Our previous work identified isoxazole-based chalcones and their dihydropyrazole derivatives as two important five-membered heterocycles having antitubercular activity. Hence, in the present study, ...we biologically evaluated 30 compounds, including 15 isoxazole ring-containing chalcones (
-
) and 15 dihydropyrazoles (
-
) derived from these chalcones for their antimicrobial, antioxidant, and anticancer activities. Chalcones exhibited superior antibacterial and antioxidant activities compared to dihydropyrazoles. Among the chalcones, compound
showed potent antibacterial (MIC = 1 µg/mL) and antioxidant activities (IC
= 5 ± 1 µg/mL). Dihydropyrazoles, on the contrary, demonstrated remarkable antifungal and anticancer activities. Compound
(IC
= 2 ± 1 µg/mL) showed excellent antifungal activity whereas two other dihydropyrazoles
(IC
= 2 ± 1 µg/mL) and
(IC
= 4 ± 1 µg/mL) exhibited potential anticancer activity. The compounds were also tested for their toxicity on normal human cell lines (LO2) and were found to be nontoxic. The active compounds that have emerged out of this study are potential lead molecules for the development of novel drugs against infectious diseases, oxidative stress, and cancer.
Abstract
Tuberculosis (TB) is one of the emerging infectious diseases in the world. DprE1 (Decaprenylphosphoryl-β-
d
-ribose 2′-epimerase), an enzyme accountable for mycobacterial cell wall synthesis ...was the first drug gable target based on discoveries of inhibitors via HTS (high throughput screening). Since then, many literature reports have been published so far enlightening varieties of chemical scaffolds acting as inhibitors of DprE1. Herein, in our present study, we have developed statistically robust GA-MLR (genetic algorithm multiple linear regression), atom-based as well as field based-3D-QSAR models. Both atom-based as well as field based-3D-QSAR models (internally as well as externally validated) were obtained with robust Training set, R
2
> 0.69 and Test set, Q
2
> 0.50. We have also developed top ranked 5 point hypothesis AAAHR_1 among 14 CPHs (common pharmacophore hypotheses). We found that our dataset molecule had more docking score (XP mode = − 9.068 kcal/mol) than the standards isoniazid and ethambutol; when docked into binding pockets of enzyme 4P8C with Glide module. We further queried our best docked dataset molecule 151 for ligand based virtual screening using “
SwissSimilarity
” platform. Among 9 identified hits, we found ZINC12196803 had best binding energies and docking score (docking score = − 9.437 kcal/mol, MMGBSA dgBind = − 70.508 kcal/mol). Finally, our molecular dynamics studies for 1.2–100 ns depicts that these complexes are stable. We have also carried out in-silico ADMET predictions, Cardiac toxicity, ‘SwissTargetPredictions’ and Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) binding energy calculations for further explorations of dataset as well as hit molecules. Our current studies showed that the hit molecule ZINC12196803 may enlighten the path for future developments of DprE1 inhibitors.
Methicillin-resistant Staphylococcus aureus (MRSA) is becoming dangerous to human beings due to easy transmission mode and leading to the difficult-to-treat situation. The rapid resistance ...development of MRSA to many approved antibiotics is of major concern. There is a lot of scope to develop novel, efficient, specific, and nontoxic drug candidates to fight against MRSA isolates. The interesting molecular structure and adaptable feature of oxadiazole moiety which are bioisosteres of esters and amides, and these functional groups show improved resistance to esterases mediated hydrolytic cleavage, attracting researchers to develop required novel antibiotics based on oxadiazole core. This review summarizes the developments of oxadiazole-containing derivatives as potent antibacterial agents against multidrug-resistant MRSA strains and discussing the structure-activity relationship (SAR) in various directions. The current survey is the highlight of the present scenario of oxadiazole hybrids on MRSA studies, covering articles published from 2011 to 2020. This collective information may become a good platform to plan and develop new oxadiazole-based small molecule growth inhibitors of MRSA with minimal side effects.
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•1,3,4- and 1,2,4-oxadiazole derivatives displayed potent antibacterial activity against tested MRSA strains.•Structure-activity relationship is explained in detail.•Oxadiazole-based analogs exhibited excellent antibacterial activity with different action of mechanism.•Substituents with different electronic effect played crucial role in altering the efficacy of the tested compounds.
