The crude material was purified by preparative HPLC to provide the pure product like a yellow solid (136 mg, 36% on a 1.0 mmolar level). 1H NMR (DMSO-10.08 (s, 1H), 7.71 (d, = 2.1 Hz, 1H), 7.48 (br s, 1H), 7.33 (dd, = 8.3, 2.3 Hz, 1H), 7.29 (dd, = 8.2, 1.1 Hz, 1H), 7.06 (d, = 8.3 Hz, 1H), 6.81 (d, = 8.8 Hz, 1H), 6.72 (s, 1H), 2.78 (t, = 7.5 Hz, 2H), 1.66 (quin, = 7.5 Hz, 2H), 1.36 (sxt, = 7.4 Hz, 2H), 0.92 (t, = 7.3 Hz, 3H); 13C NMR (DMSO-174.1, 161.2, 151.9, 149.0, 143.6, 129.7, 128.4, 126.7, 126.5, 123.4, 121.4, 118.6 (2C), 114.9, 99.2, 29.0, 25.6, 21.6, 13.5; HPLC purity 98.0%; MS (ESI+) 378 (M+H+, 35Cl2); HRMS (ESI+) calcd for C19H18Cl2NO3 378.0658 (M+H+, 35Cl2), found 378.0644. 2-(2,4-Dichlorophenoxy)-5-(5-phenyl-1,2-oxazol-3-yl)phenol (20b) The title compound was prepared following a General Procedure B with 19b as the starting material. be accompanied with fever and adenopathy or additional symptoms, but asymptomatic infections can also happen. However, recrudescence in immunocompromised individuals can lead to severe pathologic conditions, including lethal encephalitis.[3] Congenital toxoplasmosis may result in abortion, neonatal death, or fetal abnormalities,[4] and children congenitally infected with parasites almost all develop ocular disease during fetal existence, in the perinatal period, or at later ages if not treated during fetal existence or infancy.[5] Several distinct phases are involved in life cycle, which is comprised of two phases: sexual and asexual. The former phase takes place only in the primary hosts, which are home and crazy pet cats from your Felidae family, whereas the asexual phase can occur in any warm-blooded animal, which serves as the intermediate sponsor for the parasites.[6, 7] Tachyzoites and bradyzoites are present in the human being stage of the life cycle. Tachyzoites are the obligate intracellular forms of and their primary goal is to rapidly expand the parasite populace within the sponsor cells during acute infections. In contrast, bradyzoites are the latent forms of parasites contain a non-photosynthetic relict plastid, called apicoplast.[9, 10] Small circular genome and biochemical pathways such as isoprenoid and type II fatty acid synthesis systems were detected within this particular organelle.[11, 12] The mechanism of the apicoplast-localized type II fatty acid synthesis pathway (FAS II) was initially studied in (and protozoan, parasites, the conversion of acetyl coenzyme A (acetyl-CoA) to full-length fatty acid chains is an iterative process mediated by discrete mono-functional enzymes, known as FAS II.[13, 14] On the contrary, the eukaryotic type I fatty acid synthesis system (FAS I) operates while a single multi-functional enzyme that catalyzes all the steps of the pathway. Also acetyl-CoA carboxylase (ACCase), an enzyme responsible for the synthesis of malonyl-CoA, significantly differs in these two systems. The ACCase of prokaryotes consists of four individual subunits linked to a small acyl carrier protein, whereas the ACCase of eukaryotes is definitely a single large multi-domain protein.[15] The prokaryotic origin of the biochemical pathways inside apicoplasts offers provided a plethora of novel drug targets. Since these are fundamentally different from the related systems operating in the human being sponsor cells, several enzymes involved in apicomplexan FAS II became validated molecular focuses on for the development of potent anti-protozoan medicines.[11] The enoyl-acyl carrier protein (ACP) reductase (ENR or FabI) is one of the key enzymes involved in FAS II that reduces, inside a nicotinamide adenine dinucleotide (NADH)-dependent manner, enoyl-ACP to acyl-ACP, which is the final and rate-determining step in the fatty acid chain elongation process. [16] You will find three additional isoforms of ENR: FabK, FabL and FabV, which are present in bacteria.