Hybrid Pharmacophore Approach Research Articles

Design and synthesis of triazole-functionalized isatin hybrids with potent anti-proliferative action against triple-negative breast cancer MDA-MB-231 cell line: a hybrid pharmacophore approach

Design and synthesis of triazole-functionalized isatin hybrids with potent anti-proliferative action against triple-negative breast cancer MDA-MB-231 cell line: a hybrid pharmacophore approach

4-Thiazolidinone-Bearing Hybrid Molecules in Anticancer Drug Design.

Oncological diseases have currently reached an epidemic scale, especially in industrialized countries. Such a situation has prompted complex studies in medicinal chemistry focused on the research and development of novel effective anticancer drugs. In this review, the data concerning new 4-thiazolidinone-bearing hybrid molecules with potential anticancer activity reported during the period from the years 2017-2022 are summarized. The main emphasis is on the application of molecular hybridization methodologies and strategies in the design of small molecules as anticancer agents. Based on the analyzed data, it was observed that the main directions in this field are the hybridization of scaffolds, the hybrid-pharmacophore approach, and the analogue-based drug design of 4-thiazolidinone cores with early approved drugs, natural compounds, and privileged heterocyclic scaffolds. The mentioned design approaches are effective tools/sources for the generation of hit/lead compounds with anticancer activity and will be relevant to future studies.

Pyrazolyl-Imidazole clubbed 1,2,3-triazoles: Synthesis, structure explication and antimicrobial evaluation

A small library of novel pyrazolyl-imidazole-triazole hybrids (3a-3r) has been designed and synthesized based on hybrid pharmacophore approach using click reaction of N-propargylated pyrazolyl-imidazole (1) with several aryl azides carrying different substituents. The hybrids were characterized by different spectral techniques like IR, 1H, 13C NMR, HRMS and X-ray crystallography. ADME profile was assessed for these derivatives to get an insight on their pharmacokinetic/dynamic attributes. The synthesized hybrids were screened for antimicrobial activities against bacterial and fungal strains. Hybrid 3o and 3k demonstrated broad spectrum antibacterial activity against all tested bacterial strains except S. aureus and even better than clinically approved drug Norfloxacin. Hybrids 3c (MIC, 0.0082 µmol/mL), 3d (MIC, 0.0075 µmol/mL), 3e (MIC, 0.0077 µmol/mL) and 3m (MIC, 0.0081 µmol/mL) showed more than two-fold inhibitory efficacy against C. albicans while against A. niger, 3c (MIC, 0.0082 µmol/mL) showed five-fold inhibitory efficacy as compared with Fluconazole. Moreover, in-silico molecular docking study investigated on E. coli topoisomerase-II DNA gyrase revealed a good binding interaction with most potent hybrids 3o and 3k.

Evaluation of Anticonvulsant Activity of Dual COX-2/5-LOX Inhibitor Darbufelon and Its Novel Analogues

Neuroinflammation is an integral part of epilepsy pathogenesis and other convulsive conditions, and non-steroidal anti-inflammatory drugs (NSAIDs) present a potent tool for the contemporary search and design of novel anticonvulsants. In the present paper, evaluation of the anticonvulsant activity of the potential NSAID dual COX-2/5-LOX inhibitor darbufelone methanesulfonate using an scPTZ model in mice in dose 100 mg/kg is reported. Darbufelone possesses anticonvulsant properties in the scPTZ model and presents interest for in-depth studies as a possible anticonvulsant multi-target agent with anti-inflammatory activity. The series of 4-thiazolidinone derivatives have been synthesized following the analogue-based drug design and hybrid-pharmacophore approach using a darbufelone matrix. The synthesized derivatives showed a significant protection level for animals in the scPTZ model and are promising compounds for the design of potential anticonvulsants with satisfactory drug-like parameters.