Compounds bearing thiazole and chalcone pharmacophores have been reported to possess excellent antitubercular and anticancer activities. In view of this, we designed, synthesized and characterized a ...novel series of thiazole-chalcone hybrids (
-
) and further evaluated them for antitubercular and antiproliferative activities by employing standard protocols. Among the twenty compounds, chalcones
and
, containing 2,4-difluorophenyl and 2,4-dichlorophenyl groups, showed potential antitubercular activity higher than the standard pyrazinamide (MIC = 25.34 µM) with MICs of 2.43 and 4.41 µM, respectively. Chalcone
containing heteroaryl 2-thiazolyl moiety exhibited promising antiproliferative activity against the prostate cancer cell line (DU-145), higher than the standard methotrexate (IC
= 11 ± 1 µM) with an IC
value of 6.86 ± 1 µM. Furthermore, cytotoxicity studies of these compounds against normal human liver cell lines (L02) revealed that the target molecules were comparatively less selective against L02. Additional computational studies using AutoDock predicted the key binding interactions responsible for the activity and the SwissADME tool computed the in silico drug likeliness properties. The lead compounds generated through this study, create a way for the optimization and development of novel drugs against tuberculosis infections and prostate cancer.
A series of newer previously synthesized fluorinated chalcones and their 2-amino-pyridine-3-carbonitrile and 2-amino-4H-pyran-3-carbonitrile derivatives were screened for their in vitro ...antitubercular activity and in silico methods. Compound 40 (MIC~ 8 μM) was the most potent among all 60 compounds, whose potency is comparable with broad spectrum antibiotics like ciprofloxacin and streptomycin and three times more potent than pyrazinamide. Additionally, compound 40 was also less selective and hence non-toxic towards the human live cell lines-LO2 in its MTT assay. Compounds 30, 27, 50, 41, 51, and 60 have exhibited streptomycin like activity (MIC~16-18 μM). Fluorinated chalcones, pyridine and pyran derivatives were found to occupy prime position in thymidylate kinase enzymatic pockets in molecular docking studies. The molecule 40 being most potent had shown a binding energy of -9.67 Kcal/mol, while docking against thymidylate kinase, which was compared with its in vitro MIC value (~8 μM). These findings suggest that 2-aminopyridine-3-carbonitrile and 2-amino-4H-pyran-3-carbonitrile derivatives are prospective lead molecules for the development of novel antitubercular drugs.
Cutaneous wounds pose a significant health burden, affecting millions of individuals annually and placing strain on healthcare systems and society. Nanofilm biomaterials have emerged as promising ...interfaces between materials and biology, offering potential for various biomedical applications. To explore this potential, our study aimed to assess the wound healing efficacy of amniotic fluid and
-loaded nanoclay films by using in vivo models. Additionally, we investigated the antioxidant and antibacterial properties of these films. Using a burn wound healing model on rabbits, both infected and non-infected wounds were treated with the nanoclay films for a duration of twenty-one days on by following protocols approved by the Animal Ethics Committee. We evaluated wound contraction, proinflammatory mediators, and growth factors levels by analyzing blood samples. Histopathological changes and skin integrity were assessed through H&E staining. Statistical analysis was performed using SPSS software (version 2; Chicago, IL, USA) with significance set at
< 0.05. Our findings demonstrated a significant dose-dependent increase in wound contraction in the 2%, 4%, and 8% AMF-
treatment groups throughout the study (
< 0.001). Moreover, macroscopic analysis revealed comparable effects (
> 0.05) between the 8% AMF-
treatment group and the standard treatment. Histopathological examination confirmed the preservation of skin architecture and complete epidermal closure in both infected and non-infected wounds treated with AMF-
-loaded nanofilms. RT-PCR analysis revealed elevated concentrations of matrix metalloproteinases (MMPs) and vascular endothelial growth factor (VEGF), along with decreased levels of tumor necrosis factor-alpha (TNF-α) in AMF-
-loaded nanofilm treatment groups. Additionally, the antimicrobial activity of AMF-
-loaded nanofilms contributed to the decontamination of the wound site, positioning them as potential candidates for effective wound healing. However, further extensive clinical trials-based studies are necessary to confirm these findings.
