Pyrido[1,2‐a]pyrimidin‐4‐ones: Ligand‐based Design,Synthesis, and Evaluation as an Anti‐inflammatory Agent

In the present study, a series of novel pyrido[1,2‐a]pyrimidin‐4‐one derivatives ( 1 – 45 ) were synthesized, characterized, and evaluated for their anti‐inflammatory activity. The structures of all newly synthesized compounds were confirmed by ¹H NMR, ¹³C NMR, mass spectroscopy, and C, H, and N analyses. Preliminary these newly synthesized compounds were evaluated for their in vitro cyclooxygenase (COX)‐2/COX‐1 inhibitory activity. The celecoxib, a COX‐2 inhibitor, was used as a reference standard drug. In this inhibitory study, compounds 42 , 43 , 44 , and 45 were found to have significant in vitro inhibitory profile as compared with the reference drug. These compounds were then subjected to their in vivo anti‐inflammatory assay by using carrageenan‐induced rat paw edema method in next level of screening. Later, these same compounds were tested for their ulcerogenic property. Based on these activity data, the compound 43 (in vitro COX‐2 activity—IC₅₀ = 0.4 μM, SI = 400, in vivo anti‐inflammatory activity—72% inhibition after 3 h, and 0.38%—Ulcer index) was emerged as most promising anti‐inflammatory agent with very low ulcerogenic action.     

Novel arylpyridine‐based 1,3,4‐oxadiazoles: Synthesis,antibacterial, and anti‐inflammatory evaluation

In view of developing novel bioactive compounds, a series of 2‐(5‐[2‐methyl‐6‐arylpyridin‐3‐yl]‐1,3,4‐oxadiazol‐2‐ylthio)‐1‐arylethanones (6a–n) were designed and synthesized in good yield. Novel compounds were evaluated for their antibacterial and anti‐inflammatory activities. All synthesized compounds were screened for their antibacterial activity against Staphylococcus aureus, Bascillus subtilis, Eschericia coli, and Pseudomonas aeruginosa strains. Compounds 6a , 6b , 6c , 6h , and 6i displayed the highest antibacterial activity with minimal inhibitory concentration (MIC) values ranging from 6.25–12.5 μg/mL in comparison with the standard Ciprofloxacin. The results of anti‐inflammatory activity of carrageenan‐induced footpad edema assay indicated that tested compounds exhibited remarkable anti‐inflammatory activity with percentage of inhibition of 63.9–70.1% (potency 96.8–106.20% of indomethacin activity) after 3 hr. Particularly, 6c – e and 6j – l were found to be excellent inhibitors of inflammation, with potential higher than that of the standard, Indomethacin.     

An Organocatalyzed Efficient One‐pot Synthesis,Biological Evaluation,and Molecular Docking Studies of 4,4′‐(Arylmethylene)bis‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ols)

The synthesis of 4,4′‐(arylmethylene)bis‐(3‐methyl‐1‐phenyl‐1H‐pyrazol‐5‐ol) derivatives catalyzed by ʟ‐proline is a simple, versatile, and efficient method. In vitro antioxidant, anti‐inflammatory, and antimicrobial activities of compounds 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j were studied. Furthermore, to rationalize the observed anti‐inflammatory activity data, molecular docking study has been performed against COX‐2 enzyme which revealed a good binding affinity for these molecules and could provide an insight into the various bonded and non‐bonded interactions guiding their binding affinity.     

Synthesis,Characterization and Biological Evaluation of a Novel Series of 1,2,4‐Triazolo‐[3,4‐b]‐1,3,4‐thiadiazines Containing an Amide Linkage

Two series of combinatorial library of 3,6‐disubstituted‐7H‐1,2,4‐triazolo‐[3,4‐b]‐1,3,4‐thiadiazines bearing an amide linkage were synthesized. All the newly synthesized compounds were characterized by spectral analyses. The newly synthesized compounds were screened for their cytotoxicity, anti‐inflammatory, and analgesic activities. Among the tested compounds, the compound 9g (Ar = 4‐(methoxybenzyl)piperazine) is the most promising molecule with half maximal inhibitory concentration (IC₅₀) value of 14.24 μM in (MCF‐7) cells. Compounds 9f (Ar = 4‐(chlorobenzyl)piperazine), 9g , and 9k (Ar = 2‐(fluorophenyl)piperazine) exhibited excellent anti‐inflammatory activity at a dose level of 50 mg/kg, almost comparable with the standard drug. In case of analgesic activity among the tested compounds, the compounds 9f , 9g , and 9k showed more potent and consistent activity in both 100 and 200 mg/kg/po doses with less ulcerogenic risk.     