Synthesis and Biological Activity Evaluation of Polyfunctionalized Anthraquinonehydrazones

Background : Anthraquinone derivatives, frequently occurring motifs in many various natural compounds, have attracted a great deal of interest as compounds with a wide spectrum of biological activities. Introduction: The hybrid pharmacophore approach has become an object of considerable interest due to the incorporation of a five- or six-membered heterocyclic rings in the structure of various natural compounds, especially anthraquinone derivatives. Methods: A series of polyfunctionalized anthraquinonehydrazones have been synthesized via the azo-coupling reaction between anthraquinone-based triazenes and methylene active compounds. The structures of synthesized compounds were confirmed by spectral data. Some of the synthesized compounds were screened for their in vitro anticancer activity according to US NCI protocols. The screening of antimicrobial and antifungal activities against Candida albicans and Lactobacillus sp. was carried out. The synthesized compounds were evaluated for their antioxidant (DPPH free radical scavenging assay) and herbicidal activity. Results: The synthesized 1-[N'-(5-oxo-2-thioxoimidazolidin-4-ylidene)-hydrazino]-anthraquinone 1.5 displayed a high level of antimitotic activity against tested human tumor cells with mean GI50/TGI values 4.06/78.52μM. The screening of antimicrobial and antifungal activities led to the identification of 1.8 and 1.9 with a moderate effect on Candida albicans and Lactobacillus sp. Antioxidant activity evaluation allowed the identification of 1-[N'-(3-methyl-5-oxo-1-phenyl-1,5- dihydropyrazol-4-ylidene)-hydrazino]-anthraquinone 1.8 with an IC50 value of 3.715 mM. The herbicidal activity screening led to compound identification 1.8 with growth inhibition of Agrostis stolonifera at 25 %. Conclusion: The obtained anthraquinonehydrazones constitute an interesting template for the design of new synthetic agents with polypharmacological activities.

Design and Synthesis of Novel Imidazole Derivatives Possessing Triazole Pharmacophore with Potent Anticancer Activity, and In Silico ADMET with GSK-3β Molecular Docking Investigations.

A library of novel imidazole-1,2,3-triazole hybrids were designed and synthesized based on the hybrid pharmacophore approach. Therefore, copper(I)catalyzed click reaction of thiopropargylated-imidazole 2 with several organoazides yielded two sets of imidazole-1,2,3-triazole hybrids carrying different un/functionalized alkyl/aryl side chains 4a–k and 6a–e. After full spectroscopic characterization using different spectral techniques (IR, 1H, 13C NMR) and elemental analyses, the resulted adducts were screened for their anticancer activity against four cancer cell lines (Caco-2, HCT-116, HeLa, and MCF-7) by the MTT assay and showed significant activity. In-silico molecular docking study was also investigated on one of the prominent cancer target receptors, i.e., glycogen synthase kinase-3β (GSK-3β), revealing a good binding interaction with our potent compound, 4k and was in agreement with the in vitro cytotoxic results. In addition, the ADMET profile was assessed for these novel derivatives to get an insight on their pharmacokinetic/dynamic attributes. Finally, this research design and synthesis offered click chemistry products with interesting biological motifs mainly 1,2,3 triazoles linked to phenyl imidazole as promising candidates for further investigation as anticancer drugs.

Design, synthesis, and biological evaluation of novel indanone-based hybrids as multifunctional cholinesterase inhibitors for Alzheimer's disease

New compounds containing indanone and carbamate moieties were designed based on the hybrid pharmacophore approach. The designed compounds were synthesized and fully characterized by using different methods such as IR, Mass, 1H NMR, 13C NMR, and HPTLC. In vitro inhibitory activities of all synthesized compounds were evaluated against acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). The compound 3-[(5,6-dimethoxy-1-oxo-2,3-dihydro-1H-inden-2-yl) methyl] phenyl (4-methoxyphenyl) carbamate (4h) showed the best inhibitory activities with IC50 values of 1.20 and 0.30 μM against AChE and BChE, respectively. In addition, this compound showed a β-amyloid self-aggregation inhibitory effect (86.8%), stronger than that of donepezil (45.5%). Moreover, significant neuroprotective activity on PC12 cells against H2O2 induced cell death was demonstrated for compound 4h at 10 and 100 µM concentrations. Kinetic studies using the 4h confirmed a partial non-competitive mixed type of inhibition mechanism on both enzymes. Considering the suggested inhibition mechanism, molecular docking was used to predict the possible allosteric binding mode of 4h with both AChE and BChE enzymes. The presented indanone-carbamate scaffold can be structurally modified and optimized through medicinal chemistry-based approaches for designing novel multi-target anti-Alzheimer agents.