[17C19] The genome contains a single ENR (and tachyzoites screens against purified tachyzoites allowed us to select interesting candidates for further biological evaluation. Overall, this work provides significant insights into the finding of fresh and effective inhibitors of (a) neopentyl glycol, H3NSO3, PhMe, 110 C, 3 h, 87%; (b) 1. For 3, 1,3-dichloro-4-fluorobenzene, Cs2CO3, DMF, 130 C, 14 h, 51%; 2. for 11, 3-chloro-4-fluorobenzaldehyde, Cs2CO3, DMF, 125 C, 16 h, 92%; (c) PPTS, damp acetone, reflux, 2.5 h, 100%; (d) NaBH4, MeOH, RT, 1.5 h. For 5, 84%; for 12, 100%; (e) CBr4, PPh3, THF, RT. 1. For 6, 14 h, 83%; 2. for 13, 2 h, 80%; (f) NaN3, DMF. 1. For 7, 110 C, 7 h, 71%; 2. for 14, 100 C, 14 h, 56%; (g) sodium ascorbate, CuSO45H2O, 1-alkyne, (a) liquid H2O-EtOH-ice (1:1:2), H2NOHHCl, 50% aq NaOH, RT, 75 min, 90%; (b) NCS, DMF, RT, 1.5 h, 100%; (c) sodium ascorbate, CuSO45H2O, KHCO3, 1-alkyne, (a) 1. 2,4-dichlorophenol, Cs2CO3, DMF, 120 C, 21 h, 65% for 26; 2. 3-chloro-4-fluorobenzonitrile, Cs2CO3, DMF, 100 C, 16 h, 75% for 34; (b) Bu4NI, CH2Cl2, RT, 5 min, bCl3 then, ?78 C, 15 min, rT then, 2 h. For 27, 82%; for 30a, R = H, R1 = Ph, 51%; for 30b, R = R1 = tachyzoites (assessed as reduced uptake of [3H] uracil or fluorescence with YFP transfected parasites [make sure you see strategies], Desk 1). Desk 1 Activity data and ADMET predictions for brand-new.The Tecan Independence Evo water handling system was utilized to dispense malaria cell lysis and culture buffer. of oocysts in water or food contaminated using the feces of felines.[1] In immunocompetent people, acute acquisition of could be followed with adenopathy and fever or other symptoms, but asymptomatic attacks may also occur. Nevertheless, recrudescence in immunocompromised sufferers can result in severe pathologic circumstances, including lethal encephalitis.[3] Congenital toxoplasmosis may bring about abortion, neonatal loss of life, or fetal abnormalities,[4] and kids congenitally contaminated with parasites virtually all develop ocular disease during fetal lifestyle, in the perinatal period, or at later on ages if not treated during fetal lifestyle or infancy.[5] Several distinct levels get excited about life cycle, which is made up of two phases: sexual and asexual. The previous phase occurs only in the principal hosts, that are local and outrageous felines in the Felidae family members, whereas the asexual stage can occur in virtually any warm-blooded pet, which acts as the intermediate web host for the parasites.[6, 7] Tachyzoites and bradyzoites can be found in the individual stage of the life span cycle. Tachyzoites will be the obligate intracellular types of and their main aim is to quickly expand the parasite inhabitants inside the web host cells during severe infections. On the other hand, bradyzoites will be the latent types of parasites include a non-photosynthetic relict plastid, known as apicoplast.[9, 10] Little circular genome and biochemical pathways such as for example isoprenoid and type II fatty acidity synthesis systems had been detected within this specific organelle.[11, 12] The mechanism from the apicoplast-localized type II fatty acidity synthesis pathway (FAS II) was studied in (and protozoan, parasites, the transformation of acetyl coenzyme A (acetyl-CoA) to full-length fatty acidity chains can be an iterative procedure mediated by discrete mono-functional enzymes, referred to as FAS II.[13, 14] On the other hand, the eukaryotic type We fatty acidity synthesis program (FAS We) operates seeing that an individual multi-functional enzyme that catalyzes all of the steps from the pathway. Also acetyl-CoA carboxylase (ACCase), an enzyme in charge of the formation of malonyl-CoA, considerably differs in both of these systems. The ACCase of prokaryotes includes four specific subunits associated with a little acyl carrier proteins, whereas the ACCase of eukaryotes is certainly a single huge multi-domain proteins.[15] The prokaryotic origin from the biochemical pathways inside apicoplasts provides provided various novel drug focuses on. Since they are fundamentally not the same as the matching systems working in the individual web host cells, many enzymes involved with apicomplexan FAS II became validated molecular goals for the introduction of powerful anti-protozoan medications.