for the purposes of promoting an understanding of the principles of the novel technology , reference will now be made to the preferred embodiments thereof , and specific language will be used to describe the same . it will nevertheless be understood that no limitation of the scope of the novel technology is thereby intended , such alterations , modifications , and further applications of the principles of the novel technology being contemplated as would normally occur to one skilled in the art to which the novel technology relates are within the scope of this disclosure and the claims . as used herein , unless explicitly stated otherwise or clearly implied otherwise the term ‘ about ’ refers to a range of values plus or minus 10 percent , e . g . about 1 . 0 encompasses values from 0 . 9 to 1 . 1 . as used herein , unless explicitly stated otherwise or clearly implied otherwise the meaning of the terms “ treatment ” or “ treating ” used in conjunction with various compounds and methods disclosed and claimed herein include , but are not limited to , applying certain compounds to various either wet or dry surfaces including , but not limited to the skin , hair or fur of animals or the outside of seeds or plants including leaves , stems , shoots , roots , branches , blooms , fruits and the like , or any inanimate object either directly or indirectly . the terms “ treatment ” or “ treating ” also includes adding compounds to liquids , either aqueous or non - aqueous or mixtures thereof including simple mixtures of such or emulsions . the terms “ treatment ” or “ treating ” used in also include administering compounds to plants , cells , animals and humans . the terms “ treatment ” or “ treating ” include but are not limited to contacting bacteria or the biofilms of bacteria , directly or indirectly and may affect the growth of bacteria , and either directly or indirectly the formation of bacteria biofilms . the terms “ treatment ” or “ treating ” as used herein may include administering a ‘ therapeutically effective dose or doses of compounds . as used herein , unless explicitly stated otherwise or clearly implied otherwise the terms ‘ therapeutically effective dose ,’ ‘ therapeutically effective amounts ,’ and the like , refers to a portion of a compound that has a net positive effect on the health and wellbeing of a human or other animal . therapeutic effects may include an improvement in longevity , quality of life and the like these effects also may also include a reduced susceptibility to developing disease or deteriorating health or well being . the effects may be immediately realized after a single dose and / or treatment or they may be cumulatively realized after a series of doses and / or treatments . pharmaceutically acceptable salts include salts of compounds of the invention that are safe and effective for use in mammals and that possess a desired therapeutic activity . pharmaceutically acceptable salts include salts of acidic or basic groups present in compounds of the invention . pharmaceutically acceptable acid addition salts include , but are not limited to , hydrochloride , hydrobromide , hydroiodide , nitrate , sulfate , bisulfate , phosphate , acid phosphate , isonicotinate , acetate , lactate , salicylate , citrate , tartrate , pantothenate , bitartrate , ascorbate , succinate , maleate , gentisinate , fumarate , gluconate , glucaronate , saccharate , formate , benzoate , glutamate , methanesulfonate , ethanesulfonate , benzensulfonate , p - toluenesulfonate , trifluoroacetic acid , and pamoate ( i . e ., 1 , 1 ′- methylene - bis -( 2 - hydroxy - 3 - naphthoate )) salts . certain compounds of the invention may form pharmaceutically acceptable salts with various amino acids . suitable base salts include , but are not limited to , aluminum , calcium , lithium , magnesium , potassium , sodium , zinc , and diethanolamine salts . for addition information on some pharmaceutically acceptable salts that can be used to practice the invention please reviews such as berge , et al ., 66 j . pharm . sci . 