Synthesis of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as potent antiproliferative agents via a hybrid pharmacophore approach

Imiquimod (1-isobutyl-1H-imidazo[4,5-c]quinolin-4-amine) is efficacious in topical therapy for certain types of skin cancers. Structurally similar EAPB0203 (N-methyl-1-(2-phenethyl)imidazo[1,2-a]quinoxalin-4-amine) has been shown higher in vitro potency than imiquimod. Besides, triazole, oxadiazole, and thiadiazole rings are privileged building blocks in drug design. A series of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole and [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-thiadiazole derivatives were therefore synthesized by incorporation of these rings into the structure of EAPB0203 and assessed their antiproliferative effects against various cancer cell lines. The 1,3,4-oxadiazole derivatives demonstrated the superior effectiveness compared to imiquimod and EAPB0203. Our findings highlight the excellent potential of [1,2,4]triazolo[4,3-a]quinoxaline-1,3,4-oxadiazole derivatives as anticancer agents.

Novel Quinolone Substituted Imidazol-5(4H)-ones as Anti-inflammatory, Anticancer Agents: Synthesis, Biological Screening and Molecular Docking Studies

Background: Quinolones and imidazolones are important heterocyclic moieties which have been reported to possess potent anti-inflammatory and anticancer properties. The activity of these compounds were related to inhibition of nuclear factor-kappaB (NF- κB) which is one of the important targets studied for designing of anti-inflammatory and antitumor drugs. Further, hybrid pharmacophore approach is used in the present study for designing potent molecules. Objectives: Aim of the study is to synthesis a series of quinolone substituted imidazolones and evaluation of their anti-inflammatory and anticancer activity. Methods: Quinolone substituted imidazolones were synthesized by aminolysis of 7-amino-4-methyl-quinoline-2(1H)-one with substituted oxazolones afforded quinolone substituted imidazolones. Structures of synthesized compounds were characterized by spectral techniques and were evaluated for anti-inflammatory activity by carrageenan-induced rat paw oedema test. Differences between control and treatment groups were tested using one way analysis of variance followed by Tukey’s test. Anticancer activity was assessed by evaluating the cytotoxicity of compounds on BT-549 and HeLa, human cancer cell lines by MTT assay. Results: Compounds 3-fluorobenzylidene substituted imidazolonyl quinolone (F3) and 4-phenoxybenzylidene substituted imidazolonyl quinolone (F12) were the most cytotoxic compounds against BT-549 and HeLa cell lines. While 2-chlorobenzylidene substituted imidazolonyl quinolone (F4) and 4-chlorobenzylidene substituted imidazolonyl quinolone (F5) exhibited the highest anti-inflammatory activity. Most of the test compounds exhibited statistically significant inhibition of paw oedema volume when compared to that of control. Conclusion: Molecular docking studies revealed that combination of two pharmacophores was crucial for binding of quinolone substituted imidazol-5(4H)-ones on NF-κB with good correlation between docking score and biological activity.

Synthesis of novel 5-substituted 2-pyrazolylthiazol-4-ones as potential bioligically active compounds

One of the effective strategies in potential “drug-like” molecules design is using a molecular hybridization approach based on the combination of several pharmacological scaffolds in one molecule. The main argument for using this approach is a polypharmacological theory based on the interaction of mentioned hybrid molecules with multiple bio-targets based on selectivity and the resulting reduction of toxicity. The aim of the work is to synthesize a number of new 5-substituted 2-pyrazolylthiazol-4-ones as potentional biologically active compounds. Materials and methods. Organic synthesis, 1 H NMR spectroscopy. Results . The synthesis of new 5-ene-2-pyrazolylthiazol-4-ones was carried out via a three-component [2+3]-cyclocondensation reaction of 3-methyl-5-aryl-4,5-dihydropyrazole-1-carbothiamides with chloroacetic acid and the corresponding carbonyl compounds in acetic acid medium. The structure of the synthesized compounds was confirmed by elemental analysis and 1 H NMR spectroscopy. Conclusions . As a result of chemical transformations, a library of new thiazole-pyrazoline conjugates was synthesized based on a hybrid-pharmacophore approach to further anticancer activity evaluation within the DTP NCI protocol.

