>-indol-3-ylamino) vinyl)-3-(1-methyl-1<em>H</em>-indol-3-yl)-3-phenylpropanamide derivatives.<strong></strong></p><p><strong>Methods: </strong>(<em>E</em>)-<em>N</em>-(2-(1<em>H</em>-indol-3-ylamino) vinyl)-3-(1-methyl-1<em>H</em>-indol-3-yl)-3 phenylpropane-amide derivatives were synthesized by combining indole ethanolamine and substituted Meldrum’s adduct. The synthesized compounds were subjected to <em>in vitro</em> antimicrobial study by cup plate method and <em>in silico</em> ADMET properties using ACD/I-Lab 2.0.</p><p><strong>Results: </strong>The <em>in vitro </em>antimicrobial screening against precarious pathogenic microorganisms <em>viz</em>, <em>Pseudomonas aureginosa</em>, <em>Staphylococcus aureus,</em> <em>Escherichia coli, </em><em>Vibrio cholerae</em>, and the antifungal activity against <em>Candida albicans, </em><em>Aspergillus niger</em>, <em>Penicillin chrysogenum</em> and <em>Cladosporium oxysporum</em> strains. The results revealed that compounds 5b, 5c, 5d and 5e showed good antimicrobial property and obeyed the <em>in silico</em> pharmacokinetic parameters.</p><p><strong>Conclusion: </strong>The encouraging results exhibited by the compounds (<em>E</em>)-<em>N</em>-(2-(1<em>H</em>-indol-3-ylamino) vinyl)-3-(1-methyl-1<em>H</em>-indol-3-yl)-3-phenyl propanamide derivatives, 5(a-e) can be explored as possible hits in antimicrobial therapy. The molecules obey the Lipinski rule of five when tested <em>in silico </em>and can be used in understanding the quantitative structure-activity relationship (QSAR) parameters.</p>