1 - 19 ( 1977 ), and haynes , et at , j . pharma . sci ., vol . 94 , no . 10 , october 2005 , pgs . 2111 - 2120 . bacteria are known to communicate via small molecules . through this communication they are able to create complex , highly - organized communities responsible for biofilm formation , antibiotic resistance , and other important processes . these biofilms are involved in many disease states , including cystic fibrosis , which is a genetically inherited disease affecting approximately 70 , 000 people worldwide . dr . richard losick and colleagues at harvard have reported that certain d - amino acids ( 1 , r 1 = naturally occurring amino acid side chains in the d configuration ) are a trigger for the disassembly of bacterial biofilms ( science , 2010 , 328 , 627 - 629 ). d - tyrosine was reported to be particularly active : using the synthetic procedure discussed herein compounds such as 1 and 2 were wherein r 1 is selected from the group consisting of a benzyl group optionally substituted with a halogen , methyl group , or a nitro group , a bi - phenyl , a naphthalene , and an anthracene . one aspect of this approach uses d3 - 6 ( scheme 1 ) developed for our distributed drug discovery ( d3 ) project to synthesize analogs of compound 1 . this approach employs solid - phase chemistry , bill - board equipment , and alkylating agents r 1 x to synthesize a small “ library ” of unnatural amino acids 1 . a straightforward biological assay was developed to provide for the study these important bacterial biofilm communities . this assay also provided an efficient means for screening for compounds that have an effect on bacterial growth and / or biofilm formation . the racemic amino acid derivatives 1 ( synthesized in row a of each bill - board ) are then screened for biological activity ( antibacterial activity in a kirby - bauer disc plate assay ) and / or k357 laboratory ( assay for biofilm formation by pseudomonas aeruginosa ). fmoc - gly - wang resin ( 15 . 725 g , 12 . 108 mmol ) was swelled for 30 minutes with 100 ml of nmp in a 250 - ml solid - phase peptide synthesis vessel . the vessel was drained and the resin was treated with 70 ml of 20 % piperidine in nmp for 2 minutes . the vessel was drained and the resin was treated with 120 ml of 20 % piperidine and was rocked for 45 minutes on an orbital shaker . the vessel was drained , the resin was washed with 6 × 75 ml × 2 min nmp . the deprotected resin was then treated with 20 . 32 ml of benzophenone imine in 110 ml of nmp followed by 6 . 02 ml of acetic acid . the vessel was rocked overnight at room temperature . after 22 h the vessel was drained and the resin was washed with 4 × 75 ml × 2 min nmp and dichloromethane each . the resin 1 was dried under a slow stream of dry nitrogen gas for approximately 30 h and was then stored at 2 ° c . 50 μmols of resin 1 was treated with 100 μmols of 0 . 20 m btpp in nmp followed by 100 μmols of 0 . 20 m fluorinated benzyl bromide r 1 x in nmp . after two days the reaction mixture was filtered and the resulting resin 2 was washed once with 3 ml of thf . to the resin was then added 2 . 5 ml of 1 . 0 n hcl in thf ( 1 : 2 ). after 20 minutes the resin was filtered and was washed with 3 ml of thf followed by 2 × 2 . 