Design, synthesis, and biological evaluation of novel benzo[b]thiophene-diaryl urea derivatives as potential anticancer agents

A hybrid pharmacophore approach was applied to design and synthesize a series of benzo[b]thiophene-diaryl urea derivatives 17a–g with potential anticancer effect. In vitro antiproliferative activities of all target compounds were evaluated against HT-29 and A549 cancer cell lines. Three compounds 17b, 17d, and 17f exhibited antiproliferative activities on both cell lines comparable to that of the positive reference drug sorafenib. Notably, compound 17d demonstrated the highest activity with IC50 values of 5.91 and 14.64 μM on HT-29 and A549 cells, respectively. It also induced apoptosis and cell cycle arrest at the G0/G1 phase on HT-29 cells based on DAPI staining and propidium iodide (PI) staining followed by flow cytometry analyses. Molecular docking studies revealed that 17d can bind well to the active site of VEGFR2 receptor. Collectively, compound 17d can be considered as a promising scaffold amenable for further optimization towards the development of new anticancer agents.

Synthesis, Biological Evaluation and In Silico Studies of Certain Oxindole-Indole Conjugates as Anticancer CDK Inhibitors.

On account of their overexpression in a wide range of human malignancies, cyclin-dependent kinases (CDKs) are among the most validated cancer targets, and their inhibition has been featured as a valuable strategy for anticancer drug discovery. In this study, a hybrid pharmacophore approach was adopted to develop two series of oxindole–indole conjugates (6a–i and 9a–f) and carbocycle–indole conjugates (11a,b) as efficient antitumor agents with potential inhibitory action toward CDK4. All oxindole–indole conjugates, except 6i, 9b, and 9c efficiently affected the growth of the human breast cancer MCF-7 (IC50: 0.39 ± 0.05–21.40 ± 1.58 μM) and/or MDA-MB-231 (IC50: 1.03 ± 0.04–22.54 ± 1.67 μM) cell lines, whereas bioisosteric replacement of the oxindole nucleus with indane or tetralin rings (compounds 11a,b) diminished the anti-proliferative activity. In addition, hybrids 6e and 6f displayed effective cell cycle disturbance and proapoptotic capabilities in MCF-7 cells. Furthermore, the efficient anti-proliferative agents towards MCF-7 and/or MDA-MB-231 cell lines (6a–h, 9a, and 9e) were investigated for their potential inhibitory action toward CDK4. Hybrids 6a and 6e displayed good CDK4 inhibitory activity with IC50s equal 1.82 and 1.26 µM, respectively. The molecular docking study revealed that oxindole moiety is implicated in two H-bonding interactions via both (NH) and (C=O) groups with the key amino acids Glu94 and Val96, respectively, whereas the indole framework is stably accommodated in a hydrophobic sub-pocket establishing hydrophobic interactions with the amino acid residues of Ile12, Val20, and Gln98 lining this sub-pocket. Collectively, these results highlighted hybrids 6a and 6e as good leads for further optimization as promising antitumor drugs toward breast malignancy and CDK inhibitors.

Click chemistry synthesis, biological evaluation and docking study of some novel 2'-hydroxychalcone-triazole hybrids as potent anti-inflammatory agents.

A hybrid pharmacophore approach is used to design and synthesize two novel series of 2'-hydroxychalcone-triazole hybrid molecules 6a-j and 8a-j. These compounds were fully characterized by spectral and elemental analyses. They were evaluated in vitro and in vivo for anti-inflammatory activity. Most of compounds were selective inhibitors for COX-2. Among them, compounds 6d, 6f, 6i, 8c, 8e and 8h demonstrated highly potent dual inhibition of COX-2 (IC50=0.037-0.041µM) and 15-LOX (IC50=1.41-1.80µM). Compounds 6i, 8c and 8h showed 116%, 113% and 109% of the in vivo anti-inflammatory activity of celecoxib. Therefore, compounds 6d, 6f, 6i, 8c, 8e and 8h-j are potent dual inhibitors of COX-2 and 15-LOX. Docking study over COX-2 and 15-LOX active sites ensures the binding affinity and selectivity. These compounds are promising candidates for further development as anti-inflammatory drugs.