A Facial Synthesis and Anticancer Activity of (Z)‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted Acid

In order to explore the anticancer and antimicrobial activity associated with the thiazole framework, we synthesized the new series (Z )‐2‐((5‐(4‐nitrobenzylidene)‐4‐oxo‐4,5‐dihydrothiazol‐2‐yl)amino)‐substituted acid derivatives 6a – l . All the synthesized compounds were evaluated for anticancer and antimicrobial activity in vitro. Among these, the compounds 6a , 6b, 6c , 6e , 6f , 6g , 6h , 6i , 6j , and 6k showed highest antibacterial and antifungal activity. The compound 6a exhibited significant antibacterial activity against Bacillus subtilis , whereas compound 6j displays significant antifungal activity against fungal strains, that is, A. oryzae . The in vitro anticancer studies revealed that 6e , 6g , 6h , 6k , and 6l are the most active compounds against MCF‐7 and BT‐474 human breast cancer cell lines, which can be regarded as the promising drug candidate for development of anticancer drugs.     

Synthesis,Characterization, and Anti‐inflammatory Activity of Novel Isoxazolyl‐4‐(2‐oxo‐2,3‐dihydro‐1H‐3‐indolyl)pyrrole‐3‐carboxylates

A series of novel isoxazolyl‐4‐(2‐oxo‐2,3‐dihydro‐1H‐3‐indolyl)pyrrole‐3‐carboxylates ( 17a – i) were synthesized by a three‐component reaction of 4‐amino‐3‐methyl‐5‐styrylisoxazole 14 , β‐keto ester 15 , and 3‐phenacylideneoxindole 16 , in the presence of CAN catalyst in ethanol. The structures of the synthesized compounds have been established on the basis of spectral and analytical data. The title compounds 17a – i were evaluated for their anti‐inflammatory activity. Compounds 17b and 17c exhibited potent anti‐inflammatory activity as that of standard drug.     

Facile Synthesis of Novel 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one Derivatives as Potential Anticancer Agents

A series of 3‐(4‐phenylisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 6a – l ) derivatives has been efficiently synthesized by straightforward sequential reactions. Tandem Vilsmeier Hack reaction/cyclization/bromination/Suzuki cross‐coupling reactions were successfully applied to the preparation of title compounds in good‐to‐high yields. In the synthetic sequences, 3‐chloro‐3‐(2‐oxo‐2H‐chromen‐3‐yl)acrylaldehydes ( 2 ) were found to react with ammonium thiocyanate to yield the corresponding 3‐(isothiazol‐5‐yl)‐2H‐chromen‐2‐ones ( 3 ). These derivatives were brominated with N‐bromo succinamide to yield the corresponding regioselective 3‐(4‐bromoisothiazol‐5‐yl)‐2H‐chromen‐2‐one ( 4 ). Finally, compound 4 was treated with various phenyl/pyrazole/7H –pyrrolo[2,3‐d]pyrimidinyl boronic acids 5a – l in the presence of K₂CO₃ and Pd catalyst in dimethylformamide to yield the corresponding title derivatives 6a – l . All the synthesized compounds were characterized by analytical and spectral studies. All the final compounds were screened against different cancer cell lines (A549, PC3, SKOV3, and B16F10), and among these compounds, 6b , 6g , 6h , and 6l displayed moderate cytotoxic activity against the tested cell lines.     