5 ml of 0 . 20 m diisopropylethylamine in nmp , 2 × 2 . 5 ml of nmp , 3 × 2 ml of thf and 3 × 3 ml of dichloromethane to give resin 3 . treatment of resin 3 with 2 ml of 35 : 60 : 5 tfa / dcm / h 2 o for 30 minutes was followed by filtering and washing the resin with 2 ml of 35 : 60 : 5 tfa / dcm / h 2 o and 2 ml of dcm . the combined filtrates were evaporated to a residue which was chromatographed on silica gel using iproh / meoh / nh 4 oh mobile phases to elute the free bases 4 . 6 . 9 mg ( 75 %), 1 hnmr ( d 2 o ) δ 3 . 04 ( dd , 1h , j = 14 . 7 and 7 . 8 hz ), 3 . 18 ( dd , 1h , j = 14 . 6 and 5 . 3 hz ), 3 . 89 ( dd , 1h , j = 7 . 8 and 5 . 3 hz ), 7 . 06 ( t , 2h , j = 8 . 9 hz ), 7 . 21 ( m , 2h ). 9 . 1 mg ( 99 %), 1 hnmr ( d 2 o ) δ 3 . 08 ( dd , 1h , j = 14 . 6 and 7 . 9 hz ), 3 . 30 ( dd , 1h , j = 14 . 6 and 5 . 4 hz ), 3 . 94 ( t , 1h , j = 6 . 6 hz ), 7 . 11 - 7 . 17 ( m , 2h ), 7 . 26 - 7 . 36 ( m , 2h ). 7 . 5 mg ( 82 %), 1 hnmr ( d 2 o ) δ 3 . 03 ( dd , 1h , j = 14 . 5 and 7 . 9 hz ), 3 . 18 ( dd , 1h , j = 14 . 6 and 5 . 3 hz ), 3 . 89 ( dd , 1h , j = 7 . 9 and 5 . 4 hz ), 6 . 96 - 7 . 00 ( m , 2h ), 7 . 02 ( d , 1h , j = 7 . 5 hz ), 7 . 28 - 7 . 32 ( m , 1h ). 4 . 0 mg ( 40 %), 1 hnmr ( d 2 o ) δ 3 . 03 ( dd , 1h , j = 14 . 6 and 7 . 7 hz ), 3 . 16 ( dd , 1h , j = 14 . 4 and 5 . 1 hz ), 3 . 88 ( t , 1h , j = 6 . 5 hz ), 6 . 99 - 7 . 01 ( br m , 1h ), 7 . 11 - 7 . 21 ( m , 2h ). a 50 - ml round - bottom flask sealed with a rubber septum and charged with 501 mg of 10 in 5 ml of dichloromethane under dry argon gas was treated dropwise via syringe 1 . 08 ml of 3 , 4 - difluorobenzyl bromide . the contents were cooled to − 78 ° c . and 0 . 734 ml of 2 - tert - butylimino - 2 - diethylamino - 1 , 3 - dimethylperhydro - 1 , 3 , 2 - diazaphosphorine ( bemp ) was added dropwise via syringe over 10 min . the solution was stirred at − 78 ° c . for 8 h and was then stored at − 20 ° c . overnight . the solution was concentrated to an oil which was chromatographed on silica gel using hexanes to remove the excess benzyl bromide and 95 / 5 hexanes / ethyl acetate to elute 11d ( 575 mg , 80 %). imine 11d ( 572 mg ) was heated under reflux in 8 ml of 6n hcl for 6 h and was allowed to cool . the solution was washed with 2 × 5 ml of diethyl ether ( 106 mg of an insoluble solid was collected and later identified as the hydrochloride salt of the desired product ). the solution was then transferred to a 200 - ml rb flask and was concentrated to dryness in vacuo . approximately 5 ml of boiling ethanol was used to transfer the residue to a 25 - ml erlenmeyer flask as a solution . upon cooling the solution was treated with 400 ul of propylene oxide and was allowed to stand . the precipitate was collected by filtration and dried in vacuo to afford 104 mg ( 38 %) of 4d . a 50 - ml round - bottom flask was charged with 500 . 4 mg of protected amino acid 6 and 10 ml of thf . to the solution was added 204 . 1 mg of n - hydroxysuccinimide . the solution was chilled in an ice bath and 367 mg of dicyclohexylcarbodiimide was added . the mixture was stirred at 0 - 5 ° c . for 4 h and then was allowed to warm to room temperature and stand overnight . the mixture was chilled in an ice bath , was filtered , and the filtrate was concentrated to give 7 quantitatively as a white solid . compound 7 ( 20 - 30 mg ) was dissolved in 1 ml of thf and was treated with 1 . 2 equivalents of the benzylamine ( x = h , cl , or ome ) and the mixture was allowed to stand overnight . the reaction mixture was then filtered and the filtrate was evaporated to dryness . the residue was then chromatographed on 500 mg of silica gel using a step gradient as follows to give 8 ; dichloromethane , 99 / 1 , 98 / 2 , 97 / 3 , 96 / 4 , and 95 / 5 dcm / meoh . compound 8 was then treated with 500 - 700 ul of 1 . 