Molecular Hybridization Approach Research Articles

Exploring the Antiproliferative Potential of Morpholine‐Functionalized Aurones: Design, Synthesis, SAR, DFT, Hirshfeld Surface, 3D Energy Frameworks and Molecular Docking Analysis

AbstractIn quest of generating a diverse array of potential cytotoxic candidates through molecular hybridization approach, herein we have designed a library of forty‐one morpholine‐functionalized aurones 7(a–ao), each with a distinct substitution pattern. These aurones were obtained by reacting 6‐hydroxyaurones, with 4‐(2‐chloroethyl)morpholine hydrochloride, characterized by various spectroscopic techniques including single crystal XRD (7b) and in‐vitro screened for their antiproliferative potential against human gastric adenocarcinoma (AGS) cells. Most of the synthesized compounds have exhibited excellent cytotoxic results. Twenty analogs were found to have cytotoxic potential better than the reference drug Leucovorin and analog 7j emerged as the most potent with IC50=5.98 μM nearly one fifth to the standard drug Leucovorin (IC50=30.8 μM). This library, consisting of twenty three novel and eighteen reported morpholine‐functionalized aurones, bearing diverse substitution pattern, further helped in making a concrete structure‐activity relationship for antiproliferative potential. Additionally, in‐silico molecular docking, Hirshfeld surface analysis and two dimensional fingerprint plots were also studied to understand the molecular interactions and various structural aspects. Further computational investigations of these compounds were conducted using the DFT/B3LYP method, for the determination of HOMO and LUMO energy values as well as the calculation of chemical softness, hardness, electronegativity and electrophilic index etc.

A novel arylpiperazine derivative (LQFM181) protects against neurotoxicity induced by 3- nitropropionic acid in in vitro and in vivo models

In the pursuit of novel antioxidant therapies for the prevention and treatment of neurodegenerative diseases, three new arylpiperazine derivatives (LQFM181, LQFM276, and LQFM277) were synthesized through a molecular hybridization approach involving piribedil and butylated hydroxytoluene lead compounds. To evaluate the antioxidant and neuroprotective activities of the arylpiperazine derivatives, we employed an integrated approach using both in vitro (SH-SY5Y cells) and in vivo (neurotoxicity induced by 3-nitropropionic acid in Swiss mice) models. In the in vitro tests, LQFM181 showed the most promising antioxidant activity at the neuronal membrane and cytoplasmic levels, and significant neuroprotective activity against the neurotoxicity induced by 3-nitropropionic acid. Hence, this compound was further subjected to in vivo evaluation, which demonstrated remarkable antioxidant capacity such as reduction of MDA and carbonyl protein levels, increased activities of succinate dehydrogenase, catalase, and superoxide dismutase. Interestingly, using the same in vivo model, LQFM181 also reduced locomotor behavior and memory dysfunction through its ability to decrease cholinesterase activity. Consequently, LQFM181 emerges as a promising candidate for further investigation into its neuroprotective potential, positioning it as a new therapeutic agent for neuroprotection.

Unveiling of Indanone‐Benzimidazole Hybrids as Anti‐Alzheimer's Agents: Computational and Experimental Studies

AbstractThe growing concern of Alzheimer's disease underscores the urgent requirement for the development of novel therapeutic agents. In this study, a series of 15 hybrid molecules containing Indanone‐Benzimidazole heterocycles were designed utilizing the molecular hybridization approach. The synthesized molecules were characterized by spectroscopic techniques and their anti‐Alzheimer's behaviour were examined. Biological assessment demonstrated that compounds 14 and 15 exhibited significant reduction of “human” amyloid beta (Aβ) peptide aggregation, expressing on transgenic Caenorhabditis elegans (C. elegans) strain CL4176. These compounds were further evaluated for their AChE inhibitory effects in transgenic C. elegans strain CL2006 and found significant. Molecular docking investigations have elucidated the commendable affinity exhibited by the studied ligands towards the Aβ pentamer (PDB: 2BEG) and acetylcholinesterase (AChE) (PDB: 4EY7). Subsequent to these docking studies, molecular dynamics simulations were conducted, affirming the stability of both ligands in association with the Aβ pentamer and ACh. Additionally, Density functional theory (DFT) calculations were performed by using B3LYP energy level with the basis set 6–311 G (d, p) basis set to correlate with experimental results. Taken together, all these findings evidenced the experimental results and this study sheds light on the anti‐Alzheimer's potential of Indanone‐Benzimidazole hybrids.

