Compounds 4g Research Articles

A convenient synthesis, characterization and biological evaluation of novel schiff base heterocycles as potential antimicrobial, antitubercular agents and their structural activity relationship

A series of (E)-1-methyl-3-((substituted phenylimino)methyl)quinolin-2(1H)-one schiff bases (3a-j) bearing quinoline moiety synthesized successfully in ethanol by condensation of starting material 1-methyl-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (1) with various substituted anilines (2a-j). The structure of the newly synthesized compounds was confirmed by proton (1H) and carbon (13C) nuclear magnetic resonance spectroscopy, Fourier transformation infrared (FT-IR), Mass spectroscopic study and elemental analysis. The in-vitro antimicrobial activity of the synthesized compounds was undertaken by agar well diffusion method against gram positive bacteria (Bacillus licheniformis and Bacillus cereus) gram negative bacteria (Escherichia coli and Acetobactor sp.) and antifungal activity against (Aspergillus Flavus and Pichnanomala). Further the compounds which shows good activity (3b, 3c, 3d, 3f, 3g and 3j) are screened for in-vitro antitubercular activity by Micro-plate alamar blue assay (MABA) method against mycobacterium tuberculosis H37Rv strain provided important information about activity against these strains. The structure activities of the synthesized compounds were also discussed. Compounds 3a, 3c, 3d, 3f and 3g show good argument with the different substituent attached to the phenyl ring.

IN VITRO ANTI-PROLIFERATIVE ACTIVITY OF NOVEL ANALOGUES OF(E)-2-BENZYLIDENE-N-(3-(3-OXO-2,3- DIHYDRO-4H-BENZO[B][1,4]OXAZIN-4-YL)PROPYL) HYDRAZINE-1-CARBOTHIOAMIDE

A novel analog of substituted-(E)-2-benzylidene-N-(3-(3-oxo-2,3-dihydro-4H-benzo[b] [1,4] oxazin-4-yl)propyl) hydrazine-1-carbothioamides (9a-j) appeared to be assess being anti-proliferative activity in vitro environment some of the newly derived derivatives have shown sufficiently great to modest suppression in the number of cells in cancer among GrowthInhibition50 was (0.180-4.20 µM). Compounds 9a, 9b, 9d, 9g, 9i, and 9j showed promising acts contrarily 4 human being tumor cell lines. Out of 9a and 9g displayed heartening cancer act in opposition to IMR-32 (Human being neuroblastoma cells) at 0.23 M and MIAPACA(human pancreatic carcinoma cells) at 0.18 M respectively. Notably, compound 9g showed significant activity at 0.18 M against the MIAPACA cell line respectively.

A highly efficient metal-free selective 1,4-addition of difluoroenoxysilanes to chromones.

A highly efficient metal-free selective 1,4-addition reaction of difluoroenoxysilanes to chromones was developed using the low-cost and readily available HOTf as the catalyst, which is a facile and straightforward method to access valuable C2-difluoroalkylated chroman-4-one derivatives. Interestingly, the products could be readily converted to the difluorinated bioisostere of the natural product (S)-2,6-dimethylchroman-4-one and a difluorinated benzo-seven-membered heterocycle via the Schmidt rearrangement reaction. In addition, the in vitro anti-proliferative activities of these synthesized derivatives against human colon carcinoma cells (HCT116) revealed that compound 3g exhibited potent inhibitory effect on HCT116 cancer cells with an IC50 value of 6.37 μM, representing a novel lead compound for further structural optimization and biological evaluation.

Discovery, synthesis, and cytotoxic evaluation of isoquinolinequinones produced by Streptomyces albidoflavus derived from lichen.

Four isoquinolinequinones (1-4) were isolated from the fermentation broth of Streptomyces albidoflavus which were derived from lichens. Among them, mansouramycin H (1) was identified as a new isoquinolinequinone by comprehensive spectroscopic data analysis. The mansouramycins from S. albidoflavus presented broad cytotoxic activities, especially against MDA-MB-231, but the SAR and mechanism were still unclear. The total synthesis of mansouramycin H (1) and its twenty-three derivatives were completed and their cytotoxic activities against MDA-MB-231 were evaluated in vitro. Primary SAR revealed that the piperazine moieties introduced into the amino group at C-7 could improve the activities of mansouramycins. Benzoyl and phenylacetyl groups on piperazine fragments had better activities than those of benzyl substitution; the alkyl substituent on piperazine exhibited optimal activity. Among them, compound 1g showed the strongest cytotoxicity against MBA-MB-231 cells with an IC50 value of 5.12 ± 0.11 μM. Mechanistic studies revealed that 1g induced apoptosis in MBA-MB-231 cells through down-regulating the protein expression of Bcl-2, up-regulating the protein expression of bax, and, meanwhile, activating the cleavage of caspase-3 and caspase-9. 1g caused S phase cell cycle arrest in MBA-MB-231 cells by reducing the protein expression of CDK2 and cyclin A2 and increasing the protein levels of p21.

