Biological evaluation and structure activity relationship of 9-methyl-1- phenyl-9H-pyrido[3,4-b]indole derivatives as anti-leishmanial agents

Penta Ashoka, Subhash Chander Terry K. Smithc, Rajnish Prakash Singhd, Prabhat Nath Jhad,Murugesan Sankaranarayanan

Medicinal Chemistry Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science Pilani, Pilani Campus, Pilani 333031, Rajasthan, India
School of Pharmacy, Maharaja Agrasen University, Atal ShikshaKunj, Solan, Himachal Pradesh 174103, India
Schools of Biology & Chemistry, BSRC, The University, St. Andrews, Fife Scotland. KY16 9ST, UK
Department of Biological Sciences, Birla Institute of Technology & Science Pilani, Pilani Campus, Pilani 333031, Rajasthan, India

 

Introduction
Leishmaniasis is caused by intracellular protozoan Leishmania spp parasites and is considered as one of the most neglected tropical diseases. Among various clinical forms of leishmaniasis, visceral leish-maniasis is the most severe, affecting internal organs like bone marrow, liver and spleen. VL is also known as kala-azar and is lethal if untreated in over 95% of cases. VL caused by Leishmania donovani and Leishmania infantum [1,2]. Leishmaniasis control is majorly dependent upon chemotherapy that includes decade old drugs, due to no effective vaccines.

 

Antimonial drugs such as sodium stibogluconate and meglumineantimoniate have been used for the last 70 years, however increasing incidence of resistance has been reported [3]. Anti-leishmanial drugs such as amphotericin B, diamidine, pentamidine and paromomycin has been restricted by cost, toxicity and resistance [4,5]. Miltefosine is originally developed as anti-cancer agent, has been approved by FDA for leishmaniasis treatment [6]. Miltefosine has restricted use in pregnancy and has high risk of resistance due to long half-life (150 h). Clinical efficacy of miltefosine has been decreased in countries like India, where it is used extensively [7]. Based upon these collective facts, there is an increased need of new anti-leishmanial agents with good therapeutic profiles.

 

Nature and natural products remain an important source for the development of therapeutic agents. Natural products especially alkaloids have been known for anti-infective activity. β-carboline represents
a tricyclic pyrido[3,4-b]indole ring system has reported for wide spectrum of biological activities. β-carboline derivatives displayed different biological activities such as anti-microbial [8], anti-cancer [9], anti-leishmanial [10,11], anti-malarial [12,13], anti-tubercular [14], anti-viral [15] and anti-thrombotic activities [16]. β-carboline alkaloids such as Harmine, annomontine and manzamines (Fig. 1) exhibited
potent anti-leishmanial activity [10,17,18]. Manzamine is a group of β-carboline alkaloids, possess complex structure of β-carboline moiety attached to a pentacyclic diamine ring having both eight and thirteen membered rings on a pyrrolo[2,3-i] isoquinoline framework. Large numbers of manzamine alkaloids are isolated from different marine sponge species and exhibited potent anti-leishmanial activity. Beside these natural β-carboline alkaloids, several synthetic β-carboline derivatives having different substitutions on 1, 2, 3 and 9 positions have exhibited significant anti-leishmanial activity [18,19]. Among these synthetic β-carboline derivatives, β-carboline derivatives with N-alkylcarboxamide group on 3 position displayed potent anti-leishmanial activity and attracted us to design new β-carboline derivatives.

 

The piperazine moiety has privileged position in medicinal chemistry with diverse biological activities [24]. Bisarylpiperazine derivatives exhibited activities such as anti-leishmanial [25], anti-microbial, anti-protozoal [28,29], anti-cancer, anti-tubercular and anti-viral (Fig. 1). Based upon literature reports, in the present study we designed β-carboline and piperazine hybrid molecules (Fig. 1) using molecular hybridization approach.

 

2. Results and discussion
2.1. Chemistry
The synthetic scheme for β-carbolinepiperazine derivatives was illustrated in Scheme 1. The titled compounds were synthesized using DL-Tryptophan (1) as starting material. Initial esterification of DL-Tryptophan (1) using thionylchloride to get an ethyl ester of tryptophan(2), was followed by pictet-spengler reaction in presence of trifluoroacetic acid to obtain tricyclic ethyl 2,3,4,9-tetrahydro-1-phenyl-
1H-pyrido[3,4-b]indole-3-carboxylate (3). Upon oxidation with potassium permanganate, ethyl-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (4) was obtained, and is continued by 9-N methylation with
methyl iodide in presence of potassium hydroxide to acquire ethyl-9-methyl-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylate (5). Further alkaline ester hydrolysis of compound (5) produced 9-methyl-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxylic acid (6) as key intermediate. The carboxylic acid key intermediate (6) was treated with appropriate amines (aryl-substitutedpiperazines) in presence of coupling agent 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt) to obtain the desired products (7a-p) in good yields.