Synthesis, biological evaluation and molecular docking study of pyrimidine linked thiazolidinedione derivatives as potential antimicrobial and antitubercular agents

The design and development of novel antimicrobial agents are highly desired to combat the emergence of medication resistance against microorganisms that cause infections. A series of new pyrimidine-linked thiazolidinedione derivatives (5a-j) were synthesized, characterized, and their antimicrobial properties assessed in the current investigation. Here, novel pyrimidine-linked thiazolidinedione compounds were designed using the molecular hybridization approach. Elemental and spectral techniques were used to determine the structures of the synthesized hybrids. The majority of compounds showed encouraging antibacterial properties. Among the active compounds, 5g, 5i, and 5j showed 1.85, 1.15, and 1.38 times the activity of streptomycin against S. aureus, respectively, with MIC values of 6.4, 10.3, and 8.6 µM. With MIC values of 10.8, 21.9, and 15.4 µM, respectively, the compounds 5g, 5i, and 5j showed 2.14, 1.05, and 1.50 times the activity of linezolid against the methicillin-resistant S. aureus (MRSA) strain. Furthermore, when compared to the reference medications, compounds 5g, 5i, and 5j demonstrated broad-range antimicrobial efficacy against all tested strains of bacteria and fungus. Out of all the compounds that were investigated, compounds 5g, 5i, and 5j showed noteworthy anti-tubercular activity. 5g is the most effective, 1.59 times more effective than reference drug isoniazid. To anticipate the binding manner, the synthesized potent compounds were subjected to molecular docking into the active binding site of MRSA and the mycobacterial membrane protein large 3 (MmpL3) protein. The compounds 5g, 5i, and 5j may eventually serve as lead compounds in the search for antimicrobial and anti-TB therapeutic agents.

Discovery of thiazolidinedione-based pancreatic lipase inhibitors as anti-obesity agents: synthesis, in silico studies and pharmacological investigations

A series of new 2,5-disubstituted arylidene derivatives of thiazolidinedione (16a-e, 17a-d, 18a-c) designed using molecular hybridization approach were synthesized, structurally characterized, and explored for their anti-obesity potential via inhibition of Pancreatic Lipase (PL). Compound 18a presented the most potent PL inhibitory activity with IC50 = 2.71 ± 0.31 µM, as compared to the standard drug, Orlistat (IC50 = 0.99 µM). Kinetic study revealed reversible competitive mode of enzyme inhibition by compound 18a with an inhibitory constant value of 1.19 µM. The most promising compound 18a revealed satisfactory binding mode within the active site of the target protein (human PL, PDB ID: 1LPB). Also, MM/PBSA binding free energy and molecular dynamics (MD) simulation analysis were performed for the most promising compound 18a, which showed potent inhibition according to the results of in vitro studies. Furthermore, a stable conformation of the 1LPB-ligand suggested the stability of this compound in the dynamic environment. The ADME and toxicity analysis of the compounds were examined using web-based online platforms. Results of in vivo studies confirmed the anti-obesity efficacy of compound 18a, wherein oral treatment with compound 18a (30 mg/kg) resulted in a significant reduction in the body weight, BMI, Lee index, feed intake (in Kcal), body fat depots and serum triglycerides. Compound 18a significantly decreased the levels of serum total cholesterol (TC) to 128.6 ± 0.59 mg/dl and serum total triglycerides (TG) to 95.73 ± 0.67 mg/dl as compared to the HFD control group. The present study identified disubstituted TZD derivatives as a new promising class of anti-obesity agents. Communicated by Ramaswamy H. Sarma

Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, Synthesis, In vitro biological evaluation, molecular docking and ADME studies

In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity as compared to the simple and N-benzyl indole-piperazine derivatives. In addition, the observed activity profile of indole-piperazines was similar to standard anti-TB drugs (isoniazid and pyrazinamide) against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains, demonstrating the compounds’ selectivity towards the Mycobacterium tuberculosis H37Rv strain. All the active anti-TB compounds are proved to be non-toxic (with IC50 > 300 μg/mL) as verified through the toxicity evaluation against VERO cell lines. Additionally, molecular docking studies against two target enzymes (Inh A and CYP121) were performed to validate the activity profile of indole-piperazine derivatives. Further, in silico-ADME prediction and pharmacokinetic parameters indicated that these compounds have good oral bioavailability.

Harnessing molecular hybridization approach to discover novel quinoline EGFR-TK inhibitors for cancer treatment.

Aim: Using molecular hybridization approach, novel 18 quinoline derivatives (6a-11) were designed and synthesized as EGFR-TK inhibitors. Materials & methods: The antiproliferative activity was assessed against breast (MCF-7), leukemia (HL-60) and lung (A549) cancer cell lines. Moreover, the most active quinoline derivatives (6d and 8b) were further investigated for their potential as EGFR-TK inhibitors. In addition, cell cycle analysis and apoptosis induction activity were conducted. Results: A considerable cytotoxic activity was attained with IC50 values spanning from 0.06 to 1.12μM. Besides, the quinoline derivatives 6d and 8b displayed potent inhibitory activity against EFGR with IC50 values of 0.18 and 0.08μM, respectively. Conclusion: Accordingly, the afforded quinoline derivatives can be used as promising lead anticancer candidates for future optimization.

Green design and synthesis of some novel thiazolidinone appended benzothiazole-triazole hybrids as antimicrobial agents.

The global increase in bacterial resistance poses a significant threat, jeopardizing the effectiveness of antibiotics. Therefore, the development of new and efficient antimicrobial agents is pre-dominant. Taking this into consideration, in the present study, we designed and reported the facile synthesis of two novel series benzothiazole-triazole and thiazolidinone-appended benzothiazole-triazole hybrids using a molecular hybridization approach in a one-pot process. The synthesized compounds were tested for microbial growth inhibition against bacterial and fungal strains. Among all the synthetics, compounds derived from methoxyphenyl and heteroaromatic ring substitutions exhibited promising inhibitory activity. The current investigation has emphasized that benzothiazole-triazole hybrids incorporating thiazolidinone can be a promising and potent category of molecules with potential biological activities. This sustainable and eco-friendly protocol involves the metal-free, catalyst-free synthesis of bioactive scaffolds, which merges broad tolerance for functional groups with a short reaction time, resulting in good to excellent yields.

Design, synthesis, docking study, cytotoxicity evaluation, and PI3K inhibitory activity of Novel di-thiazoles, and bis(di-thiazoles)

A series of novel thiazole hybrids were designed and synthesized using a molecular hybridization approach to develop more potent Pi3k inhibitors for cancer treatment. As a result of the reaction of (phenylthiazol-5-yl)ethylidenehydrazine-1-carbothioamide with the corresponding bis-bromoacetyl derivatives, reasonable yields of novel bis-dithiazoles linked via aliphatic, aromatic, or heterocyclic cores were obtained. The structural details of the new compounds were confirmed using spectral data and elemental analysis. All of the proposed compounds were molecularly docked based on their structural similarity to the alpelisib pi3k inhibitor, and compounds 11e and 11d demonstrated very good binding modes that ranged between hydrogen and pi bonds. All compounds were tested for anticancer activity against HT29 colon cancer cells. The IC50 values for compounds 11d and 11e were 4.4 and 8.3 nM, respectively. In addition, PI3K enzyme inhibition activity was assessed, and the results ranged from very low IC50 for 11e and 11d, which revealed 2.33 and 2.55 nM, to moderate for 11b, 11c, 13b, and 15b, with IC50 of 7.58, 6.15, 7.9, and 9.11 nM, respectively, when compared to alpelisib, which revealed an IC50 of 4.96 nM. The inhibitory activity of the most potent compounds was qualitatively evaluated by Western Blotting, and pi3k gene expression was found to be inhibited to half of its maximum value.