Synthesis and Biological Evaluation of 2‐substituted‐6‐(morpholinyl/piperidinyl)pyridazin‐3(2H)‐ones as Potent and Safer Anti‐inflammatory and Analgesic Agents

A series of 2‐substituted‐6‐(morpholinyl/piperidinyl)pyridazin‐3(2H )‐ones was synthesized and the structures were established using various spectroscopic techniques. The target compounds were screened for anti‐inflammatory and analgesic activities at 20 and 40 mg/kg. The safety of the synthesized derivatives was evaluated by assessing anti‐platelet activity and ulcer index. The obtained pharmacological data revealed that 6‐morpholinyl derivatives 4a–12a were found to be somewhat more potent than 6‐piperidinyl derivatives 4b–6b. The 6‐morpholinyl substituted pyridazinone 12a exhibited maximum anti‐inflammatory and analgesic activities. Homoveratrylamine substituted compounds 6a and 6b emerged as promising leads in both the series with good anti‐inflammatory and analgesic activities without any ulcerogenicity. Anti‐platelet activity results of the compounds of both the series showed significantly low bleeding time in comparison with standard drug aspirin indicating the cardiovascular safety of new pyridazinones.     

Design,Synthesis, and Bioactivity Evaluation of Novel 3‐(Substituted Phenoxy)‐6‐Methyl‐4‐(3‐Trifluoromethylphenyl) Pyridazine Derivatives

Using 3‐(4‐cyano phenoxy)‐6‐methyl‐4‐(3‐trifluoromethylphenyl) pyridazine (compound A ) as a leading compound, a total of 24 novel 3‐(substituted phenoxy)‐6‐methyl‐4‐(3‐trifluoromethylphenyl) pyridazine derivatives containing two electron‐withdrawing groups on the benzene ring (acylamine and oxime ether) were synthesized. Their herbicidal, insecticidal activities were bioassayed, and the herbicidal activity of compound CD-2 against Brassica campestris was 97.6% at 300 g/ha, which was better than the commercial herbicide diflufenican at the this concentration and is equal to the activity of the leading compound A . Compound CD-4 , CD-5 , CJ-3 , and CJ-5 displayed excellent insecticidal activity against Aphis laburni Kaltenbach (>95%). The results show that the oxime ether substitutions exhibit better bleaching and herbicidal activity than the acylamine ones. The bleaching and herbicidal activity of para‐position substitutions is better than the meta‐position ones. It seems that the para‐position on the benzene ring of oxime ether pyridazine derivatives is one of the key active sites that affect their herbicidal activities.     

Synthesis and Biological Activity of Ethyl 4‐Alkyl‐2‐(2‐(substituted phenoxy)acetamido)thiazole‐5‐carboxylate

A series of novel ethyl 4‐(methyl or trifluoromethyl)‐2‐(2‐(substituted phenoxy)acetamido)thiazole‐5‐carboxylates 7a , 7b , 7c , 7d , 7e and 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p , 8q , 8r were synthesized, and their structures were confirmed by IR, ¹H‐NMR, MS spectra and elemental analysis. The results of preliminary bioassays show that some of the title compounds exhibit moderate to good herbicidal activities. Compared with the fluorine free compounds 7a , 7b , and 7e , the compounds bearing fluorine 8g , 8j , and 8q showed higher herbicidal activities with 70–100% inhibition against Capsella bursa‐pastoris, Amaranthus restroflexus, and Eclipta prostrata at the dosage of 150 g/ha, which indicated that the trifluoromethyl on the thiazole ring was beneficial for the herbicidal activity. Furthermore, compounds 8f , 8g , 8h , 8i , 8j , 8k , 8l , 8m , 8n , 8o , 8p , 8q , 8r were tested for fungicidal activity against Pseudoperonospora cubensis at 500 µg/mL. Compounds 8f and 8q showed the best fungicidal activity with more than 80% inhibition.     