 

2.2. Biological evaluation
2.2.1. Cytotoxicity evaluation
Initially all these reported β-carboline derivatives were evaluated for cytotoxicity against HeLa cell lines at 500 μM by an Alamar blue assay, which showed most of these compounds were non-toxic to HeLa
cells at tested concentration. Compounds which showed cytotoxicity against HeLa cells were further evaluated to determine cytotoxic concentration (CC50) value. Among these reported β-carboline derivatives, compound 7o and 7p showed cytotoxicity (CC50 29.7 and 27.3 μM, respectively) against HeLa cells.

 

2.2.2. Anti-leishmanial screening
Anti-leishmanial activity of these analogues was determined by evaluating their inhibition activity against both promastigote, amastigote forms of Leishmania infantum and Leishmania donovani strains.
Compounds were screened against promastigote forms of the Leishmania strains to determine their effective concentration (EC50) values. Finally, compounds which exhibited potent inhibition of promastigote (EC50 < 20 µM) were further evaluated against amastigote forms of respective strain using established axenic and intracellular amastigote assay methodologies. Anti-leishmanial drugs miltefosine and pentamidine were used as standards for comparison purpose.

 

2.2.2.1. Leishmaniainfantum
2.2.2.1.1. Anti-promastigote activity. Anti-promastigote activity of these reported β-carboline derivatives was determined by Alamar blue assay method. In in-vitro evaluation against promastigotes of L.
infantum, compounds 7g, 7d, and 7c displayed potent antipromastigote activity (EC50 1.47, 1.59 and 3.73 µM respectively) than standard drugs pentamidine and miltefosine (EC50 8.31 and 12.36 µM
respectively). Compounds 7a, 7f, 7j and 7k displayed significant inhibition of L. infantum promastigotes (EC50 9.45, 13.8, 19.7 and 17.2 µM respectively) and inhibition potency was comparable with standard drugs. Analogues 7n, 7b and 7h exhibited moderate activity (EC50 20.4, 24.3 and 21.7 µM respectively), while 7d, 7h, 7l, 7m, 7o and 7p showed weak anti-promastigote activity (EC50 72.4, 50.9, 64.9, 93.0, 29.7 and 45.7 µM respectively) against L. infantum. Especially, compounds 7d and 7g exhibited most promising inhibition of L. infantum and are five times more potent than the standard drugs.

 

Structure activity relationship studies suggested that, para substitution with ortho-para directing groups (methoxy and chloro) enhanced promastigotes inhibition activity significantly. Ortho substitution with methyl group has increased the anti-promastigote activity significantly while substitution of other ortho-para directing and meta directing groups (methoxy, chloro) substitution on phenyl ring has decreased the activity drastically. Replacement of phenyl ring with benzyl and pyridyl ring was not favorable for anti-promastigote activity.

 

2.2.2.1.2. Anti-amastigote activity. Compounds exhibited significant inhibition of L. infantum promastigotes (EC50 < 20 μM) were further evaluated against axenic amastigote forms of L. infantum. Alamar blue assay method was used to determine inhibition potential of these β-carboline derivatives against (human life stage forms) axenic amastigotes. In L. infantum axenic amastigote inhibition assay, compounds 7d, 7g and 7c displayed potent activity (EC50 1.4, 1.9 and 2.6 µM respectively) better than standard drugs pentamidine and miltefosine (EC50 2.7 and 4.8 µM). Compound 7a showed axenic antiamastigote activity (EC50 4.5 µM) against L. infantum and potency was comparable with standard drugs. Compounds, 7j, 7k and 7f exhibited significant inhibition of L. infantum axenic amastigotes (EC50 14.6, 15.0 and 15.3). In-vitro anti-amastigote activity results (Table 1) suggested that these β-carboline derivatives were more potent against axenic amastigote forms of L. infantum.