0 m hcl in acetic acid and 50 - 70 ul of anisole and the solution was stirred for 1 . 5 - 2 h . the solution was added dropwise to 5 ml of cold , saturated potassium carbonate ( ph9 ) and was extracted two times with 15 ml of diethyl ether . the combined extracts were washed once with 5 ml of potassium carbonate and once with brine and were dried over sodium sulfate . concentration gave crude amides 9 which were chromatographed on 500 mg of silica gel using a step gradient as follows ; dichloromethane , 99 / 1 , 98 / 2 , 97 / 3 , 96 / 4 , and 95 / 5 dcm / meoh . 5 . 7 mg ( 53 %), 1 hnmr ( cdcl 3 ) δ 2 . 79 ( dd , 1h , j = 13 . 8 and 8 . 7 hz ), 3 . 21 ( dd , 1h , j = 13 . 9 and 4 . 2 hz ), 3 . 64 ( dd , 1h , j = 8 . 3 and 4 . 0 hz ), 4 . 38 ( dd , 1h , j = 14 . 7 and 6 . 1 hz ), 4 . 42 ( dd , 1h , j = 14 . 9 and 6 . 1 hz ), 6 . 69 ( t , 2h , j = 8 . 6 hz ), 7 . 15 - 7 . 18 ( m , 4h ), 7 . 29 ( d , 2h , j = 8 . 4 hz ), 7 . 59 ( br s , 1h ). 12 . 7 mg ( 67 %), 1 hnmr ( cdcl 3 ) δ 2 . 78 ( dd , 1h , j = 13 . 9 and 8 . 8 hz ), 3 . 21 ( dd , 1h , j = 13 . 9 and 4 . 2 hz ), 3 . 61 ( dd , 1h , j = 8 . 6 and 4 . 2 hz ), 3 . 80 ( s , 3h ), 4 . 33 ( dd , 1h , j = 14 . 5 and 5 . 8 hz ), 4 . 40 ( dd , 1h , j = 14 . 5 and 5 . 9 hz ), 6 . 85 ( d , 2h , j = 8 . 7 hz ), 6 . 98 ( t , 2h , j = 8 . 6 hz ), 7 . 14 - 7 . 18 ( m , 4h ), 7 . 16 br s , 1h ). 10 . 3 mg , ( 44 %), 1 hnmr ( cdcl 3 ) δ 2 . 80 ( dd , 1h , j = 13 . 8 and 8 . 7 hz ), 3 . 22 ( dd , 1h , j = 13 . 8 and 4 . 1 hz ), 3 . 64 ( br s , 1h ), 4 . 41 ( dd , 1h , j = 14 . 8 and 5 . 8 hz ), 4 . 46 ( dd , 1h , j = 14 . 8 and 6 . 0 hz ), 6 . 98 ( t , 2h , j = 8 . 7 hz ), 7 . 16 - 7 . 18 ( m , 2h ), 7 . 22 ( d , 2h , j = 7 . 0 hz ), 7 . 27 ( t , 1h , j = 7 . 2 hz ), 7 . 32 ( t , 2h , j = 6 . 9 hz ), 7 . 54 ( br s , 1h ). compound 7 ( 20 - 30 mg ) was dissolved in 1 ml of thf and was treated with 3 . 0 equivalents of isopropylamine or isobutylamine and the mixture was allowed to stand overnight . the reaction mixture was evaporated to dryness . the residue was then chromatographed on 500 mg of silica gel using a step gradient as follows ; dichloromethane , 99 / 1 , 98 / 2 , 97 / 3 , 96 / 4 , and 95 / 5 dcm / meoh . compounds 14 were then treated with 500 - 700 ul of 1 . 0 m hcl in acetic acid and 50 - 70 ul of anisole and the solution was stirred for 1 . 5 - 2 h . the solution was added dropwise to 5 ml of cold , saturated potassium carbonate ( ph9 ) and was extracted two times with 15 ml of diethyl ether . the combined extracts were washed once with 5 ml of potassium carbonate and once with brine and were dried over sodium sulfate . concentration gave crude amides of 5g / 5h which were chromatographed on 500 mg of silica gel using a step gradient as follows ; dichloromethane , 99 / 1 , 98 / 2 , 97 / 3 , 96 / 4 , and 95 / 5 dcm / meoh . 7 . 0 mg ( 38 %), 1 hnmr ( cdcl 3 ) δ 1 . 12 ( d , 3h , j = 6 . 1 hz ), 1 . 13 ( d , 3h , j = 6 . 1 hz ), 1 . 50 ( br s , 2h ), 2 . 74 ( dd , 1h , j = 13 . 8 and 8 . 7 hz ), 3 . 17 ( dd , 1h , j = 13 . 8 and 4 . 3 hz ), 3 . 54 ( dd , 1h , j = 8 . 3 and 4 . 0 hz ), 4 . 05 ( octet , 1h , j = 7 . 1 hz ), 6 . 96 - 7 . 02 ( m , 3h ), 7 . 17 - 7 . 19 ( m , 2h ). 6 . 7 mg ( 38 %), 1 hnmr ( cdcl 3 ) δ 0 . 89 ( d , 3h , j = 6 . 7 hz ), 0 . 94 ( d , 3h , j = 6 . 7 hz ), 1 . 75 ( nonet , 1h , j = 6 . 7 hz ), 2 . 74 ( dd , 1h , j = 13 . 8 and 8 . 9 hz ), 3 . 08 ( nonet , 2h , j = 6 . 5 hz ), 3 . 21 ( dd , 1h , j = 13 . 9 and 4 . 0 hz ), 3 . 59 ( br s , 1h ), 7 . 00 ( t , 2h , j = 8 . 7 hz ), 7 . 