[11] The enoyl-acyl carrier protein (ACP) reductase (ENR or FabI) is among the key enzymes involved with FAS II that reduces, within a nicotinamide adenine dinucleotide (NADH)-reliant manner, enoyl-ACP to acyl-ACP, which may be the last and rate-determining part of the fatty acidity chain elongation procedure. [16] A couple of three various other isoforms of ENR: FabK, FabL and FabV, which can be found in bacterias.[17C19] The genome contains an individual ENR (and tachyzoites displays against purified tachyzoites allowed us to choose interesting candidates for even more biological evaluation. General, this function provides significant insights in to the breakthrough of brand-new and effective inhibitors of (a) neopentyl glycol, H3NSO3, PhMe, 110 C, 3 h, 87%; (b) 1. For 3, 1,3-dichloro-4-fluorobenzene, Cs2CO3, DMF, 130 C, 14 h, 51%; 2. for 11, 3-chloro-4-fluorobenzaldehyde, Cs2CO3, DMF, 125 C, 16 h, 92%; (c) PPTS, moist acetone, reflux, 2.5 h, 100%; (d) NaBH4, MeOH, RT, 1.5 h. For 5, 84%; for 12, 100%; (e) CBr4, PPh3, THF, RT. 1. For 6, 14 h, 83%; 2. for 13, 2 h, 80%; (f) NaN3, DMF. 1. For 7, 110 C, 7 h, 71%; 2. for 14, 100 C, 14 h, 56%; (g) sodium ascorbate, CuSO45H2O, 1-alkyne, Encequidar (a) water H2O-EtOH-ice (1:1:2), H2NOHHCl, 50% aq NaOH, RT, 75 min, 90%; (b) NCS, DMF, RT, 1.5 h, 100%; (c) sodium ascorbate, CuSO45H2O, KHCO3, 1-alkyne, (a) 1. 2,4-dichlorophenol, Cs2CO3, DMF, 120 C, 21 h, 65% for 26; 2. 3-chloro-4-fluorobenzonitrile, Cs2CO3, DMF, 100 C, 16 h, 75% for 34; (b) Bu4NI, CH2Cl2, RT, 5 min, after that BCl3, ?78 C, 15 min, then RT, 2 h. For 27, 82%; for 30a, R = H, R1 = Ph, 51%; for 30b, R = R1 = tachyzoites (assessed as reduced uptake of [3H] uracil or fluorescence with YFP transfected parasites [make sure you see strategies], Desk 1). Desk 1 Activity ADMET and data predictions for fresh group of triclosan-based parasite, human sponsor cell, and enzyme data along with predictions for the chosen ADMET guidelines are shown in Desk 1. The setting of actions of.D6 (CDC/Sierra Leone), TM91C235 (WRAIR, Thailand), and W2 (CDC/Indochina III) lab strains of were used for every drug sensitivity evaluation. occurs primarily by usage of meat contaminated with cells cysts or by ingestion of oocysts in meals or water polluted using the feces of pet cats.[1] In immunocompetent people, acute acquisition of could be followed with adenopathy and fever or other symptoms, but asymptomatic attacks may also occur. Nevertheless, recrudescence in immunocompromised individuals can result in severe pathologic circumstances, including lethal encephalitis.[3] Congenital toxoplasmosis may bring about abortion, neonatal loss of life, or fetal abnormalities,[4] and kids congenitally contaminated with parasites virtually all develop ocular disease during fetal Rabbit polyclonal to AGPAT3 existence, in the perinatal period, or at later on ages if not treated during fetal existence or infancy.[5] Several distinct phases get excited about life Encequidar cycle, which is made up of two phases: sexual and asexual. The previous phase occurs only in the principal hosts, that are home and crazy pet cats through the Felidae family members, whereas the asexual stage can occur in virtually any warm-blooded pet, which acts as the intermediate sponsor for the parasites.[6, 7] Tachyzoites and bradyzoites can be found in the human being stage of the life span cycle. Tachyzoites will be the obligate intracellular types of and their main aim is to quickly expand the parasite human population inside the sponsor cells during severe infections. On the other hand, bradyzoites will be the latent types of parasites include a non-photosynthetic relict plastid, known as apicoplast.[9, 10] Little circular genome and biochemical pathways such as for example isoprenoid and type II fatty acidity synthesis systems had been detected within this specific organelle.