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4-N-(4-methylphenyl)pyridine-3,4-diamine Catalog No.:AA01AFC8 CAS No.:1038315-36-4 MDL No.:MFCD11202092 MF:C12H13N3 MW:199.2517	5-[(Carbamoylmethyl)sulfamoyl]furan-2-carboxylic acid Catalog No.:AA01AKIR CAS No.:1038327-92-2 MDL No.:MFCD11203529 MF:C7H8N2O6S MW:248.2132
1-(4-Fluorophenyl)-1h-1,3-benzodiazole-2-thiol Catalog No.:AA019Y45 CAS No.:1038333-46-8 MDL No.:MFCD11202249 MF:C13H9FN2S MW:244.2874	2-[(1-tert-Butyl-1h-imidazol-2-yl)sulfanyl]acetic acid Catalog No.:AA01A8K2 CAS No.:1038334-94-9 MDL No.:MFCD11201206 MF:C9H14N2O2S MW:214.2847
2-[4-(3-methylbut-2-enamido)phenyl]acetic acid Catalog No.:AA019SSZ CAS No.:1038334-99-4 MDL No.:MFCD11202662 MF:C13H15NO3 MW:233.2631	4-[(3-methylbut-2-enamido)methyl]benzoic acid Catalog No.:AA019SRE CAS No.:1038335-01-1 MDL No.:MFCD11202664 MF:C13H15NO3 MW:233.2631
4-(2,2,2-Trifluoroethyl)-4h-1,2,4-triazole-3-thiol Catalog No.:AA01A82D CAS No.:1038337-22-2 MDL No.:MFCD11201338 MF:C4H4F3N3S MW:183.1549	4-(6-Methoxypyridin-3-yl)-4h-1,2,4-triazole-3-thiol Catalog No.:AA01AAMT CAS No.:1038337-28-8 MDL No.:MFCD11201342 MF:C8H8N4OS MW:208.2403
5-(1-Phenylpropyl)-1,3,4-oxadiazole-2-thiol Catalog No.:AA01A9YE CAS No.:1038340-13-4 MDL No.:MFCD11201452 MF:C11H12N2OS MW:220.2908	H-Thr(tbu)-NH2 HCl Catalog No.:AA0095ZH CAS No.:1038343-47-3 MDL No.:MFCD08458641 MF:C8H19ClN2O2 MW:210.7017
3-(Piperidin-3-yloxy)pyridine dihydrochloride Catalog No.:AA009A2O CAS No.:1038351-48-2 MDL No.:MFCD09879211 MF:C10H16Cl2N2O MW:251.1528	(2-Fluoro-5-methylphenyl)thiourea Catalog No.:AA01A7KF CAS No.:1038356-01-2 MDL No.:MFCD11202366 MF:C8H9FN2S MW:184.2339
2-(3-tert-Butyl-1,2,4-oxadiazol-5-yl)benzoic acid Catalog No.:AA01A9IQ CAS No.:1038356-45-4 MDL No.:MFCD11543487 MF:C13H14N2O3 MW:246.2619	4-(3-methyl-1,2,4-oxadiazol-5-yl)butanoic acid Catalog No.:AA019MVJ CAS No.:1038356-82-9 MDL No.:MFCD11099590 MF:C7H10N2O3 MW:170.1659
3-[3-(4H-1,2,4-triazol-3-yl)-1,2,4-oxadiazol-5-yl]propanoic acid Catalog No.:AA01A87F CAS No.:1038356-87-4 MDL No.:MFCD11203663 MF:C7H7N5O3 MW:209.1622	4-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]butanoic acid Catalog No.:AA019MWA CAS No.:1038356-92-1 MDL No.:MFCD11099600 MF:C9H14N2O3 MW:198.2191
5-(1-Chloroethyl)-3-(4h-1,2,4-triazol-3-yl)-1,2,4-oxadiazole Catalog No.:AA019SE4 CAS No.:1038358-79-0 MDL No.:MFCD11203766 MF:C6H6ClN5O MW:199.5977	(1E,4E)-1,5-Bis(4-(trifluoromethyl)phenyl)penta-1,4-dien-3-one Catalog No.:AA008XIB CAS No.:103836-71-1 MDL No.:MFCD05662426 MF:C19H12F6O MW:370.2884
2-(4,4-dimethyl-1,2,3,4-tetrahydronaphthalen-1-yl)acetic acid Catalog No.:AA01A8X4 CAS No.:1038360-49-4 MDL No.:MFCD11200492 MF:C14H18O2 MW:218.2915	2-{[4-(1-methoxypropan-2-yl)-5-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl}acetic acid Catalog No.:AA01A91D CAS No.:1038360-54-1 MDL No.:MFCD13465840 MF:C14H17N3O3S MW:307.3681