Molecular hybridization (MH) of heterocyclic rings has enabled scientists to design and develop novel drugs and drug-like candidates. In our previous work, considering the importance of MH, we ...synthesized different kinds of chloropyrazine-tethered pyrimidine derivatives (22–40) containing either substituted phenyl or heteroaryl rings at position-6 of the pyrimidine ring and evaluated their antitubercular activity. Herein, we report the antimicrobial and antiproliferative activities of 22–40. The antiproliferative activity of the target hybrids was superior to the antimicrobial activity. However, some compounds showed greater antimicrobial activity than the standard drugs. For instance, among the nineteen derivatives, compound 31 containing a 2″,4″-dichlorophenyl ring, showed the most potent antibacterial and antifungal activities (MIC 45.37 µM), followed by compounds 25 and 30 bearing 4″-nitrophenyl and 2″,4″-difluorophenyl scaffolds with minimum inhibitory concentrations (MIC) values of 48.67 µM and 50.04 µM, respectively. Compound 35, containing a bioisosteric 2″-pyridinyl ring, showed the most potent antiproliferative activity against the prostate cancer cell line (DU-145) with an IC50 value of 5 ± 1 µg/mL. Additional testing of compounds 22–40 on human normal liver cells (LO2) indicated that the compounds were more selective to cancer cell lines over normal cells. Further, molecular docking of the most potent compound 35 against dihydrofolate reductase (DHFR) (PDB ID: 1U72) had a good binding affinity with a docking score of −6.834. The SwissADME program estimated the drug-likeness properties of compound 35. Hybrid 35 is a potential lead molecule for the development of new anticancer drugs, whereas 31 is a promising antimicrobial lead candidate.
Infectious diseases caused by fungi and mycobacteria pose an important problem for humankind. Similarly, cancer is one of the leading causes of death globally. Therefore, there is an urgent need for ...the development of novel agents to combat the deadly problems of cancer, tuberculosis, and also fungal infections. Hence, in the present study, we designed, synthesized, and characterized 30 compounds including 15 chalcones (
-
) and 15 dihydropyrazoles (
-
) containing dichlorophenyl moiety and also screened these compounds for their antifungal, antitubercular, and antiproliferative activities. Among these compounds, the dihydropyrazoles showed excellent antifungal and antitubercular activities whereas the chalcones exhibited promising antiproliferative activity. Among the dihydropyrazoles, compound
containing 2-thienyl moiety showed promising antifungal activity (MIC 5.35 µM), whereas compounds
and
containing 2,4-difluorophenyl and 4-trifluoromethyl scaffolds revealed significant antitubercular activity with the MICs of 3.96 and 3.67 µM, respectively. Compound
containing 2-thienyl moiety in the chalcone series showed the highest anti-proliferative activity with an IC
value of 17 ± 1 µM. The most active compounds identified through this study could be considered as starting points in the development of drugs with potential antifungal, antitubercular, and antiproliferative activities.
Cancer is a life-threatening disease and is the second leading cause of death worldwide. Although many drugs are available for the treatment of cancer, survival outcomes are very low. Hence, rapid ...development of newer anticancer agents is a prime focus of the medicinal chemistry community. Since the recent past, computational methods have been extensively employed for accelerating the drug discovery process. In view of this, in the present study we performed 2D-QSAR (Quantitative Structure-Activity Relationship) analysis of a series of compounds reported with potential anticancer activity against breast cancer cell line MCF7 using QSARINS software. The best four models exhibited a
value of 0.99. From the generated QSAR equations, a series of pyrimidine-coumarin-triazole conjugates were designed and their MCF7 cell inhibitory activities were predicted using the QSAR equations. Furthermore, molecular docking studies were carried out for the designed compounds using AutoDock Vina against dihydrofolate reductase (DHFR), colchicine and vinblastine binding sites of tubulin, the key enzyme targets in breast cancer. The most active compounds identified through these computational studies will be useful for synthesizing and testing them as prospective novel anti-breast cancer agents.
Despite the availability of many drugs to treat infectious diseases, the problems like narrow antimicrobial spectrum, drug resistance, hypersensitivities and systemic toxicities are hampering their ...clinical utility. Based on the above facts, in the present study, we designed, synthesized and evaluated the antibacterial and antifungal activity of novel fluorinated compounds comprising of chalcones bearing trifluoromethyl (
-
) and trifluoromethoxy (
-
) substituents. The compounds were characterized by spectroscopic techniques and evaluated for their antimicrobial activity against four pathogenic Gram-positive (
and
) and Gram-negative (
and
) bacterial and fungal (
and
) strains. In this study, the compounds with trifluoromethoxy group were more effective than those with trifluoromethyl group. Among the 20 fluorinated chalcones, compound
/
bearing an indole ring attached to the olefinic carbon have been proved to possess the most antimicrobial activity compared to the standard drugs without showing cytotoxicity on human normal liver cell line (L02). Further, the minimum inhibitory concentration (MIC) for
/
was determined by serial tube dilution method and showed potential activity. These results would provide promising access to future study about the development of novel agents against bacterial and fungal infections.
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