17 - 7 . 20 ( m , 2h ), 7 . 31 ( br s , 1h ). using the procedure above for 5g and 5h gave 2 - 3 mg of crude product . the aqueous phase was concentrated to dryness and was then continuously extracted for six hours in a soxhlet extractor using dichloromethane affording 13 mg of material which was chromatographed as above for 5g / 5h to give 7 . 0 mg ( 41 %), 1 hnmr ( cdcl 3 ) δ 2 . 79 ( dd , 1h , j = 13 . 9 and 8 . 7 hz ), 3 . 22 ( dd , 1h , j = 13 . 9 and 4 . 1 hz ), 3 . 65 ( dd , 1h , j = 8 . 7 and 4 . 2 hz ), 4 . 43 ( dd , 1h , j = 15 . 0 and 6 . 0 hz ), 4 . 48 ( dd , 1h , j = 15 . 0 and 6 . 1 hz ), 6 . 99 ( t , 2h , j = 8 . 7 hz ), 7 . 15 - 7 . 18 ( m , 2h ), 7 . 26 ( dd , 1h , j = 7 . 8 and 4 . 9 hz ), 7 . 57 ( d , 1h , j = 7 . 8 hz ), 7 . 70 ( br s , 1h ), 8 . 52 ( br s , 2h ). using the procedure above for 5g and 5h gave intermediate 14j . the boc group was removed by treatment with 25 % trifluoroacetic acid in dichloromethane over three hours . the reaction mixture was evaporated to 32 . 9 mg of a residue which was chromatographed of silica gel using 18 : 2 : 1 isopropanol : methanol : ammonium hydroxide and proceeding to 9 : 2 : 1 to give 4 . 2 mg ( 14 %) and 19 . 3 mg of contaminated target material , 1 hnmr ( cd 3 od ) δ 3 . 13 ( dd , 1h , j = 13 . 9 and 8 . 7 hz ), 3 . 20 ( dd , 1h , j = 13 . 8 and 7 . 9 hz ), 4 . 13 ( t , 1h , j = 7 . 5 hz ), 4 . 37 ( d , 1h , j = 16 . 0 hz ), 4 . 48 ( d , 1h , j = 16 . 0 hz ), 7 . 08 ( t , 2h , j = 8 . 7 hz ), 7 . 27 - 7 . 29 ( m , 4h ), 8 . 55 ( br s , 2h ). 8 . 8 mg ( 42 %), 1 hnmr ( cdcl 3 ) δ 2 . 79 ( dd , 1h , j = 14 . 0 and 8 . 8 hz ), 3 . 21 ( dd , 1h , j = 13 . 9 and 3 . 9 hz ), 3 . 67 ( br s , 1h ), 3 . 82 - 4 . 00 ( m , 2h ), 7 . 01 ( t , 2h , j = 8 . 6 hz ), 7 . 16 - 7 . 18 ( m , 2h ), 7 . 79 ( br s , 1h ). 14 . 4 mg ( 64 %); 1 hnmr ( cdcl 3 ) δ 2 . 69 ( dd , 1h , j = 13 . 9 and 8 . 8 hz ), 2 . 79 ( t , 2h , j = 7 . 0 hz ), 3 . 17 ( dd , 1h , j = 13 . 9 and 4 . 2 hz ), 3 . 46 - 3 . 57 ( m , 3h ), 6 . 99 ( t , 2h , j = 8 . 6 hz ), 7 . 14 - 7 . 16 ( m , 4h ), 7 . 20 - 7 . 25 ( m , 2h ), 7 . 26 - 7 . 30 ( m , 2h ). using the procedure above for 5g and 5h gave intermediate 14m . the boc group was removed by treatment with 25 % trifluoroacetic acid in dichloromethane over three hours . the reaction mixture was evaporated to a residue which was chromatographed of silica gel using 95 : 5 and 9 : 1 dichloromethane : methanol to give 18 . 7 mg ( 69 %) of 5m ; 1 hnmr ( d 2 o ) δ 3 . 11 ( m , 2h ), 3 . 22 ( m , 2h ), 3 . 44 ( m , 1h ), 3 . 50 ( m , 1h ), 4 . 08 ( t , 1h , j = 7 . 4 hz ), 7 . 07 ( t , 2h , j = 8 . 9 hz ), 7 . 20 - 7 . 22 ( m , 2h ); 1 hnmr ( cd 3 od ) δ 3 . 06 ( dd , 1h , j = 13 . 8 and 7 . 3 hz ), 3 . 19 ( dd , 1h , j = 12 . 8 and 6 . 5 hz ), 3 . 27 - 3 . 37 ( m , 2h ), 3 . 52 - 3 . 62 ( m , 2h ), 4 . 00 ( br t , 1h , j = 5 . 9 hz ), 7 . 11 ( t , 2h , j = 8 . 7 hz ), 7 . 29 - 7 . 32 ( m , 2h ). appreciable water - solubility required three extractions of the basic aqueous phase with dichloromethane to give 10 . 9 mg ( 47 %); 1 hnmr ( cdcl 3 ) δ 2 . 41 - 2 . 46 ( m , 6h ), 2 . 76 ( dd , 1h , j = 13 . 8 and 8 . 6 hz ), 3 . 17 ( dd , 1h , j = 13 . 8 and 4 . 6 hz ), 3 . 35 ( q , 2h , j = 5 . 9 hz ), 3 . 57 ( dd , 1h , j = 8 . 4 and 4 . 6 hz ), 3 . 67 ( t , 4h , j = 4 . 6 hz ), 7 . 00 ( t , 2h , j = 8 . 6 hz ), 7 . 17 - 7 . 20 ( m , 2h ), 7 . 35 ( br s , 1h ). 10 . 1 mg ( 59 %); 1 hnmr ( cdcl 3 ) δ 1 . 14 - 1 . 22 ( m , 1h ), 1 . 40 - 1 . 63 ( m , 5h ), 2 . 74 ( dd , 1h , j = 13 . 4 and 7 . 2 hz ), 2 . 91 ( dd , 1h , j = 13 . 4 and 6 . 7 hz ), 3 . 12 - 3 . 16 ( m , 1h ), 3 . 27 - 3 . 32 ( m , 1h ), 3 . 49 - 3 . 58 ( m , 2h ), 3 . 93 ( br s , 1h ), 6 . 