4-(chloromethyl)-2-(2-fluorophenyl)-1,3-oxazole Catalog No.:AA01BXJP CAS No.:1038362-92-3 MDL No.:MFCD11200990 MF:C10H7ClFNO MW:211.6201	5-[(3-methoxyphenyl)methyl]-1,3,4-oxadiazole-2-thiol Catalog No.:AA01A9YF CAS No.:1038368-50-1 MDL No.:MFCD16716810 MF:C10H10N2O2S MW:222.2636
1-[2-(pyridin-2-yl)ethyl]-1H-1,3-benzodiazol-2-amine Catalog No.:AA019TTT CAS No.:1038373-23-7 MDL No.:MFCD11202267 MF:C14H14N4 MW:238.2878	1-(3-Ethoxypropyl)-1h-1,3-benzodiazol-2-amine Catalog No.:AA01AA6O CAS No.:1038373-35-1 MDL No.:MFCD11202279 MF:C12H17N3O MW:219.2829
1-(2-methoxyethyl)-1H-1,3-benzodiazol-2-amine Catalog No.:AA01AC7A CAS No.:1038373-41-9 MDL No.:MFCD11202284 MF:C10H13N3O MW:191.2297	7-Hydroxy-2,2-dimethyl-2,3-dihydro-1-benzofuran-6-carboxylic acid Catalog No.:AA01A9N9 CAS No.:1038374-76-3 MDL No.:MFCD11203619 MF:C11H12O4 MW:208.2106
1-N-(2,4-Difluorophenyl)-4-fluorobenzene-1,2-diamine Catalog No.:AA01A1TG CAS No.:1038374-82-1 MDL No.:MFCD11201979 MF:C12H9F3N2 MW:238.2085	2-Hydroxy-3-(2-hydroxyethoxy)benzoic acid Catalog No.:AA00HA41 CAS No.:1038374-86-5 MDL No.:MFCD11203634 MF:C9H10O5 MW:198.1727
2-[3-(propan-2-yl)-1,2,4-oxadiazol-5-yl]benzoic acid Catalog No.:AA01A9IP CAS No.:1038375-52-8 MDL No.:MFCD11203665 MF:C12H12N2O3 MW:232.2353	4-(3-Cyclopropyl-1,2,4-oxadiazol-5-yl)butanoic acid Catalog No.:AA01AK2E CAS No.:1038375-57-3 MDL No.:MFCD11203667 MF:C9H12N2O3 MW:196.2032
4-(3-ethyl-1,2,4-oxadiazol-5-yl)butanoic acid Catalog No.:AA019MZR CAS No.:1038375-62-0 MDL No.:MFCD12087067 MF:C8H12N2O3 MW:184.1925	N1-[2-(trifluoromethyl)phenyl]benzene-1,2-diamine Catalog No.:AA01BUKW CAS No.:1038384-29-0 MDL No.:MFCD11201640 MF:C13H11F3N2 MW:252.2350
2-[4-(methylsulfanyl)phenyl]-2-{4H,5H,6H,7H-thieno[3,2-c]pyridin-5-yl}ethan-1-amine Catalog No.:AA019UBE CAS No.:1038385-53-3 MDL No.:MFCD11641622 MF:C16H20N2S2 MW:304.4734	1-Methyl-2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-6-carboxylic acid Catalog No.:AA00IUKN CAS No.:1038385-70-4 MDL No.:MFCD11203524 MF:C10H8N2O4 MW:220.1815
Ethyl 8-bromo-2-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylate Catalog No.:AA0090WS CAS No.:1038389-86-4 MDL No.:MFCD12025881 MF:C11H8BrF3N2O2 MW:337.0926	Ethyl 8-bromoimidazo[1,2-a]pyridine-2-carboxylate Catalog No.:AA0097E0 CAS No.:1038393-19-9 MDL No.:MFCD11976183 MF:C10H9BrN2O2 MW:269.0947
(R)-1-(4-(Methylsulfonyl)phenyl)ethanamine Catalog No.:AA008TLQ CAS No.:1038393-47-3 MDL No.:MFCD06761967 MF:C9H13NO2S MW:199.2700	(E)-(4-(2-(1H-Indazol-3-yl)vinyl)phenyl)(piperazin-1-yl)methanone hydrochloride Catalog No.:AA008TEF CAS No.:1038395-65-1 MDL No.:MFCD20526429 MF:C26H31Cl2N3O3 MW:504.4486
3-(4-(Trifluoromethyl)phenyl)-1H-pyrazole-5-carboxylic acid Catalog No.:AA00HA48 CAS No.:1038398-68-3 MDL No.:MFCD09749428 MF:C11H7F3N2O2 MW:256.1807	1,2-BenzenediaMine, 4-broMo-N2-(1-Methylethyl)- Catalog No.:AA00950E CAS No.:1038408-35-3 MDL No.:MFCD12923357 MF:C9H13BrN2 MW:229.1169
6-Bromo-1-isopropyl-2-methyl-1h-benzo[d]imidazole Catalog No.:AA0093RS CAS No.:1038408-36-4 MDL No.:MFCD11113090 MF:C11H13BrN2 MW:253.1383	(m-tolylsulfonyl)proline Catalog No.:AA01FLUK CAS No.:1038410-49-9 MDL No.:MFCD06319793 MF:C12H15NO4S MW:269.3168