Investigating the role of indole and quinazolinone-based hybrid analogues with ketoamide fragment and alkyl extension for potential PL inhibition

Pancreatic lipase (PL) is a key enzyme responsible for the digestion of dietary fat. Hence the inhibition of PL is an effective strategy for mitigating obesity. In this study, a novel series of 18 indolyl oxoacetamide–quinazolinone hybrid analogues (9a-h, 13aa-13fd) were designed, synthesized, and evaluated for PL inhibition activity. An approach of molecular hybridization was utilized by considering the PL inhibitory potential of indole, α-ketoamide, and quinazolinone scaffolds. A Propyl linker was attached for better binding at the PL active site, leading to enhanced PL inhibitory potential. Among all the synthesized analogues, 13be exhibited the highest PL inhibitory activity (IC50 = 4.71 ± 0.851 μM) with a docking score of -147.06 kcal/mol. The activities of all the synthesized analogues were compared with the orlistat (IC50 = 0.86 ± 0.090 µM). The most potent analogue, 13be revealed the competitive mode of enzyme inhibition with the Ki value of 1.826 µM. The molecular docking and dynamics simulation analysis also revealed the strong binding of 13be at the active site of PL. Interestingly, the potent analogue 13be when tested on RAW 264.7 cell line using MTT assay, was found to be nontoxic at a concentration range of 1-20 µM. Therefore, the current work validates the effectiveness of the molecular hybridization approach for designing indolyl oxoacetamide–quinazolinone hybrids for inhibiting PL.

Synthesis and Characterization of a New Class of Chromene-Azo Sulfonamide Hybrids as Promising Anticancer Candidates with the Exploration of Their EGFR, hCAII, and MMP-2 Inhibitors Based on Molecular Docking Assays

In this study, novel selective antitumor compounds were synthesized based on their fundamental pharmacophoric prerequisites associated with EGFR inhibitors. A molecular hybridization approach was employed to design and prepare a range of 4H-chromene-3-carboxylates 7a–g, 8, and 11a–e derivatives, each incorporating a sulfonamide moiety. The structures of these hybrid molecules were verified using comprehensive analytical and spectroscopic techniques. During the assessment of the newly synthesized compounds for their anticancer properties against three tumor cell lines (HepG-2, MCF-7, and HCT-116), compounds 7f and 7g displayed remarkable antitumor activity against all tested cell lines, outperforming the reference drug Cisplatin in terms of efficacy. Consequently, these promising candidates were selected for further investigation of their anti-EGFR, hCAII, and MMP-2 potential, which exhibited remarkable effectiveness against EGFR and MMP2 when compared to Sorafenib. Additionally, docking investigations regarding the EGFR binding site were implemented for the targeted derivatives in order to attain better comprehension with respect to the pattern in which binding mechanics occur between the investigated molecules and the active site, which illustrated a higher binding efficacy in comparison with Sorafenib.