Design, synthesis and evaluation of structurally diverse chrysin-chromene-spirooxindole hybrids as anticancer agents

A series of structurally diverse chrysin-chromene-spirooxindole hybrids were designed, synthesized via a Knoevenagel/Michael/cyclization of chrysin and isatylidene malononitrile derivatives through utilizing a hybrid pharmacophore approach. The newly synthesized compounds were evaluated for their in vitro anticancer activity, and most of the compounds showed stronger anti-proliferative activity than parent compound chrysin. In particular, compound 3e had the highest cytotoxicity towards A549 cells (IC50 = 3.15 ± 0.51 μM), and had better selectivity in A549 cells and normal MRC-5 cells. Furthermore, compound 3e could significantly inhibit the proliferation and migration of A549 cells in a dose-dependent manner, as well as induce the apoptosis possibly through mitochondria-mediated caspase-3/8/9 activation and multi-target co-regulation of the p53 signaling pathway. Thus, our results provide in vitro evidence that compound 3e may be a potential candidate for the development of new anti-tumour drugs.

Chalcone-Thiazole Hybrids: Rational Design, Synthesis, and Lead Identification against 5-Lipoxygenase.

A hybrid pharmacophore approach is used to design and synthesize novel chalcone-thiazole hybrid molecules. Herein, thiazole has been hybridized with chalcone to obtain a new class of 5-LOX inhibitors. In vitro biological evaluation showed that most of the compounds were better 5-LOX inhibitors than the positive control, Zileuton (IC50 = 1.05 ± 0.03 μM). The best compounds in the series, namely, 4k, 4n, and 4v (4k: IC50 = 0.07 ± 0.02 μM, 4n: IC50 = 0.08 ± 0.05 μM, 4v: 0.12 ± 0.04 μM) are found to be 10 times more active than previously reported 2-amino thiazole (2m: IC50 = 0.9 ± 0.1 μM) by us. Further, 4k has redox (noncompetitive) while 4n and 4v act through a competitive inhibition mechanism. SAR indicated that the presence of methoxy/methyl either in the vicinity of chalcone or both thiazole and chalcone contributed to the synergistic inhibitory effect.

Examination of novel 4-aminoquinoline derivatives designed and synthesized by a hybrid pharmacophore approach to enhance their anticancer activities

In an attempt to develop effective and potentially safe anticancer agents, thirty-six 4-aminoquinoline derived sulfonyl analogs were designed and synthesized using a hybrid pharmacophore approach. The cytotoxicity of these compounds was determined using three breast tumor cell lines (MDA-MB231, MDA-MB468 and MCF7) and two matching non-cancer breast epithelial cell lines (184B5 and MCF10A). Although most of the compounds were quite effective on the breast cancer cells, the compound 7-chloro-4-(4-(2,4-dinitrophenylsulfonyl)piperazin-1-yl)quinoline (13; VR23) emerged as potentially the most desirable one in this series of compounds. Data from the NCI-60 cancer panel screening show that compound 13 is effective on a wide range of different cancers. Importantly, compound 13 is needed up to 17.6-fold less doses to achieve the same IC50 against cancer than non-cancer cells (MDA-MB468 vs MCF10A), suggesting that it can potentially be less toxic to normal cells. Cancer cells formed multiple centrosomes in the presence of compound 13, resulting in the cell cycle arrest at prometa-meta phase. This abnormality leads to eventual cell demise with sub-G1 DNA content typically shown with apoptotic cells. In addition, compound 13 also causes an increase in lysosomal volume in cancer but not in non-cancer cells, which may contribute at least in part to its preferential cancer cell-killing. The cancer cell-killing effect of compound 13 is highly potentiated when combined with either bortezomib or monastrol.