N-[ε-Maleimidocaproyloxy]sulfosuccinimide Ester Catalog No.:AA00857E CAS No.:103848-61-9 MDL No.:MFCD01310272 MF:C14H16N2O9S MW:388.3498	4-(Benzyloxy)butanoic acid Catalog No.:AA003KQX CAS No.:10385-30-5 MDL No.:MFCD01321257 MF:C11H14O3 MW:194.2271
1-Bromo-2,3,4-trimethoxybenzene Catalog No.:AA003FA2 CAS No.:10385-36-1 MDL No.:MFCD01318955 MF:C9H11BrO3 MW:247.0858	2-Acetamido-1,3,4,6-tetra-O-acetyl-2-deoxy-a-D-galactopyranose Catalog No.:AA007WWS CAS No.:10385-50-9 MDL No.:MFCD15144916 MF:C16H23NO10 MW:389.3545
Methyl benzo[d]thiazole-7-carboxylate Catalog No.:AA007X0E CAS No.:1038509-28-2 MDL No.:MFCD13190218 MF:C9H7NO2S MW:193.2224	7-chlorobenzofuran-4-carboxylic acid Catalog No.:AA01C821 CAS No.:1038509-42-0 MDL No.:MFCD20527735 MF:C9H5ClO3 MW:196.5872
pyrrolo[2,1-b]thiazole-7-carboxylic acid Catalog No.:AA0090BE CAS No.:1038509-46-4 MDL No.:MFCD20646091 MF:C7H5NO2S MW:167.1851	(1S,3S,5S)-tert-Butyl 3-(aminomethyl)-2-azabicyclo[3.1.0]hexane-2-carboxylate Catalog No.:AA00HA4C CAS No.:1038509-56-6 MDL No.:MFCD28501263 MF:C11H20N2O2 MW:212.2887
5-[(Dimethylamino)methyl]-2-furohydrazide Catalog No.:AA00857A CAS No.:103852-00-2 MDL No.:MFCD06358042 MF:C8H13N3O2 MW:183.2077	4-Hydroxy-2-methylquinoline-6-carboxylic acid Catalog No.:AA008Y2B CAS No.:103853-88-9 MDL No.:MFCD00455298 MF:C11H9NO3 MW:203.1941
(S)-2-Amino-3-(2,6-dimethylphenyl)propanoic acid Catalog No.:AA009137 CAS No.:103854-26-8 MDL No.:MFCD09842594 MF:C11H15NO2 MW:193.2423	Ketone, methyl 5-quinolyl (6CI) Catalog No.:AA008U8C CAS No.:103854-56-4 MDL No.:MFCD09754106 MF:C11H9NO MW:171.1953
1-(Quinolin-7-yl)ethanone Catalog No.:AA009NPN CAS No.:103854-57-5 MDL No.:MFCD09754107 MF:C11H9NO MW:171.1953	8-Methoxyquinoline-4-carbaldehyde Catalog No.:AA0095RI CAS No.:103854-62-2 MDL No.:MFCD06824369 MF:C11H9NO2 MW:187.1947
8-Methoxyquinoline-2-carbaldehyde Catalog No.:AA007WWT CAS No.:103854-64-4 MDL No.:MFCD05864557 MF:C11H9NO2 MW:187.1947	1-Butyl-6-oxo-1,6-dihydropyridazine-3-carboxylic acid Catalog No.:AA008577 CAS No.:103854-71-3 MDL No.:MFCD05263553 MF:C9H12N2O3 MW:196.2032
CAY10622 Catalog No.:AA008SOP CAS No.:1038549-25-5 MDL No.:MFCD18206887 MF:C25H25N5O3 MW:443.4977	4-(4-Bromophenyl)-1,2,3,6-tetrahydropyridine hydrochloride Catalog No.:AA0092F4 CAS No.:103855-00-1 MDL No.:MFCD03412448 MF:C11H13BrClN MW:274.5846
tert-butyl N-[(6S)-2-amino-4,5,6,7-tetrahydro-1,3-benzothiazol-6-yl]carbamate Catalog No.:AA01BASF CAS No.:1038555-08-6 MDL No.:MFCD23162858 MF:C12H19N3O2S MW:269.3632	N-(4-Methoxyphenyl)-2-methylalanine Catalog No.:AA007FC3 CAS No.:103856-06-0 MDL No.:MFCD05228759 MF:C11H15NO3 MW:209.2417
3-(Pyridin-4-yloxy)phenol Catalog No.:AA01A1HP CAS No.:103856-58-2 MDL No.:MFCD12800361 MF:C11H9NO2 MW:187.1947	5-Methyl-1-(2-nitrophenyl)-1H-pyrazole-3-carboxylic acid Catalog No.:AA007WWP CAS No.:103856-74-2 MDL No.:MFCD13190657 MF:C11H9N3O4 MW:247.2069