Design, synthesis and antifungal activity of novel pyrazole amides derivates

With the help of active substructure splicing strategy, 36 novel pyridine ring pyrazolamide derivatives were designed and synthesized. The structures of those compounds were confirmed and characterized by 1H NMR, 13C NMR, FT-IR, and HRMS. The compound 2i was identified by X-ray crystal diffraction. The fungicidal effects of the pyrazolamide derivates against four plant pathogenic fungi, Colletotrichum gloeosporioides, Fusarium oxysporum, Sphaeropsis sapinea and Fusarium moniliforme, was determined by the mycelial growth rate. The results showed that the designed compounds had certain antifungal activity at the concentration of 200 mg/L. Compared with the positive control carbendazim, compounds 1e, 1g and 1h exhibited stronger antifungal activity on Sphaeropsis sapinea and Fusarium moniliforme. The antifungal activity of compound 1a-1s (R1 = H) was better than that of compound 2a-2p (R1 = CH3). Compounds 1d, 1e, 1g, 1h, 1i, 2g and 2i showed good antifungal activity, and the introduction of halogen groups (except F) on benzene ring may have an important effect on biological activity. Compound 1g had a good inhibitory effect on the growth of a variety of plant pathogenic fungi. Molecular docking revealed that the -CH3 group at R1 position would reduce the binding affinity between these compounds and receptor, which would reduce the antifungal activity of the compound. Compound 1g is promising to become the lead compound of pesticide in the future, which is worthy of further study.

Synthesis and antibacterial activity of novel 2‑fluoro ketolide antibiotics with 11,12‑quinoylalkyl side chains

A series of novel 2‑fluoro ketolide antibiotics with 11,12‑quinoylalkyl side chains derived from telithromycin and cethromycin were designed and synthesized. The corresponding targets 2a-o were tested for their in vitro activities against a series of macrolide-sensitive and macrolide-resistant pathogens. Some of them showed a similar antibacterial spectrum and comparable or slightly better activity to telithromycin. Among them, compounds 2g and 2k, displayed excellent activities against macrolide-sensitive and macrolide-resistant pathogens.

Novel Camphor Sulfonohydrazide and Sulfonamide Derivatives as Potential Succinate Dehydrogenase Inhibitors against Phytopathogenic Fungi/Oomycetes.

To discover novel fungicidal agrochemicals for treating wheat scab, 39 novel camphor sulfonohydrazide/sulfonamide derivatives 4a-4t and 6a-6s were designed and synthesized. In the in vitro antifungal/antioomycete assay, compounds 4g, 4n, and 4o displayed significant inhibitory activities against Fusarium graminearum, Botryosphaeria dothidea, and Phytophthora capsici. Among them, 4n exhibited the best antifungal activity against F. graminearum with an EC50 value of 0.41 mg/L, which was at the same level as that of pydiflumetofen. The in vivo experiment revealed that 4n presented excellent protective and curative efficacy toward F. graminearum. In the antifungal mechanism study, 4n could increase the cell membrane permeability and reduce the exopolysaccharide and ergosterol content of F. graminearum. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) analyses revealed that 4n could significantly damage the surface morphology and the cell ultrastructure of mycelia to interfere with the growth of F. graminearum. Furthermore, 4n exhibited potent succinate dehydrogenase (SDH) inhibitory activity in vitro with an IC50 value of 3.94 μM, which was equipotent to pydiflumetofen (IC50 = 4.07 μM). The molecular dynamics simulation and docking study suggested that compound 4n could well occupy the active site and form strong interactions with the key residues of SDH. The above-mentioned results demonstrated that the title camphor sulfonohydrazide/sulfonamide derivatives could be promising lead compounds for further succinate dehydrogenase inhibitor (SDHI) fungicide development.