New 1,2,3-triazole tethered-1,4-dihydropyridines as potential antioxidant agents: Synthesis and molecular docking study

We have designed the molecules containing 1,2,3-triazole and 1,4-dihydropyridine pharmacophoric scaffolds in a single molecular framework by using molecular hybridization approach. Accordingly, we have planned and executed for the synthesis of a library of aryl-1,2,3-triazole incorporated 1,4-dihydropyridines and evaluated for their antioxidant activity. The compounds 12o, 12s and 12t showed excellent antioxidant activity with an IC50 values of 08.34 ± 0.17, 08.04 ± 0.17 and 08.80 ± 0.15 µg/mL, respectively. The compound 12a and 12m exhibited excellent antioxidant activity with IC50 values of 09.11 ± 0.34 and 11.39 ± 0.94 µg/mL, respectively. Furthermore, the compound 12k and 12n showed very good antioxidant activity with IC50 values of 12.22 ± 0.43 and 16.05 ± 0.11 µg/mL, respectively. In silico molecular docking study was performed to examine their binding modes and interactions with myeloperoxidase (MPO) enzyme which exhibited excellent correlation with observed antioxidant activites. Finally, in silico ADMET properties of the synthesized compounds were also investigated. The obtained results showed that most of the synthesized compounds had a positive drug-likeness profile.

Design, synthesis, theoretical studies, and biological activity evaluation of new nitrogen-containing poly heterocyclic compounds as promising antimicrobial agents

The increasing threat of antibiotic resistance has led to a pressing need for the development of new antimicrobial agents. Nitrogen-containing heterocycles are widely used in the development of drugs due to their broad spectrum of pharmacological activities, including antimicrobial properties. In this study, a series of 13 hybrid molecules containing two to four nitrogen heterocycles were designed using the molecular hybridization approach. The synthesized compounds were characterized and their antimicrobial properties were examined against two bacterial strains and a Candida strain. The most promising compounds were found to be those bearing the quinoline unit, exhibiting a MIC of less than 31.25 μg/mL against S. typhimurium and Bacillus subtilis. Molecular docking studies revealed that these compounds have excellent affinity with the DNA gyrase enzyme, making them potential candidates for further development as antimicrobial agents.

Structure-Based Optimization and Biological Evaluation of Potent and Selective MMP-7 Inhibitors for Kidney Fibrosis.

Matrix metalloproteinase-7 (MMP-7) has been shown to play important roles in pathophysiological processes involved in the development/progression of diseases such as cancer and fibrosis. We discovered selective MMP-7 inhibitors composed of arylsulfonamide, carboxylate, and short peptides by a molecular hybridization approach. These compounds interacted with MMP-7 via multiple hydrogen bonds in the cocrystal structures. To obtain compounds for in vivo evaluation, we attempted structural optimization, particularly targeting Tyr167 at the S3 subsite through structure-based drug design, and identified compound 15 as showing improved MMP-7 potency and MMP subtype selectivity. A novel π-π stacking interaction with Tyr167 was achieved when 4-pyridylalanine was introduced as the P3 residue. Compound 15 suppressed the progression of kidney fibrosis in a dose-dependent manner in a mouse model of unilateral ureteral obstruction. Thus, we demonstrated, for the first time, that potent and selective MMP-7 inhibitors could prevent the progression of kidney fibrosis.

Design, synthesis, and biological evaluation of quinoline-piperazine/pyrrolidine derivatives as possible antileishmanial agents

In pursuance of our efforts to expand the scope of novel antileishmanial entities, a series of thirty-five quinoline-piperazine/pyrrolidine, and other heterocyclic amine derivatives were synthesized via a molecular hybridization approach and examined against intracellular amastigotes of luciferase-expressing Leishmania donovani. The preliminary in vitro screening suggests that twelve compounds in the series exhibited better inhibition against amastigote form with good IC50 values ranging from 2.09 to 8.89 μM and lesser cytotoxicity in contrast to the standard drug miltefosine (IC50 9.25 ± 0.17 μM). Based on the satisfactory selectivity index (SI), two compounds were tested for in vivo leishmanicidal efficacy against Leishmania donovani/golden hamster model. Compounds 33 and 46 have shown significant inhibition of 56.32%, and 49.29%, respectively, in vivo screening at a daily dose of 50 mg/kg for 5 days. The pharmacokinetic results confirmed that 33 and 46 have satisfactory IP exposure with adequate parameters. Collectively, Compound 33 was identified as the most significant potential lead that could be employed as a prototype for future optimizations.