98 ( t , 2h , j = 8 . 6 hz ), 7 . 15 - 7 . 18 ( m , 2h ). appreciable water - solubility required three extractions of the basic aqueous phase with dichloromethane to give 10 . 8 mg ( 58 %); 1 hnmr ( cdcl 3 ) δ 1 . 67 - 1 . 86 ( m , 4h ), 2 . 77 ( dd , 1h , j = 13 . 3 and 7 . 0 hz ), 2 . 82 - 2 . 86 ( m , 1h ), 2 . 92 ( dd , 1h , j = 13 . 2 and 7 . 4 hz ), 3 . 35 - 3 . 40 ( m , 2h ), 3 . 45 - 3 . 50 ( m , 1h ), 3 . 69 ( t , 1h , j = 7 . 1 hz ), 6 . 97 ( t , 2h , j = 8 . 6 hz ), 7 . 15 - 7 . 18 ( m , 2h ). the procedure in scheme 2 for the preparation of resins 3 was used . resins 3 were then treated with 7n methanolic ammonia or 33 % methylamine in ethanol or isoamylamine in ethanol for four to twelve days . the vessels were drained and the resins washed with thf . the filtrates were then evaporated to dryness to afford crude amides 5a - f , and i . 7 . 1 mg ( 78 %), 1 hnmr ( dmso - d 6 ) δ 2 . 65 ( dd , 1h , j = 13 . 3 and 8 . 3 hz ), 2 . 94 ( dd , 1h , j = 13 . 3 and 5 . 2 hz ), 3 . 36 ( dd , 1h , j = 8 . 3 and 5 . 8 hz ), 6 . 96 ( br s , 1h ), 7 . 10 - 7 . 14 ( m , 2h ), 7 . 23 - 7 . 27 ( m , 1h ), 7 . 29 - 7 . 32 ( m , 1h ), 7 . 34 ( br s , 1h ). 9 . 0 mg ( 99 %), 1 hnmr ( dmso - d 6 ) δ 2 . 65 ( dd , 1h , j = 13 . 2 and 8 . 2 hz ) 2 . 93 ( dd , 1h , j = 13 . 3 and 4 . 9 hz ), 3 . 39 ( dd , 1h , j = 7 . 9 and 5 . 2 hz ), 7 . 01 - 7 . 04 ( m , 2h ), 7 . 06 ( d , 2h , j = 7 . 9 hz ), 7 . 29 - 7 . 33 ( m , 1h ), 7 . 36 ( br s , 1h ). 15 . 2 mg ( 38 %), 1 hnmr ( d 2 o ) δ 2 . 82 ( dd , 1h , j = 13 . 7 and 6 . 9 hz ), 2 . 87 ( dd , 1h , j = 13 . 6 and 6 . 7 hz ), 3 . 57 ( t , 1h , j = 6 . 8 hz ), 7 . 02 ( t , 2h , j = 8 . 9 hz ), 7 . 18 ( m , 2h ). 4 . 0 mg , ( 40 %), 1 hnmr ( 5 % cd 3 od in cdcl 3 ) δ 2 . 75 ( dd , 1h , j = 13 . 5 and 8 . 7 hz ), 3 . 14 ( br d , 1h , j = 13 . 1 hz ), 3 . 61 ( br s , 1h ), 6 . 00 ( br s , 1h ), 6 . 94 - 6 . 96 ( br m , 1h ), 7 . 05 - 7 . 14 ( m , 2h ), 7 . 18 ( br s , 1h ). 3 . 9 mg ( 40 %), 1 hnmr ( cd 3 od ) 2 . 60 ( s , 3h ), 2 . 73 ( dd , 1h , j = 13 . 5 and 7 . 0 hz ), 2 . 88 ( dd , 1h , j = 13 . 5 and 6 . 7 hz ), 3 . 40 ( t , 1h , j = 6 . 6 hz ), 6 . 94 ( t , 2h , j = 8 . 8 hz ), 7 . 12 - 7 . 15 ( m , 2h ). 4 . 4 mg ( 41 %), 1 hnmr ( cdcl 3 ) 2 . 73 ( dd , 1h , j = 13 . 9 and 8 . 9 hz ), 2 . 82 ( d , 3h , j = 4 . 9 hz ), 3 . 20 ( dd , 1h , j = 13 . 9 and 4 . 1 hz ), 3 . 58 ( dd , 1h , j = 8 . 8 and 4 . 1 hz ), 6 . 91 - 6 . 94 ( br m , 1h ), 7 . 04 ( ddd , 1h , j = 10 . 6 , 7 . 5 , and 1 . 9 hz ), 7 . 07 - 7 . 13 ( m , 1h ), 7 . 21 ( br s , 1h ). 5 . 6 mg ( 44 %), 1 hnmr ( cdcl 3 ) δ 0 . 91 ( d , 6h , j = 6 . 7 hz ), 1 . 37 ( q , 2h , j = 7 . 3 hz ), 1 . 58 ( heptet , 1h , j = 6 . 7 hz ), 2 . 73 ( dd , 1h , j = 13 . 9 and 8 . 9 hz ), 3 . 20 ( dd , 1h , j = 13 . 9 and 4 . 2 hz ), 3 . 26 ( ddd , 2h , j = 9 . 1 , 7 . 1 , 1 . 3 hz ), 3 . 56 ( dd , 1h , j = 8 . 8 and 4 . 2 hz ), 7 . 00 ( t , 2h , j = 8 . 6 hz ), 7 . 14 ( br s , 1h ), 7 . 14 - 7 . 19 ( m , 2h ). compound 4a ( prepared as described above for 4d ), 209 . 1 mg , was treated with 711 μl of t - butanol , 142 . 8 μl of water , and 570 . 2 μl of 2 . 0 n naoh . to this solution was added 268 . 5 μl of di - t - butyl - dicarbonate . the solution was stirred overnight and was then transferred to a separatory funnel containing 10 ml of diethylether and mixed . the layers were separated and the aqueous phase was washed with 5 ml of diethyl ether and was adjusted to ph2 - 3 with 1n hcl . the mixture was extracted with 2 × 10 ml of ethyl acetate . the combined extracts were washed with 2 ml of water and were dried ( mgso 4 ). concentration gave 242 . 