Synthesis and Fungicidal Activity of (E)‐5‐[1‐(2‐Oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐4‐one Derivatives

The novel fungicidal agents, (E )‐5‐[1‐(2‐oxo‐1‐oxaspiro[4,5]dec/non‐3‐en‐3‐yl)ethylidene]‐2‐aminoimidazolin‐ 4‐one derivatives, were designed and synthesized in moderate to excellent yields in four steps using α ‐hydroxyketone and diketene as raw materials and characterized by HR‐ESI‐MS , ¹H NMR and X‐ray diffraction. The preliminary bioassay showed that some of these compounds, such as 5e , 6a , 6e , and 7 h exhibit 87.8%, 91.3%, 89.9% and 87.8% inhibition rates against Sclerotinia scleotiorum , 3b , 3c , 4c and 7 h exhibit 96.4%, 92.5%, 90.3% and 76.9% inhibition rates against Phytophthora capsici at the concentration of 50 µg/mL , respectively. These compounds exhibited significant fungicidal activities against S. scleotiorum and P. capsici with EC₅₀ values of 2.56–11.60 µg/mL , and compounds 6e and 7 h exhibited weak inhibition against the spore germination of S. scleotiorum , while the spore germination of P. capsici was strongly inhibited by compound 7 h solution. Scanning electron microscopy (SEM ) and transmission electron microscopy (TEM ) observation indicated that compound 7 h had a significant impact on the structure and function of the hyphal cell wall of P. capsici mycelium.     

Synthesis and biological evaluation of several 3‐(coumarin‐4‐yl)tetrahydroisoxazole and 3‐(coumarin‐4‐yl)dihydropyrazole derivatives

A series of novel 3‐(coumarin‐4‐yl)tetrahydroisoxazoles 5a,b, 7, 9 and 3‐(coumarin‐4‐yl)dihydropyra‐zoles 13a‐d, 14,15a,b were synthesized from coumarin‐4‐carboxaldehyde 1 via the intermediate N‐methyl nitrone 3 and N‐phenyl or N‐methyl hydrazones 11a,b . These coumarin derivatives were isolated, characterized and evaluated in vitro for their ability to inhibit trypsin, β‐glucuronidase, soybean lipoxygenase and to interact with the stable radical 1,1‐diphenyl‐2‐picrylhydrazyl. The compounds were tested in vivo as anti‐inflammatory agents in the rat carrageenin paw edema assay. Compound 15a seems to be a lead molecule to be modified in order to improve the lipoxygenase inhibition. The results are discussed in terms of structural characteristics.     

Synthesis and antimicrobial activity of novel 2‐(aryl)‐3‐[5‐(2‐oxo‐2H‐3‐chromenyl)‐1,3‐oxazol‐2‐yl]‐1,3‐thiazolan‐4‐ones

A series of novel 2‐(aryl)‐3‐[5‐(2‐oxo‐2H‐3‐chromenyl)‐1,3‐oxazol‐2‐yl]‐1,3‐thiazolan‐4‐ones 4a , 4b , 4c , 4e , 4f , 4g , 4h , 4i , 4j have been synthesized and assayed for their antibacterial activity against Gram‐positive bacteria viz. Bacillus subtilis (ATCC 6633), Staphylococcus aureus (ATCC 6538p), Micrococcus luteus (IFC 12708), and Gram‐negative bacteria viz. Proteus vulgaris (ATCC 3851), Salmonella typhimurium (ATCC 14028), Escherichia coli (ATCC 25922), and also antifungal activity against Candida albicans (ATCC 10231), Aspergillus fumigatus (HIC 6094), Trichophyton rubrum (IFO 9185), and Trichophyton mentagrophytes (IFO 40996). Among the screened compounds, 4d , 4e , 4f , 4g , and 4j exhibited potent inhibitory activity compared with the standard drug at the tested concentrations. The results reveal that, the presence of difluorophenyl in 4f and pipernyl ring in 4j at 2‐position of thiazolidine‐4‐one ring show significant inhibitory activity. The other compounds also showed appreciable activity against the test bacteria and fungi and emerged as potential molecules for further development. J. Heterocyclic Chem., 2011.     