Design, synthesis, in vitro and in silico evaluation of novel substituted 1,2,4-triazole analogues as dual human VEGFR-2 and TB-InhA inhibitors

Cancer is a leading cause of death globally and has been associated with Mycobacterium tuberculosis (Mtb). The angiogenesis-related VEGFR-2 is a common target between cancer and Mtb. Here, we aimed to synthesize and validate potent dual human VEGFR-2 inhibitors as anticancer and anti-mycobacterial agents. Two series of 1,2,4-triazole-based compounds (6a-l and 11a-e) were designed and synthesized through a molecular hybridization approach. Activities of all synthesized compounds were evaluated against human VEGFR-2 in addition to drug-sensitive, multidrug-resistant and extensive-drug resistant Mtb. Compounds 6a, 6c, 6e, 6f, 6h, 6l, 11a, 11d and 11e showed promising inhibitory effect on VEGFR-2 (IC50 = 0.15 – 0.39 µM), anti-proliferative activities against cancerous cells and low cytotoxicity against normal cells. The most potent compounds (6e and 11a) increased apoptosis percentage. Additionally, compounds 6h, 6i, 6l and 11c showed the highest activities against all Mtb strains, and thus were evaluated against enoyl-acyl carrier protein reductase (InhA) which is essential for Mtb cell wall synthesis. Interestingly, the compounds showed excellent InhA inhibition activities with IC50 range of 1.3 – 4.7 µM. Docking study revealed high binding affinities toward targeted enzymes; human VEGFR-2 and Mtb InhA. In conclusion, 1,2,4-triazole analogues are suggested as potent anticancer and antimycobacterial agents via inhibition of human VEGFR-2 and Mtb InhA.

Discovery of new diaryl ether inhibitors against Mycobacterium tuberculosis targeting the minor portal of InhA

Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) affects 10 million people each year and the emergence of resistant TB augurs for a growing incidence. In the last 60 years, only three new drugs were approved for TB treatment, for which resistances are already emerging. Therefore, there is a crucial need for new chemotherapeutic agents capable of eradicating TB. Enzymes belonging to the type II fatty acid synthase system (FAS-II) are involved in the biosynthesis of mycolic acids, cell envelope components essential for mycobacterial survival. Among them, InhA is the primary target of isoniazid (INH), one of the most effective compounds to treat TB. INH acts as a prodrug requiring activation by the catalase-peroxidase KatG, whose mutations are the major cause for INH resistance. Herein, a new series of direct InhA inhibitors were designed based on a molecular hybridization approach. They exhibit potent inhibitory activities of InhA and, for some of them, good antitubercular activities. Moreover, they display a low toxicity on human cells. A study of the mechanism of action of the most effective molecules shows that they inhibit the biosynthesis of mycolic acids. The X-ray structures of two InhA/NAD+/inhibitor complexes have been obtained showing a binding mode of a part of the molecule in the minor portal, rarely seen in the InhA structures reported so far.

Acenaphthotriazine Thio-triazole Derivatives as Anti-cancer Agents Triggering Cell Cycle Arrest in Breast Cancer Cells

Background: Cancer is one of the most devastating diseases, affecting the lives of millions of people around the world. Introduction: A series of acenaphtho[1,2-e][1,2,4]triazine containing different thiomethyl-1,2,3-triazole derivatives were designed based on a fragment-based and molecular hybridization approach as anti-cancer agents. Methods: Designed compounds were synthesized using cycloaddition condensation followed by click reaction. Cytotoxicity of prepared compounds was evaluated by MTT reduction assay against four different cancer cell lines. Results: The biological evaluation indicated that derivative 6d with para-fluorobenzyl moiety was the most active cytotoxic agent with IC50 values of 70.1, 12.8, 41.5, and 16.0 μM against K562, MOLT-4, HT-29, and MCF-7 cells, respectively. Cell cycle analysis showed that acenaphtho triazine derivatives could induce G0/G1 phase arrest in MCF-7 breast cancer cells. Conclusion: Synthesized derivatives can be ideal candidates for further exploration as anti-cancer agents.