4 mg of 12a . compound 12a ( 117 mg ) under dry argon gas was dissolved in 874 μl of dmf and the solution was chilled to − 9 ° c . to the solution was then added 45 . 6 μl of n - methylmorpholine followed by 56 . 6 μl of isobutyl chloroformate . after 5 - 10 min , 600 μl of 7n ammonia in methanol was added . the mixture was stirred at − 15 to 2 ° c . over a 4 . 5 h period and was then added to 20 - 25 ml of crushed ice and saturated sodium bicarbonate . the mixture was extracted with 2 × 15 ml of ethyl acetate . the combined extracts were washed once with 5 ml of water , once with 5 ml of 10 % citric acid , and once with water and were dried ( mgso 4 ). concentration gave 123 . 8 mg of 13a as a white solid . to 121 . 8 mg of 13a was added a solution of 782 μl of 1 . 0 m hcl in acetic acid and 77 . 2 μl of anisole . after one hour , 5 ml of diethyl ether was added . the precipitate was collected and was dried in vacuo to afford 70 mg of 5c as its hydrochloride salt . a portion ( 35 . 3 mg ) was stirred in 3 ml of saturated potassium carbonate for 3 h . collection afforded 15 . 2 mg of 5c . for additional information , see u . s . pat . no . 4 , 265 , 808 , disclosure of which is incorporated by reference in its entirety to the extent that it is not inconsistent with the explicit teachings of this specification . referring now to fig1 , compounds were synthesized and tested for the chemical activity . compounds in red ( i . e ., 2 - f , 3 - f , 4 - f , and 4 - i ) showed activity in preliminary screens . referring now to fig2 , twenty - one “ unnatural ” amino acids were synthesized . referring now to fig3 , reproducible p . aeruginosa biofilm assays were carried out using newly synthesized twenty - one “ unnatural ” amino acids . see george a . o &# 39 ; toole , microtiter dish biofilm formation assay , j . v is e xp . 2011 ; ( 47 ): 2437 , disclosures of which are incorporated by reference in its entirety to the extent that they are not inconsistent with the explicit teachings of this specification . referring now to fig2 , four compounds ( 2 - f , 3 - f , 4 - f , and 3 , 4 - f2 ) showed activity in the biofilm assay . subsequent assay of a purified sample of these compounds confirmed this activity , and the compounds were active in a dose dependent manner ( fig2 - 28 ). referring now to fig2 , in the biofilm assay 4 - f was shown to be as potent as tobramycin ( the current treatment for p . aeruginosa infections in patients with cystic fibrosis ). enantiomers were separated by chiral chromatography using a regis technologies ( morton grove , ill .) chirosil sca (−) 4 . 6 × 150 mm , 5 - micron column using 7 / 3 meoh / h 2 o with 10 mm acoh at a flow rate of 1 . 0 ml / min and detection at 214 , 230 , and 254 nm . a typical injection volume was 30 μl ( 34 . 5 μg ) of a 1 . 15 mg / ml solution of purified , racemic compound in 7 / 3 meoh / h 2 o . each enantiomer was collected manually in separate test tubes . the process was repeated a second time . combined solutions of individual enantiomers were evaporated to dryness and the residues were dissolved in 200 μl of 7 / 3 meoh / h 2 o . these solutions were then each analyzed on the chiral column ( 5 μl injections ) to verify enantiopurity and then on an agilent technologies ( santa clara , calif .) zorbax sb c18 , 4 . 6 × 150 mm , 5 - micron column ( 30 % 1 : 1 meoh : mecn with 5 mm nh 4 oac — 70 % h 2 o with 5 mm nh 4 oac , 1 . 