Microwave‐Assisted Synthesis and Antituberculosis Screening of Some 4‐((3‐(Trifluoromethyl)‐5,6‐dihydro‐[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐l)methyl)benzenamine Hybrids

In the present investigation, a series of 4‐((3‐(trifluoromethyl)‐5,6‐dihydro‐[1,2,4]triazolo[4,3‐a]pyrazin‐7(8H)‐yl)methyl)benzenamine analogs 6a–o were synthesized and characterized by IR, NMR (¹H and ¹³C), and mass spectra. All newly synthesized compounds 6a–o were prepared under conventional and microwave irradiation methods. These compounds obtained in higher yields and in shorter reaction times in the microwave irradiation method when compared with the conventional method. Synthesized compounds 6a–o were inspected for their in vitro antitubercular activity against Mycobacterium tuberculosis H₃₇Ra using an established XTT reduction menadione assay. Among the screened compounds, 6i (IC₅₀: 1.82 μg/mL), 6j (IC₅₀: 1.02 μg/mL), and 6k (IC₅₀: 1.59 μg/mL) showed excellent activity. Furthermore, compound 6i showed MIC₉₀ value of 16.02 μg/mL. In summary, the results indicate the identification of some novel, selective, and specific inhibitors against M. tuberculosis that can be explored further for the potential antitubercular drug.     

Synthesis and biological evaluation of new 4‐(4‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)phenyl)‐2‐phenylthiazole derivatives

A novel series of 4‐(4‐(1‐benzyl‐1H‐1,2,3‐triazol‐4‐yl)phenyl)‐2‐substitutedthiazole derivatives ( 8a‐l) have been synthesized by [3 + 2] cycloaddition reaction of 4‐(4‐ethynylphenyl)‐2‐substitutedthiazole with substituted benzyl azide in aqueous DMF. Starting compounds 4‐(4‐ethynylphenyl)‐2‐substitutedthiazole ( 6a‐d ) were synthesized by reaction of 4‐(2‐substitutedthiazol‐4‐yl)benzaldehyde with Ohira‐Bestmann reagent in methanol. The structures of these novel triazole‐thiazole clubbed derivatives were confirmed by the spectral analysis. The title compounds ( 8a‐l ) were tested for antimycobacterial activity against Mycobacterium tuberculosis H37Ra active and dormant (MTB, ATCC 25177) and antimicrobial activity against standard Gram‐positive bacteria, Staphylococcus aureus (NCIM 2602) and Bacillus subtilis (NCIM 2162), and Gram‐negative bacteria, Escherichia coli (NCIM 2576) and Pseudomonas flurescence (NCIM 2059). Compounds 8a , 8b , 8c , and 8h reported good activity against B subtilis, compounds 8a , 8b , and 8c showed good activity against S aureus, and compound 8b showed good activity against dormant M tuberculosis H37Rv strain. Compounds 8b and 8c found more potent against Gram positive and dormant M tuberculosis H37Rv strains. These novel triazole‐thiazole clubbed analogues found to be a capable leads for further optimization and development.     

Synthesis of (E)‐5‐Methoxy‐2‐styryl‐4‐pyrones as Potent Growth‐Inhibitory Agents Against Hepatocellular Carcinoma Cells

The present study a series of (E)‐5‐methoxy‐2‐styryl‐4H‐pyran‐4‐ones 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j was synthesized and evaluated for growth inhibitory inhibition against carcinoma cells. The growth inhibition study of eight carcinoma cell lines was examined and demonstrated that SKHep cells exhibit significant structure‐activity relationship in response to the tested compounds. Among them, 6f showed the most potent activity against SKHep, A549, AGS, and H460 cell lines with GI₅₀ values of 0.17, 8.3, 3.6, 8.0 μM, respectively.     

Design,Synthesis, and Herbicidal Activities of 3‐Aryl‐4‐substituted‐5‐[3‐(trifluoromethyl)phenoxy]‐1,2,4‐triazoles