Design, Synthesis, Characterization, and Analysis of Antimicrobial Property of Novel Benzophenone Fused Azetidinone Derivatives through In Vitro and In Silico Approach.

A sequence of novel 2-(4-benzoyl-2-methyl-phenoxy)-N-(3-chloro-2-oxo-4-phenyl-azetidin-1-yl)-acetamide analogues 9(a-n) were synthesized by multistep synthesis. The newly synthesized compounds were well characterized, and their antimicrobial activities were carried out by disc diffusion and broth dilution methods. Further, all the novel series of compounds (9a-n), were tested against a variety of bacterial and fungal strains in comparison to Ketoconazole, Chloramphenicol, and Amoxicillin as standard drugs, respectively. Compounds 9a, 9e, and 9g as a lead molecule demonstrated a good inhibition against tested strains. Further, molecular docking studies have been performed for the potent compounds to check the three-dimensional geometrical view of the ligand binding to the targeted proteins.

A facile and practical p-toluenesulfonic acid catalyzed route to dicoumarols and their biological evaluation

ABSTRACT New Dicoumarols 2a-g efficiently synthesized employing p-TSA as a catalyst from the reaction of 4-hydroxycoumarin with aryl aldehydes in water. This method offers direct access to structurally diverse Dicoumarols derivatives in a good yields (65-94%). Upon heating 3,3' -arylidenebis-4-hydroxycoumarins derivative in acetic anhydride, the epoxydicoumarins were formed. 1H, 13C{1H}-NMR, elemental analysis, and infrared spectroscopic techniques were used for the characterization of the obtained compounds. A possible relationship between such hydrogen-bonded structures and the antimicrobial and the antioxidant activities of compounds is suggested. The synthetized compounds 2a-g and 3a-g were subjected to in vitro antimicrobial and antifungal activities against DNA gyrase and Mycobacterium tuberculosis-CYP51 target proteins at the active sites. Compound 3d shows effective inhibitory effect in terms of MIC = 15 µg mL-1. against Salmonella typhimuriumATCC 14028. Compounds 2b, 2c, 3b, 3c, 3e and 3g have recorded an important scavenging activity against the radical DPPH. The EC50 of these compounds was 47.17, 46.90, 50.55,48.27 , 46.55 and 47.54 µg mL-1 respectively. Investigation of the anti-inflammatory activity of the synthesized compounds showed that compounds 2b,2c, 3f, 3b and 3c are the most potent inflammatory activities.

1-(Arylsulfonyl-isoindol-2-yl)piperazines as 5-HT6R Antagonists: Mechanochemical Synthesis, In Vitro Pharmacological Properties and Glioprotective Activity

In addition to the canonical Gs adenylyl cyclase pathway, the serotonin type 6 receptor (5-HT6R) recruits additional signaling pathways that control cognitive function, brain development, and synaptic plasticity in an agonist-dependent and independent manner. Considering that aberrant constitutive and agonist-induced active states are involved in various pathological mechanisms, the development of biased ligands with different functional profiles at specific 5-HT6R-elicited signaling pathways may provide a novel therapeutic perspective in the field of neurodegenerative and psychiatric diseases. Based on the structure of SB-258585, an inverse agonist at 5-HT6R-operated Gs and Cdk5 signaling, we designed a series of 1-(arylsulfonyl-isoindol-2-yl)piperazine derivatives and synthesized them using a sustainable mechanochemical method. We identified the safe and metabolically stable biased ligand 3g, which behaves as a neutral antagonist at the 5-HT6R-operated Gs signaling and displays inverse agonist activity at the Cdk5 pathway. Inversion of the sulfonamide bond combined with its incorporation into the isoindoline scaffold switched the functional profile of 3g at Gs signaling with no impact at the Cdk5 pathway. Compound 3g reduced the cytotoxicity of 6-OHDA and produced a glioprotective effect against rotenone-induced toxicity in C8-D1A astrocyte cell cultures. In view of these findings, compound 3g can be considered a promising biased ligand to investigate the role of the 5-HT6R-elicited Gs and Cdk5 signaling pathways in neurodegenerative diseases.