[11, 12] The mechanism from the apicoplast-localized type II fatty acidity synthesis pathway (FAS II) was studied in (and protozoan, parasites, the transformation of acetyl coenzyme A (acetyl-CoA) to full-length fatty acidity chains can be an iterative procedure mediated by discrete mono-functional enzymes, referred to as FAS II.[13, 14] On the other hand, the eukaryotic type We fatty acidity synthesis program (FAS We) operates while an individual multi-functional enzyme that catalyzes all of the steps from the pathway. Also acetyl-CoA carboxylase (ACCase), an enzyme in charge of the formation of malonyl-CoA, considerably differs in both of these systems. The ACCase of prokaryotes includes four specific subunits associated with a little acyl carrier proteins, whereas the ACCase of eukaryotes can be a single huge multi-domain proteins.[15] The prokaryotic origin from the biochemical pathways inside apicoplasts offers provided various novel drug focuses on. Since they are fundamentally not the same as the related systems working in the human being sponsor cells, many enzymes involved with apicomplexan FAS II became validated molecular focuses on for the introduction of powerful anti-protozoan medicines.[11] The enoyl-acyl carrier protein (ACP) reductase (ENR or FabI) is among the key enzymes involved with FAS II that reduces, inside a nicotinamide adenine dinucleotide (NADH)-reliant manner, enoyl-ACP to acyl-ACP, which may be the last and rate-determining part of the fatty acidity chain elongation procedure. [16] You can find three additional isoforms of ENR: FabK, FabL and FabV, which can be found in bacterias.[17C19] The genome contains an individual ENR (and tachyzoites displays against purified tachyzoites allowed us to choose interesting candidates for even more biological evaluation. General, this function provides significant insights in to the finding of fresh and effective inhibitors of (a) neopentyl glycol, H3NSO3, PhMe, 110 C, 3 h, 87%; (b) 1. For 3, 1,3-dichloro-4-fluorobenzene, Cs2CO3, DMF, 130 C, 14 h, 51%; 2. for 11, 3-chloro-4-fluorobenzaldehyde, Cs2CO3, DMF, 125 C, 16 h, 92%; (c) PPTS, damp acetone, reflux, 2.5 h, 100%; (d) NaBH4, MeOH, RT, 1.5 h. For 5, 84%; for 12, 100%; (e) CBr4, PPh3, THF, RT. 1. For 6, 14 h, 83%; 2. for 13, 2 h, 80%; (f) NaN3, DMF. 1. For 7, 110 C, 7 h, 71%; 2. for 14, 100 C, 14 h, 56%; (g) sodium ascorbate, CuSO45H2O, 1-alkyne, (a) water H2O-EtOH-ice (1:1:2), H2NOHHCl, 50% aq NaOH, RT, 75 min, 90%; (b) NCS, DMF, RT, 1.5 h, 100%;.Purification by preparative HPLC gave the pure item seeing that an off-white great (38 mg, 20% on the 0.52 mmolar range). 1H NMR (DMSO-9.63 (br s, 1H), 7.66 (d, = 2.5 Hz, 1H), 7.29 (dd, = 8.9, 2.6 Hz, 1H), 7.00 (d, = 1.9 Hz, 1H), 6.91 (d, = 8.1 Hz, 1H), 6.78 (dd, = 8.2, 1.9 Hz, 1H), 6.62 (d, = 8.9 Hz, 1H), 3.65 (s, 2H), 2.50 (m, 1H), 2.37 (m, 1H), 1.85 C 1.82 (m, 2H), 1.70 C 1.65 Encequidar (m, 2H), 1.54 (m, 1H), 1.23 C 0.99 (m, 5H); 13C NMR (DMSO-152.7, 148.5, 140.0, 129.5, 128.1, 125.7, 122.6, 121.3 (2C), 119.0, 117.3, 116.7, 55.4, 49.5, 32.9 (2C), 25.9, 24.4 (2C); HPLC purity 100%; MS (ESI+) 366 (M+H+, 35Cl2), HRMS (ESI+) calcd for C19H22Cl2NO2 366.1022 (M+H+, 35Cl2), found 366.1006. 2-(2,4-Dichlorophenoxy)-5-[(hexylamino)methyl]phenol (39c) The title chemical substance was prepared following General Procedure C with 38c as the beginning materials. the perinatal period, or at afterwards ages if not really treated during fetal lifestyle or infancy.[5] Several distinct levels get excited about life cycle, which is made up of two phases: sexual and asexual. The previous phase occurs only in the principal hosts, that are local and wild felines in the Felidae family members, whereas the asexual stage can occur in virtually any warm-blooded pet, which acts as the intermediate web host for the parasites.[6, 7] Tachyzoites and bradyzoites can be found in the individual stage of the life span cycle. Tachyzoites will be the obligate intracellular types of and their main aim is to quickly expand the parasite people inside the web host cells during severe infections. On the other hand, bradyzoites will be the latent types of parasites include a non-photosynthetic relict plastid, known as apicoplast.