In order to find novel bleaching herbicide lead compounds, a series of novel 3‐aryl‐4‐substituted‐5‐[3‐(trifluoromethyl)phenoxy]‐1,2,4‐triazoles were designed and synthesized by the multi‐step reactions. N‐(Arylformamido)phenylthioureas undergo ring closure in the presence of sodium hydroxide to generate 3‐aryl‐4‐substituted‐4H‐[1,2,4]triazol‐5‐thiols 1 , which reacted with methyl sulfate in the presence of K₂CO₃ to give 3‐aryl‐5‐methylsulfanyl‐4‐substituted‐4H‐[1,2,4]triazoles 2 . The target compounds 4 were synthesized by the oxidation of 2 in the presence of H₂O₂ and Na₂WO₄, followed by the substitution with 3‐(trifluoromethyl)phenol in moderate to good yields. Their structures were confirmed by IR, ¹H NMR, EI–MS, and elemental analyses. The preliminary bioassay indicated that some of them displayed moderate to good selective herbicidal activity against Brassica campestris L at the concentration of 100 µg/mL. Compounds 4c and 4i possessed 75.0% and 82.6% inhibition against Brassica campestris L at the concentration of 100 µg/mL. However, the target compounds 4 showed weak herbicidal activity against Echinochloa crus‐galli at the concentration of 100 and 10 µg/mL.     

Synthesis,Characterization, and Antimicrobial Screening of 4″‐methyl‐2,2″‐diaryl‐4,2′:4′,5″‐terthiazole Derivatives

A series of novel 4″‐methyl‐2,2″‐diaryl‐4,2′:4′,5″‐terthiazole ( 8a‐p ) derivatives has been synthesized and screened for antibacterial activity against four pathogenic bacteria, Escherichia coli, Pseudomonas flurescence, Staphylococcus aureus, and Bacillus subtilis. Among them, compounds 8a and 8j exhibited excellent antibacterial activity with minimum inhibitory concentration range of 1.0 to 5.3 μg/mL and compounds 8m and 8p exhibited moderate to good antibacterial activity with minimum inhibitory concentration range of 16.9 to 29.7 μg/mL against all tested strains. All the synthesized compounds were screened for their in vitro antifungal activity against Cocinida candida. Most of the compounds reported moderate antifungal activity. This study provides valuable directions to our ongoing endeavor of rationally designing more potent antimicrobial agent.     

Glycerol Mediated Synthesis,Biological Evaluation,and Molecular Docking Study of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines as Potent Antitubercular Agents

A series of 4‐(1H‐pyrazol‐4‐yl)‐polyhydroquinolines were synthesized through one‐pot four‐component Hantzsch condensation of 1,3‐diphenyl‐1H‐pyrazole‐4‐carbaldehydes, ammonium acetate, dimedone, and alkyl acetoacetate in glycerol as a green reaction medium. The structures of the compounds are verified by spectroscopic methods and screened for their antimicrobial activity against Mycobacterium tuberculosis H37RV strain. Almost all the synthesized derivatives reveal excellent antitubercular activity based on minimum inhibitory concentration. Especially the compounds 5h and 5k exhibit outstanding antitubercular activity with minimum inhibitory concentration 1.6 μg/mL. In addition, molecular docking study of synthesized scaffolds against enoyl‐acyl carrier protein reductase from M. tuberculosis was performed to propose the binding modes.     

Synthesis and Antimicrobial Activity of Some Novel [4‐(1,2,3‐thiadiazol‐4‐yl)phenoxy]methylene anchored 1,3,4‐triazoles and 1,3,4‐thiadiazoles

A series of novel [4‐(1,2,3‐thiadiazol‐4‐yl)phenoxy]methylene anchored 1,3,4‐triazoles ( 8a , 8b , 8c , 8d , 8e , 8f , 8g , 8h ) and 1,3,4‐thiadiazoles ( 9a , 9b , 9c , 9d , 9e , 9f , 9g , 9h , 9i ) were synthesized from thiosemicarbazide ( 7a , 7b , 7c , 7d , 7e , 7f , 7g , 7h , 7i , 7j ). The structures of these newly synthesized compounds were confirmed on the basis of IR, ¹H‐NMR, mass spectral techniques, and elemental analysis. The in vitro antimicrobial screenings of the synthesized compounds were carried out against four bacterial pathogens, namely Staphylococcus aureus, Streptococcus pyogenes, Escherichia coli, Pseudomonas aeruginosa and three fungal pathogens Candida albicans, Aspergillus niger and Aspergillus clavatus, using broth microdilution minimum inhibitory concentration method. The compounds 7d , 7j , 8a , 9a , 9b , and 9i exhibited promising antibacterial activity against the tested strains, whereas some compounds were found to be active against one of the tested bacterial strains.