0 ml / min , 210 , 214 , 254 nm ) to determine mass quantities from peak areas using the calibration equation . initially , un - purified samples of two of these compounds , of structures 4 - fluorophenylalanine ( 4 - f ) and 2 - fluorophenylalanine ( 2 - f ), were found to be active in the k357 biofilm assay . subsequent assay of a purified sample of 4 - f confirmed this activity . it was then demonstrated that in the biofilm assay 4 - f is as potent as tobramycin ( the current treatment for p . aeruginosa infections in patients with cystic fibrosis ). expanding on these initial results an enantiomeric purification was carried out and the resolved enantiomers were tested in the bioassay . using these preparations it was established that one of the enantiomers of 4 - f is primarily responsible for the direct or indirect potent inhibition of biofilm formation by p . aeruginosa . the other enantiomer of 4 - f appears to have some activity but at a significantly higher concentration . a structure activity relationship ( sar ) was developed to provide a means for improving the utility of these compounds in modulating biofilm formation , and / or inhibiting growth . critical findings reported in these studies are the potent activity , in addition to 4 - f and 2 - f , of molecules 3 - fluorophenylalanine ( 3 - f ) and 3 , 4 - difluorophenylalanine ( 3 , 4 - f ). also determined using a similar experimental approach is that the amide derivative ( 4 - fluorophenylalanine amide ) of 4 - f is very potent inhibitor of biofilm development . referring now to fig2 , one of the enantiomers (“ isomer b ”) was found to be primarily responsible for the direct or indirect potent inhibition of biofilm formation by p . aeruginosa . the other enantiomer (“ isomer a ”) appears to have some activity but at a significantly higher concentration . referring now to fig3 - 35 , newly synthesized compounds were prepared according to the schemes described above . these compounds include , but not limited to , compounds having the formula : referring to fig3 - 35 , all newly synthesized compounds prepared according to the schemes described above were assayed for biofilm formation in multiplicate 24 well plates at a screening dose of 20 μg / ml using crystal violet optical density ( od ) readings as the readout . results were expressed as % biofilm formation relative to a control ( control = bacteria alone = 100 % biofilm formation ). the procedure for the biofilm assay was the same as that used by students in the k357 biofilm laboratory . referring now to fig3 - 38 , all compounds assayed in either 96 well or 24 well plates at a screening dose of either 20 or 40 μg / ml , using a biofilm assay with crystal violet optical density ( od ) readings as the readout . results were expressed as % biofilm formation ( control = bacteria alone = 100 % biofilm formation ). the procedure for the biofilm assay was the same as that used by students in the k357 biofilm laboratory . referring now to fig3 - 38 , the following compounds , for example , exhibited 50 % or greater inhibition of biofilm formation at 20 μg / ml : while the novel technology has been illustrated and described in detail in the figures and foregoing description , the same is to be considered as illustrative and not restrictive in character , it being understood that only the preferred embodiments have been shown and described and that all changes and modifications that come within the spirit of the novel technology are desired to be protected . as well , while the novel technology was illustrated using specific examples , theoretical arguments , accounts , and illustrations , these illustrations and the accompanying discussion should by no means be interpreted as limiting the technology . all patents , patent applications , and references to texts , scientific treatises , publications , and the like referenced in this application are incorporated herein by reference in their entirety .