Design, Synthesis, Biological Activity and Molecular Docking Study of Coumarin Derivatives Bearing 2-Methylbiphenyl Moiety

A hybrid pharmacophore approach was used to design and synthesize a series of coumarin derivatives bearing 2-methylbiphenyl moiety, which were evaluated for their in vitro anticancer activities against four cancer cell lines(MCF-7, A549, H460 and HT29) and PD-1/PD-L1 inhibitory activities. Moreover, several compounds with excellent anticancer activities were selected to evaluate the cytotoxicities against one normal cell line(HEK-293). The most promising compound 11o showed the best anticancer activities against the four tested cancer cell lines with the IC50 values of 6.45, 8.65, 6,57 and 8.13 μmol/L, respectively, and displayed weak cytotoxicity on the normal cell(HEK-293). Furthermore, screening of PD-1/PD-L1inhibitory activity revealed that compound 11o could effectively inhibit the binding of PD-1/PD-L1, and the binding interactions of compound 11o with PD-L1 protein were explored by molecular docking. All above evidences showed that compound 11o might be worthy of further study as a valuable leading compound for the treatment of cancer.

Synthesis of sulfonamide, amide and amine hybrid pharmacophore, an entry of new class of carbonic anhydrase II inhibitors and evaluation of chemo-informatics and binding analysis

Selective inhibition of carbonic anhydrase (CA) enzyme is an active area of research for medicinal chemists. In the current account, a hybrid pharmacophore approach was employed to design sulfonamide, amide and amine containing new series of potent carbonic anhydrase II inhibitors. The aromatic fragment associated with pharmacophore was altered suitably in order to find effective inhibitors of CA-II. All the derivatives 4a-4m showed better inhibition compared to the standard acetazolamide. In particular, compound 4l exhibited significant inhibition with IC50 value of 0.01796 ± 0.00036 µM. The chemo-informatics analysis justified that all the designed compounds possess <10 HBA and <5 HBD. The ligands-protein binding analyses showed that 4l confined in the active binding pocket with three hydrogen bonds observed with His63, Asn66 and Thr197 residues.

Design and synthesis of 4-piperazinyl quinoline derived urea/thioureas for anti-breast cancer activity by a hybrid pharmacophore approach

In an attempt to improve anti-breast cancer activity, a new series of 4-piperazinylquinoline derivatives based on the urea/thiourea scaffold were designed and synthesised by a pharmacophore hybrid approach. We then examined for their antiproliferative effects on three human breast tumor cell lines, MDA-MB231, MDA-MB468 and MCF7, and two non-cancer breast epithelial cell lines, 184B5 and MCF10A. Among those 26 novel compounds examined, 5, 9, 17, 18, 21, 23 and 29 showed significantly improved antiproliferative activity on breast cancer cells. Compound 23 (4-(7-chloro-quinolin-4-yl)-piperazine-1-carbothioic acid (2-morpholin-4-yl-ethyl)-amide) (RL-15) is especially desirable, since its antigrowth/cell-killing activity is 7-11 fold higher on cancer than non-cancer cells. Data from cell biological studies demonstrated that cancer cells compromised plasma membrane integrity in the presence of compound 23. The cancer cell-specific property of compound 23 shown in cell culture stands in vivo test, this compound can be an excellent lead for effective and safe anticancer drug.

Synthesis, crystal structure and antimicrobial activity of 2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide derivatives against phytopathogens.

A total of eighteen 2-((2-(4-(1H-1,2,4-triazol-1-yl)phenyl)quinazolin-4-yl)oxy)-N-phenylacetamide derivatives were designed and synthesized, via hybrid pharmacophore approach. Among these compounds, chemical structure of compound 4a was unambiguously confirmed by means of single-crystal X-ray diffraction analysis. All the compounds were evaluated in vitro for their inhibition activity against several important phytopathogenic bacteria and fungi in agriculture. The obtained results indicated that several compounds demonstrated potent antibacterial activity against Xanthomonas oryzae pv. oryzae (Xoo). For example, compounds 4c, 4g and 4q had EC50 values of 35.0, 36.5 and 32.4µg/mL toward this bacterium, respectively, around 1.5 times more active than commercial bactericide bismerthiazol (EC50 = 89.8µg/mL). Additionally, compounds 4j and 4p were found to display comparable antifungal activity against Gloeosporium fructigenum at 50µg/mL, to commercial fungicide hymexazol. Finally, the relationships between antibacterial activities and molecular structures of this class of compounds were discussed in detail.