In Silico Development of Novel Benzofuran-1,3,4-Oxadiazoles as Lead Inhibitors of M. tuberculosis Polyketide Synthase 13.

Benzofuran and 1,3,4-oxadiazole are privileged and versatile heterocyclic pharmacophores which display a broad spectrum of biological and pharmacological therapeutic potential against a wide variety of diseases. This article reports in silico CADD (computer-aided drug design) and molecular hybridization approaches for the evaluation of the chemotherapeutic efficacy of 16 S-linked N-phenyl acetamide moiety containing benzofuran-1,3,4-oxadiazole scaffolds BF1-BF16. This virtual screening was carried out to discover and assess the chemotherapeutic efficacy of BF1-BF16 structural motifs as Mycobacterium tuberculosis polyketide synthase 13 (Mtb Pks13) enzyme inhibitors. The CADD study results revealed that the benzofuran clubbed oxadiazole derivatives BF3, BF4, and BF8 showed excellent and remarkably significant binding energies against the Mtb Pks13 enzyme comparable with the standard benzofuran-based TAM-16 inhibitor. The best binding affinity scores were displayed by 1,3,4-oxadiazoles-based benzofuran scaffolds BF3 (-14.23 kcal/mol), BF4 (-14.82 kcal/mol), and BF8 (-14.11 kcal/mol), in comparison to the binding affinity score of the standard reference TAM-16 drug (-14.61 kcal/mol). 2,5-Dimethoxy moiety-based bromobenzofuran-oxadiazole derivative BF4 demonstrated the highest binding affinity score amongst the screened compounds, and was higher than the reference Pks13 inhibitor TAM-16 drug. The bindings of these three leads BF3, BF4, and BF8 were further confirmed by the MM-PBSA investigations in which they also exhibited strong bindings with the Pks13 of Mtb. Moreover, the stability analysis of these benzofuran-1,3,4-oxadiazoles in the active sites of the Pks13 enzyme was achieved through molecular dynamic (MD) simulations at 250 ns virtual simulation time, which indicated that these three in silico predicted bio-potent benzofuran tethered oxadiazole molecules BF3, BF4, and BF8 demonstrated stability with the active site of the Pks13 enzyme.

New benzylidene festooned thiazolidinone-coumarin molecular hybrids targeting Human Breast adenocarcinoma cells: Design, synthesis, SAR, molecular Modelling and biological evaluation as CDK2 inhibitors

Novel benzylidene-coumarin bearing thiazolidinone derivatives (5a-5j) are synthesized by coupling methodology using 7-(3-Chloro-propoxy)-4-methyl-chromen-2-one and substituted benzylidine-thiazolidine-2,4-one. The synthesized novel thiazolidinone-coumarin derivatives in the structure-based molecular hybridization approach are screened to learn their in-vitro cytotoxicity against the Human Breast cancer cells (MCF-7). Spectroscopic studies and elemental analysis were used to characterize the synthesized compounds. IC50 values (15.7 and 12.15 µg/ml) obtained from cytotoxicity studies against MCF-7 cancer cell lines indicate higher kinase inhibitory activities of compounds 5a and 5j among the synthesized derivatives which are on par to that of standard doxorubicin (7.50 µg/ml). Molecular docking simulation shows the involvement of CDK2 protein in the formation of three conventional hydrogen bonds with compound 5j. Superior LibDock score (145.146 kcal/mol) and -62.687 kcal/mol as a binding energy were due to 5j docked complex in its finest conformation with CDK2 protein. Finally, we discovered that these new scaffolds of 5-(benzylidene)-3-[3-(4-methyl-2-oxo-2H-chromen-7-yloxy)-propyl] thiazolidine-2,4-dione result in expedient compounds towards the treatment of cancer in upcoming days.