Spectrofluorimetric and Computational Investigation of New Phthalimide Derivatives towards Human Neutrophil Elastase Inhibition and Antiproliferative Activity

Herein, nine phthalimide-based thiazoles (4a-4i) were synthesized and investigated as new human neutrophil elastase (HNE) inhibitors using spectrofluorimetric and computational methods. The most active compounds containing 4-trifluoromethyl (4c), 4-naphthyl (4e) and 2,4,6-trichloro (4h) substituents in the phenyl ring exhibited high HNE inhibitory activity with IC50 values of 12.98-16.62 µM. Additionally, compound 4c exhibited mixed mechanism of action. Computational investigation provided a consistent picture of the ligand-receptor pattern of inter-actions, common for the whole considered group of compounds. Moreover, compounds 4b, 4c, 4d and 4f showed high antiproliferative activity against human cancer cells lines MV4-11, and A549 with IC50 values of 8.21 to 25.57 µM. Additionally, compound 4g showed high activity against MDA-MB-231 and UMUC-3 with IC50 values of 9.66 and 19.81 µM, respectively. Spectrophotometric analysis showed that the most active compound 4c demonstrated high stability under physiological conditions.

Elaboration of novel urea bearing schiff bases as potent in vitro anticancer candidates with low in vivo acute oral toxicity

A novel series of urea Schiff base derivatives were synthesized via the condensation of o-phenylenediamine, naphthyl isocyanate and appropriate aryl aldehyde. The results of the in vitro cytotoxic activities of compounds 5a–h against cancer cells lines PC3, SKOV-3 and HeLa, revealed that almost all compounds exhibited good to moderate activities Compound 5g owing bromine atom at p-position displayed higher activity compared to homolog 5b possessing chlorine atom due to adequate diameter of bromine which is more favourable than chlorine for the inhibition activity. In addition, compound 5h is the best candidate of this series exhibiting excellent activity for three cancer cells lines. Compound 5h demonstrated also an excellent activity with IC50 value of 0.6±0.3μg/mL for prostate cancer cell line PC3 and it is considered more effective than the standard drug doxorubicin Dox (IC50 = 2.6±0.03μg/mL). The most active compound 5h displayed the best activity against ovarian cancer cell line SKOV3 with IC50 = 1.8±0.2μg/mL. This results are higher than clinically used drug Dox (IC50. 2.2±0.02μg/mL). The results of screening activities cytotoxic effect toward cervix cancer cell line HeLa, affirm that compound 5h manifest an activity with IC50 value of 2.2±0.4μg/mL comparable to Dox (IC50. 1.9±0.04μg/mL). In the current study, in vivo acute oral toxicity assessment of urea Schiff base hybrid compounds 5a – h indicated that there was no mortality on treated female mice during 14 days assessment test compared with the vehicle-treated group confirming the safety with LD50 greater than 2000 mg/kg. In the actual study, the results affirmed that compounds 5a–h manifested in vivo no toxicity to saint cells, the compounds 5b, 5g and 5h presented higher anticancer activities against three cancer cells which authorizes promoters to use them as candidate anticancer agents.

Design, Synthesis, Computational Docking and Biological Evaluation of Novel 4-Chloro-1,3-Benzoxazole Derivatives as Anticancer Agents

ABSTRACT: An efficient, cost effective and ecologically safe method for the design of series of novel 2-[(4-chloro-1,3-benzoxazol-2-yl)sulfanyl]-N'-[phenylmethylidene] acetohydrazides 5(a-j) have been synthesized by fusing 2-[(4-chloro-1,3-benzoxazol-2-yl)sulfanyl] acetohydrazide with substituted aromatic aldehyde. The prepared compounds were characterized via LC-MS, IR, 1H NMR, 13C NMR and C, H, N analysis technique. All the synthesized compounds were evaluated for biological potency, which includes antimicrobial, antifungal, antioxidant and anticancer activities. The compounds 5a, 5b, 5d, 5e, 5g and 5h showed appreciable antimicrobial, MIC and antioxidant activity. Further, it was also noticed that the prior mentioned compounds showcased more than 70% of cell viability. We also performed molecular docking for all the synthesized compounds and examined their binding affinities to the anticancer receptor 2A91 to qualitatively elucidate their anticancer activity. The data generated from the molecular modeling and the values obtained from the biological screening were correlated.

Synthesis, Characterization and Biological Evaluation of Benzothiazole-Isoquinoline Derivative.