3-(Dimethylamino)-1-(1-hydroxycyclohexyl)propan-1-one hydrochloride Catalog No.:AA00J3Z5 CAS No.:103857-05-2 MDL No.:MFCD26959483 MF:C11H22ClNO2 MW:235.7509	4-(3-bromopropoxy)-1,2-dimethylbenzene Catalog No.:AA019LXO CAS No.:103857-79-0 MDL No.:MFCD16653302 MF:C11H15BrO MW:243.1402
2-(2-Methoxyphenyl)pyrrolidine Catalog No.:AA007FC1 CAS No.:103857-96-1 MDL No.:MFCD02663408 MF:C11H15NO MW:177.2429	8-ethyl-1,2,3,4-tetrahydroquinoline Catalog No.:AA01AHHZ CAS No.:103858-38-4 MDL No.:MFCD09732239 MF:C11H15N MW:161.2435
3-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-5-ol Catalog No.:AA01B517 CAS No.:103858-43-1 MDL No.:MFCD20694319 MF:C11H15NO MW:177.2429	2-Bromo-4,6-dimethylquinoline Catalog No.:AA00HA4G CAS No.:103858-47-5 MDL No.:MFCD21647772 MF:C11H10BrN MW:236.1078
Ethyl 4-bromo-1H-indole-2-carboxylate Catalog No.:AA00386K CAS No.:103858-52-2 MDL No.:MFCD12174997 MF:C11H10BrNO2 MW:268.1066	Ethyl 6-bromoindole-2-carboxylate Catalog No.:AA00386J CAS No.:103858-53-3 MDL No.:MFCD03094942 MF:C11H10BrNO2 MW:268.1066
Ethyl 6-bromo-1h-indole-3-carboxylate Catalog No.:AA003QAK CAS No.:103858-55-5 MDL No.:MFCD11617101 MF:C11H10BrNO2 MW:268.1066	2-(3,5-dimethyl-1H-pyrazol-4-yl)aniline Catalog No.:AA019UTE CAS No.:103858-98-6 MDL No.:MFCD09732791 MF:C11H13N3 MW:187.2410
4-DIISOPROPYLAMINO-1-BUTANOL Catalog No.:AA008RV2 CAS No.:103859-38-7 MDL No.:MFCD00026378 MF:C10H23NO MW:173.2957	(3-Methoxy-4-propoxyphenyl)methanol Catalog No.:AA009SH2 CAS No.:103859-81-0 MDL No.:MFCD06340073 MF:C11H16O3 MW:196.2429
4-(4-Methoxyphenyl)pyrrolidin-2-one Catalog No.:AA008R63 CAS No.:103859-86-5 MDL No.:MFCD00297168 MF:C11H13NO2 MW:191.2264	4-bromo-2-isopropoxybenzoic acid Catalog No.:AA019X72 CAS No.:1038595-51-5 MDL No.:MFCD11651855 MF:C10H11BrO3 MW:259.0965
2-Bromoisonicotinonitrile Catalog No.:AA003GL9 CAS No.:10386-27-3 MDL No.:MFCD07367879 MF:C6H3BrN2 MW:183.0054	4,4'-Dibromooctafluorobiphenyl Catalog No.:AA003KC4 CAS No.:10386-84-2 MDL No.:MFCD00000310 MF:C12Br2F8 MW:455.9236
1-(chloromethyl)-2-isobutylbenzene Catalog No.:AA01BIUM CAS No.:103861-30-9 MDL No.:MFCD20636680 MF:C11H15Cl MW:182.6898	1-ethyl-1,2,3,4-tetrahydroisoquinoline hydrochloride Catalog No.:AA00HA4I CAS No.:103861-49-0 MDL No.:MFCD18838970 MF:C11H16ClN MW:197.7044
2-(3-Methoxyphenyl)pyrrolidine Catalog No.:AA007FBX CAS No.:103861-77-4 MDL No.:MFCD02663445 MF:C11H15NO MW:177.2429	((4-chloro-3-(trifluoromethyl)phenyl)sulfonyl)leucine Catalog No.:AA01FMYT CAS No.:1038619-52-1 MDL No.:MFCD03619023 MF:C13H15ClF3NO4S MW:373.7757
5-Bromo-8-methoxy-2-methylquinoline Catalog No.:AA008RNQ CAS No.:103862-55-1 MDL No.:MFCD04966993 MF:C11H10BrNO MW:252.1072	4-Chloro-6-ethoxyquinoline Catalog No.:AA007WWJ CAS No.:103862-63-1 MDL No.:MFCD09787733 MF:C11H10ClNO MW:207.6562
5-(chloromethyl)-2-methylquinolin-8-ol hydrochloride Catalog No.:AA01BD6W CAS No.:103862-65-3 MDL No.:MFCD28023739 MF:C11H11Cl2NO MW:244.1171	4-Phenylnicotinic acid Catalog No.:AA007FAA CAS No.:103863-14-5 MDL No.:MFCD04114252 MF:C12H9NO2 MW:199.2054