[9, 10] Little circular genome and biochemical pathways such as for example isoprenoid and type II fatty acidity synthesis systems had been detected within this specific organelle.[11, 12] The mechanism from the apicoplast-localized type II fatty acidity synthesis pathway (FAS II) was studied in (and protozoan, parasites, the transformation of acetyl coenzyme A (acetyl-CoA) to full-length fatty acidity chains can be an iterative procedure mediated by discrete mono-functional enzymes, referred to as FAS II.[13, 14] On the other hand, the eukaryotic type We fatty acidity synthesis program (FAS We) operates seeing that an individual multi-functional enzyme that catalyzes all of the steps from the pathway. Also acetyl-CoA carboxylase (ACCase), an enzyme in charge of the formation of malonyl-CoA, considerably differs in both of these systems. The ACCase of prokaryotes includes four specific subunits associated with a little acyl carrier proteins, whereas the ACCase of eukaryotes is normally a single huge multi-domain proteins.[15] The prokaryotic origin from the biochemical pathways inside apicoplasts provides provided various novel drug focuses on. Since they are fundamentally not the same as the matching systems working in the individual web host cells, many enzymes involved with apicomplexan FAS II became validated molecular goals for the introduction of powerful anti-protozoan medications.[11] The enoyl-acyl carrier protein (ACP) reductase (ENR or FabI) is among the key enzymes involved with FAS II that reduces, within a nicotinamide adenine dinucleotide (NADH)-reliant manner, enoyl-ACP to acyl-ACP, which may be the last and rate-determining part of the fatty acidity chain elongation procedure. [16] A couple of three various other isoforms of ENR: FabK, FabL and FabV, which can be found in bacterias.[17C19] The genome contains an individual ENR (and tachyzoites displays against purified tachyzoites allowed us to choose interesting candidates for even more biological evaluation. General, this function provides significant insights in to the breakthrough of brand-new and effective inhibitors of (a) neopentyl glycol, H3NSO3, PhMe, 110 C, 3 h, 87%; (b) 1. For 3, 1,3-dichloro-4-fluorobenzene, Cs2CO3, DMF, 130 C, 14 h, 51%; 2. for 11, 3-chloro-4-fluorobenzaldehyde, Cs2CO3, DMF, 125 C, 16 h, 92%; (c) PPTS, moist acetone, reflux, 2.5 h, 100%; (d) NaBH4, MeOH, RT, 1.5 h. For 5, 84%; for 12, 100%; (e) CBr4, PPh3, THF, RT. 1. For 6, 14 h, 83%; 2. for 13, 2 h, 80%; (f) NaN3, DMF. 1. For 7, 110 C, 7 h, 71%; 2. for 14, 100 C, 14 h, 56%; (g) sodium ascorbate, CuSO45H2O, 1-alkyne, (a) water H2O-EtOH-ice (1:1:2), H2NOHHCl, 50% aq NaOH, RT, 75 min, 90%; (b) NCS, DMF, RT, 1.5 h, 100%; (c) sodium ascorbate, CuSO45H2O, KHCO3, 1-alkyne, (a) 1. 2,4-dichlorophenol, Cs2CO3, DMF, 120 C, 21 h, 65% for Encequidar 26; 2. 3-chloro-4-fluorobenzonitrile, Cs2CO3, DMF, 100 C, 16 h, 75% for 34; (b) Bu4NI, CH2Cl2, RT, 5 min, after that BCl3, ?78 C, 15 min, then RT, 2 h. For 27, 82%; for 30a, R = H, R1 = Ph, 51%; for 30b, R = R1 = tachyzoites (assessed as reduced uptake of [3H] uracil or fluorescence with YFP transfected parasites [make sure you see strategies], Desk 1). Desk 1 Activity data and ADMET predictions for brand-new group of triclosan-based parasite, individual host cell, and enzyme data along.Such accommodation of compound 33 facilitates its efficient packing into the active site of ENR, which in turn corresponds to the high inhibitory activity of this analog. of can be accompanied with fever and adenopathy or other symptoms, but asymptomatic infections can also occur. However, recrudescence in immunocompromised patients can lead to severe pathologic conditions, including lethal encephalitis.[3] Congenital toxoplasmosis may result in abortion, neonatal death, or fetal abnormalities,[4] and children congenitally infected with parasites almost all develop ocular disease during fetal life, in the perinatal period, or at later ages if not treated during fetal life or infancy.