Currently, no suitable clinical drugs are available for patients with neurodegenerative diseases complicated by depression. Based on a fusion technique to create effective multi-target-directed ligands (MTDLs), we synthesized a series of (R)-N-(benzo[d]thiazol-2-yl)-2-(1-phenyl-3,4-dihydroisoquinolin-2(1H)-yl) acetamides with substituted benzothiazoles and (S)-1-phenyl-1,2,3,4-tetrahydroisoquinoline. All compounds were tested for their inhibitory potency against monoamine oxidase (MAO) and cholinesterase (ChE) by in vitro enzyme activity assays, and further tested for their specific inhibitory potency against monoamine oxidase B (MAO-B) and butyrylcholinesterase (BuChE). Among them, six compounds (4b-4d, 4f, 4g and 4i) displayed excellent activity. The classical antidepressant forced swim test (FST) was used to verify the in vitro results, revealing that six compounds reduced the immobility time significantly, especially compound 4g. The cytotoxicity of the compounds was assessed by the MTT method and Acridine Orange (AO) staining, with cell viability found to be above 90% at effective compound concentrations, and not toxic to L929 cells reversibility, kinetics and molecular docking studies were also performed using compound 4g, which showed the highest MAO-B and BuChE inhibitory activities. The results of these studies showed that compound 4g binds to the primary interaction sites of both enzymes and has good blood-brain barrier (BBB) penetration. This study provides new strategies for future research on neurodegenerative diseases complicated by depression.

Triazole based novel molecules as potential therapeutic agents: Synthesis, characterization, biological evaluation, in-silico ADME profiling and molecular docking studies

In this study, eight new compounds (7a-h) based on triazole compounds containing ester groups were synthesized with high yields. The structures of the synthesized compounds (7a-h) were elucidated by various spectroscopic methods (element analysis, FT-IR, 1H-(13C) NMR). Antioxidant, anticancer, and α-amylase enzyme inhibition activities of synthesized new triazole derivatives were carried out, and the effects of different groups on the activity were investigated. When the determined antioxidant properties of the compounds were examined, all synthesized compounds showed a moderate radical scavenging effect against radicals depending on the concentration (6.25–200 g/mL). All compounds except the three derivatives were found to have higher IC50 values than the standard drug acarbose (IC50: 891 μg/mL) according to the α-amylase enzyme inhibition results. Compound 7g (IC50: 50 g/mL) was discovered to have nearly eighteen (18) times the activity of the conventional medication acarbose (IC50: 891 μg/mL). Compounds synthesized for anticancer activity studies were screened against the Hela cell line, and the results were compared with standard cis-platinum (IC50: 16.30 μg/mL). Compound 7g (IC50: 19.78 μg/mL) was found to have almost the same activity as cis-platinum. Using Qikprop, the compounds were thoroughly tested for ADME qualities, and none violated any drug similarity standards. According to ADME data, whole physicochemical drug-likeness parameters of molecules remained within defined ranges as stipulated in the Lipinski rules (RO5) and revealed a high bioavailability profile. The molecular docking results with 2QV4 and 4GQR alpha-amylase enzymes demonstrated that all molecules have a high affinity, indicating polar and apolar interaction with critical amino acids in the α-amylase binding pocket.

Dithiocarbamates and dithiocarbonates containing 6-nitrosaccharin scaffold: Synthesis, antimycobacterial activity and in silico target prediction using ensemble docking-based reverse virtual screening

Tuberculosis is a curable disease that costs the lives of 1.5 million people per year. It continues to pose a threat to global public health owing to the prevalence of multi-drug resistant (MDR) Mycobacterium tuberculosis strains which make its eradication a continuous challenge. To explore novel and effective antimycobacterial agents, a series of dithiocarbamates/dithiocarbonate-nitrosaccharin hybrids were prepared, characterized by spectral analyses, and assessed for their antimycobacterial activity against M.tuberculosis strain H37Rv. Some compounds showed activity with a minimum inhibitory concentration (MIC) of 0.45–6.09 µg/mL. Reverse ensemble docking against nine putative targets with fifteen different crystal structures was conducted to understand the mechanism of action of the most potent compound 6g. The in silico studies suggested enoyl ACP-reductase (InhA) and polyketide synthase 13 (Pks13) as possible targets for compound 6g.

Repositioning of acefylline as anti-cancer drug: Synthesis, anticancer and computational studies of azomethines derived from acefylline tethered 4-amino-3-mercapto-1,2,4-triazole.