3-Phenylpicolinic acid Catalog No.:AA008SBH CAS No.:103863-15-6 MDL No.:MFCD04114112 MF:C12H9NO2 MW:199.2054	2-bromo-5-methanesulfonylbenzene-1-sulfonyl chloride Catalog No.:AA019WR4 CAS No.:1038695-53-2 MDL No.:MFCD11204486 MF:C7H6BrClO4S2 MW:333.6071
3-(2,4-dichlorophenyl)-4,5-dihydro-1,2-oxazole-5-carboxylic acid Catalog No.:AA019VCY CAS No.:1038696-41-1 MDL No.:MFCD11203720 MF:C10H7Cl2NO3 MW:260.0735	ethyl 3-amino-4-cyano-1-ethyl-1H-pyrrole-2-carboxylate Catalog No.:AA01C3JT CAS No.:1038697-86-7 MDL No.:MFCD11203768 MF:C10H13N3O2 MW:207.2291
3-[2-(methylamino)ethoxy]benzonitrile Catalog No.:AA01AH9P CAS No.:1038699-39-6 MDL No.:MFCD11199907 MF:C10H12N2O MW:176.2151	9,10-Bis(chloromethyl)anthracene Catalog No.:AA00856R CAS No.:10387-13-0 MDL No.:MFCD00045388 MF:C16H12Cl2 MW:275.1725
Potassium thioacetate Catalog No.:AA0035FO CAS No.:10387-40-3 MDL No.:MFCD00137704 MF:C2H3KOS MW:114.2079	N-Methyl-2-(2-nitrophenoxy)ethanamine Catalog No.:AA003T3D CAS No.:1038700-63-8 MDL No.:MFCD11053870 MF:C9H12N2O3 MW:196.2032
1-[2-(Morpholin-4-yl)ethyl]-1h-1,2,3-triazole-4-carboxylic acid Catalog No.:AA019QVX CAS No.:1038705-22-4 MDL No.:MFCD11204200 MF:C9H14N4O3 MW:226.2325	1-[2-(dimethylamino)ethyl]-1H-1,2,3-triazole-4-carboxylic acid Catalog No.:AA01AKRG CAS No.:1038705-93-9 MDL No.:MFCD11204216 MF:C7H12N4O2 MW:184.1958
4-(chloromethyl)-2-(2-methoxyphenyl)-1,3-oxazole Catalog No.:AA01C03W CAS No.:1038708-65-4 MDL No.:MFCD11200993 MF:C11H10ClNO2 MW:223.6556	3-methoxy-3,4-dihydro-2H-1-benzopyran-4-amine Catalog No.:AA01EI5U CAS No.:1038710-36-9 MDL No.:MFCD11126269 MF:C10H13NO2 MW:179.2157
3-(3-Hydroxyphenyl)-1,3-oxazolidin-2-one Catalog No.:AA007WWH CAS No.:1038713-37-9 MDL No.:MFCD11054000 MF:C9H9NO3 MW:179.1727	3-Chloro-2-hydroxy-5-phenylbenzoic acid Catalog No.:AA019T5T CAS No.:1038713-54-0 MDL No.:MFCD11203649 MF:C13H9ClO3 MW:248.6618
1-[3-(Trifluoromethyl)phenyl]cyclohexane-1-carboxylic acid Catalog No.:AA019QU5 CAS No.:1038719-16-2 MDL No.:MFCD11037182 MF:C14H15F3O2 MW:272.2629	4-(4-Bromophenoxy)-3-fluoroaniline Catalog No.:AA00947O CAS No.:1038720-42-1 MDL No.:MFCD11193296 MF:C12H9BrFNO MW:282.1084
[3-fluoro-4-(2-fluorophenoxy)phenyl]methanamine Catalog No.:AA019R3N CAS No.:1038721-54-8 MDL No.:MFCD11191877 MF:C13H11F2NO MW:235.2293	{3-fluoro-4-[4-(pyrimidin-2-yl)piperazin-1-yl]phenyl}methanol Catalog No.:AA019WRM CAS No.:1038724-53-6 MDL No.:MFCD12913218 MF:C15H17FN4O MW:288.3201
1-(2,5-difluorophenyl)-2,2-difluoroethan-1-amine Catalog No.:AA01BFPD CAS No.:1038724-69-4 MDL No.:MFCD16618193 MF:C8H7F4N MW:193.1415	3-(aminomethyl)-N-[(3-fluorophenyl)methyl]benzene-1-sulfonamide Catalog No.:AA019VEC CAS No.:1038725-38-0 MDL No.:MFCD12177502 MF:C14H15FN2O2S MW:294.3445
5-(2,4-Dimethylphenyl)thiophene-2-carboxylic acid Catalog No.:AA007FA5 CAS No.:1038729-21-3 MDL No.:MFCD07375939 MF:C13H12O2S MW:232.2982	5-Bromo-4-methylbenzo[d]thiazol-2-amine Catalog No.:AA0096PZ CAS No.:103873-80-9 MDL No.:MFCD23705662 MF:C8H7BrN2S MW:243.1236