[5] Several distinct stages are involved in life cycle, which is comprised of two phases: sexual and asexual. The former phase takes place only in the primary hosts, which are domestic and wild cats from your Felidae family, whereas the asexual phase can occur in any warm-blooded animal, which serves as the intermediate host for the parasites.[6, 7] Tachyzoites and bradyzoites are present in the human stage of the life cycle. Tachyzoites are the obligate intracellular forms of and their primary goal is to rapidly expand the parasite populace within the host cells during acute infections. In contrast, bradyzoites are the latent forms of parasites contain a non-photosynthetic relict plastid, called apicoplast.[9, 10] Small circular genome and biochemical pathways such as isoprenoid and type II fatty acid synthesis systems were detected within this particular organelle.[11, 12] The mechanism of the apicoplast-localized type II fatty acid synthesis pathway (FAS II) was initially studied in (and protozoan, parasites, the conversion of acetyl coenzyme A (acetyl-CoA) to full-length fatty acid chains is an iterative process mediated by discrete mono-functional enzymes, known as FAS II.[13, 14] On the contrary, the eukaryotic type I fatty acid synthesis system (FAS I) operates as a single multi-functional enzyme that catalyzes all the steps of the pathway. Also acetyl-CoA carboxylase (ACCase), an enzyme responsible for the synthesis of malonyl-CoA, significantly differs in these two systems. The ACCase of prokaryotes consists of four individual subunits linked to a small acyl carrier protein, whereas the ACCase of eukaryotes is usually a single large multi-domain protein.[15] The prokaryotic origin of the biochemical pathways inside apicoplasts has provided a plethora of novel drug targets. Since these are fundamentally different from the corresponding systems operating in the human host cells, several enzymes involved in apicomplexan FAS II became validated molecular targets for the development of potent anti-protozoan drugs.[11] The enoyl-acyl carrier protein (ACP) reductase (ENR or FabI) is one of the key enzymes involved in FAS II that reduces, in a nicotinamide adenine dinucleotide (NADH)-dependent manner, enoyl-ACP to acyl-ACP, which is the final and rate-determining step in the fatty acid chain elongation process. [16] You will find three other isoforms of ENR: FabK, FabL and FabV, which are present in bacteria.[17C19] The genome contains a single ENR (and tachyzoites screens against purified tachyzoites allowed us to select interesting candidates for further biological evaluation. Overall, this work provides significant insights into the discovery of new and effective inhibitors of (a) neopentyl glycol, H3NSO3, PhMe, 110 C, 3 h, 87%; (b) 1. For 3, 1,3-dichloro-4-fluorobenzene, Cs2CO3, DMF, 130 C, 14 h, 51%; 2. for 11, 3-chloro-4-fluorobenzaldehyde, Cs2CO3, DMF, 125 C, 16 h, 92%; (c) PPTS, wet acetone, reflux, 2.5 h, 100%; (d) NaBH4, MeOH, RT, 1.5 h. For 5, 84%; for 12, 100%; (e) CBr4, PPh3, THF, RT. 1. For 6, 14 h, 83%; 2. for 13, 2 h, 80%; (f) NaN3, DMF. 1. For 7, 110 C, 7 h, 71%; 2. for 14, 100 C, 14 h, 56%; (g) sodium ascorbate, CuSO45H2O, 1-alkyne, (a) liquid H2O-EtOH-ice (1:1:2), H2NOHHCl, 50% aq NaOH, RT, 75 min, 90%; (b) NCS, DMF, RT, 1.5 h, 100%; (c) sodium ascorbate, CuSO45H2O, KHCO3, 1-alkyne, (a) 1. 2,4-dichlorophenol, Cs2CO3, DMF, 120 C, 21 h, 65% for 26; 2. 3-chloro-4-fluorobenzonitrile, Cs2CO3, DMF, 100 C, 16 h, 75% for 34; (b) Bu4NI, CH2Cl2, RT, 5 min, then BCl3, ?78 C, 15 min, then RT, 2 h. For 27, 82%; for 30a, R = H, R1 = Ph, 51%; for 30b, R = R1 = tachyzoites (measured as diminished uptake of [3H] uracil or fluorescence with YFP transfected parasites [please see methods], Table 1). Table 1 Activity data and ADMET predictions for new series of triclosan-based parasite, human host cell, and enzyme data along with predictions for the selected ADMET parameters are offered in Table 1..