Novel azomethines derived from acefylline tethered triazole hybrids (7a-k) have been synthesized and evaluated against human liver cancer cell line (Hep G2) using MTT assay. The synthesized series of azomethines exhibited promising efficacy against liver cancer cell line. Screening of the synthesized series identified compound 7d with the least cell viability value (11.71 ± 0.39%) as the most potent anticancer agent in contrast to the reference drug acefylline (cell viability = 80 ± 3.87%). In this study, the potentials of the novel agents (7a-k) to inhibit liver cancer proteins were assessed. Subsequently, the structure-activity relationship of the potential drug candidates was assessed via ADME/T molecular screening. The cytotoxic potential of these derivatives was also investigated by hemolysis and thrombolysis. Their hemolytic and thrombolytic studies showed that all of these drugs had very low cytotoxicity and moderate clot lysis activity. Compound 7g (0.26% hemolysis) and 7k (52.1% clot lysis) were the least toxic and moderate thrombolytic agents respectively.

Structure-activity and binding orientations analysis of potent, newly synthesized, acetylcholinesterase inhibitors

Fourteen novel N-benzylpiperidine and N,N-diarylpiperazine conjugates were synthesized and pharmacologically evaluated as donepezil analogs, in a ligand-based drug design approach. All compounds possessed high to moderate in vitro inhibitory activity with IC50 in range 2.3–20 µM and selectivity towards acetylcholinesterase, while being inactive towards butyrylcholinesterase. Structure-activity relationship analysis revealed the influence of N,N-diarylpiperazine moiety and the linker connecting two pharmacophores on the inhibitory activity. Kinetic studies on the two most active compounds 7g and 8g (IC50 = 2.3 and 4 µM, respectively) revealed mixed type mode of inhibition, binding to both, free enzyme and enzyme-substrate complex. For further understanding of mechanism of action and binding orientations, molecular docking was performed for all compounds, while the ligand transport simulation and molecular dynamics simulations were performed for 7g and 8g. Computational results corroborated well with in vitro activities and kinetic studies.

Novel fluorophenyl tethered thiazole and chalcone analogues as potential anti-tubercular agents: Design, synthesis, biological and in silico evaluations

Novel analogues of fluorophenyl tethered thiazoles 7a-k and chalcones 10a-k were designed through molecular hybridization approach. All the synthesized final compounds were evaluated for their in vitro antimycobacterial activity against M. tuberculosis H37Rv strain. Among the two series, compound 10g displayed potent inhibition with MIC99 of 1.56 µM against parental and isoniazid-resistant strains of M. tuberculosis. Further, the same compound inhibited the growth of intracellular M. tuberculosis. To gain an insight into the molecular mechanism of actions, in silico molecular docking experiments were conducted using the molecular structure of the DNA gyrase enzyme, which revealed crucial interactions. This was further substantiated through molecular dynamics simulation study of the mycobacterial DNA Gyrase protein against the lead compound 10g and the reference drug (CFX-Ciprofloxacin). Furthermore, the drug-likeliness of the synthesized compounds was computed based on Lipinski's rule of five and ADME pharmacokinetic parameters. Thus, a chalcone-based lead 10g was identified in our study and showed promising antitubercular activity with drug-like properties. The identified lead molecule could act as a starting point to develop novel, potent antitubercular agents against the parental and drug-resistant tuberculosis strains.

Dual functional cholinesterase and carbonic anhydrase inhibitors for the treatment of Alzheimer's disease: Design, synthesis, in vitro, and in silico evaluations of coumarin-dihydropyridine derivatives

Alzheimer's disease (AD) is a complex, progressive, and predominant form of cognitive disorders. The useful effect of cholinesterase (ChE) inhibitors in treatment of AD has been well-documented. In addition to ChE inhibitors, several studies confirmed that inhibition of human carbonic anhydrases (hCAs) can be help to AD treatment. In an attempt to introduce of potent ChE and hCA inhibitors, new coumarin-dihydropyridine derivatives (6a-m) were designed based on the molecular hybridization of effective pharmacophores. A simple synthetic route consisting of three steps was used to synthesis of title compounds 6a-m. The latter compounds were evaluated against acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and two important isoforms of hCA including hCA I and hCA II. The results of in vitro assays exhibited that compounds 6b, 6f, and 6i were the most promising derivatives against AChE and BChE and the most potent compounds against studied hCAs were compounds 6g, 6i, and 6j. Furthermore, the most potent compounds were subjected to in silico screening using Autodock software and preADMET online software to identify the binding modes and prediction of pharmacokinetic property, respectively.