3-(2-Bromoethoxy)-1,1,2,2-tetrafluoropropane Catalog No.:AA01B1H0 CAS No.:1038730-08-3 MDL No.:MFCD11197517 MF:C5H7BrF4O MW:239.0061	5-Bromo-n-[3-(1h-imidazol-1-yl)propyl]pyridin-2-amine Catalog No.:AA01B8C7 CAS No.:1038733-36-6 MDL No.:MFCD11196038 MF:C11H13BrN4 MW:281.1517
(4-ethoxy-3,5-dimethylphenyl)methanol Catalog No.:AA01A9XJ CAS No.:1038733-45-7 MDL No.:MFCD11188447 MF:C11H16O2 MW:180.2435	3-chloro-4-fluoro-N-(2-methylpropyl)aniline Catalog No.:AA01AYBV CAS No.:1038734-58-5 MDL No.:MFCD11189033 MF:C10H13ClFN MW:201.6683
1-(2-fluoro-5-methylphenyl)-1H,4H,5H,6H-cyclopenta[c]pyrazole-3-carboxylic acid Catalog No.:AA01C3J2 CAS No.:1038738-52-1 MDL No.:MFCD12469973 MF:C14H13FN2O2 MW:260.2636	1-(3-chloro-2-fluorophenyl)-1H,4H,5H,6H-cyclopenta[c]pyrazole-3-carboxylic acid Catalog No.:AA01C436 CAS No.:1038738-53-2 MDL No.:MFCD12559986 MF:C13H10ClFN2O2 MW:280.6821
N-Biotinylcaproylaminocaproylaminoethyl Methanethiosulfonate Catalog No.:AA007WWG CAS No.:1038749-81-3 MDL No.:MFCD03453616 MF:C25H45N5O6S3 MW:607.8497	4-Hydroxy Omeprazole Sulfide Catalog No.:AA008X5M CAS No.:103876-98-8 MDL No.:MFCD18379486 MF:C16H17N3O2S MW:315.3901
5-O-Desmethyl Omeprazole Sulfide Catalog No.:AA007WWC CAS No.:103877-02-7 MDL No.:MFCD28898411 MF:C32H34N6O4S2 MW:630.7802	Benzoylchloride, 2,5-difluoro-4-methyl- Catalog No.:AA00856L CAS No.:103877-56-1 MDL No.:MFCD04972819 MF:C8H5ClF2O MW:190.5745
2-Chloro-5-fluoro-4-methylbenzoic acid Catalog No.:AA0039WJ CAS No.:103877-61-8 MDL No.:MFCD18426003 MF:C8H6ClFO2 MW:188.5834	3-Amino-5-fluoro-4-methylbenzoic acid Catalog No.:AA008UDJ CAS No.:103877-75-4 MDL No.:MFCD09835203 MF:C8H8FNO2 MW:169.1530
3,5-Difluoro-4-methylbenzoic acid Catalog No.:AA0039WK CAS No.:103877-76-5 MDL No.:MFCD20545741 MF:C8H6F2O2 MW:172.1288	5-Fluoro-4-methyl-2-nitrobenzoic acid Catalog No.:AA01BECN CAS No.:103877-78-7 MDL No.:MFCD28063998 MF:C8H6FNO4 MW:199.1359
2,5-Difluoro-4-methylbenzoic acid Catalog No.:AA0038X5 CAS No.:103877-80-1 MDL No.:MFCD00078261 MF:C8H6F2O2 MW:172.1288	3-phenoxypyridine-2-carboxylic acid Catalog No.:AA01B889 CAS No.:103877-89-0 MDL No.:MFCD13178194 MF:C12H9NO3 MW:215.2048
3-Ethoxypyridine-2-carboxylic acid Catalog No.:AA00HA4J CAS No.:103878-09-7 MDL No.:MFCD11878609 MF:C8H9NO3 MW:167.1620	5-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid Catalog No.:AA01BHSQ CAS No.:103878-37-1 MDL No.:MFCD09965920 MF:C7H7NO4 MW:169.1348
PYRIDINE-2-CARBOXYLIC ACID (2-AMINO-ETHYL)-AMIDE Catalog No.:AA008S9S CAS No.:103878-43-9 MDL No.:MFCD05022406 MF:C8H11N3O MW:165.1924	5-Bromothiazole-4-carboxylic acid Catalog No.:AA003MIB CAS No.:103878-58-6 MDL No.:MFCD08275714 MF:C4H2BrNO2S MW:208.0332
N-(2-aminoethyl)-5-bromopyridine-2-carboxamide hydrochloride Catalog No.:AA01B3UY CAS No.:103878-71-3 MDL No.:MFCD29991740 MF:C8H11BrClN3O MW:280.5494	Lazabemide hydrochloride Catalog No.:AA00856H CAS No.:103878-83-7 MDL No.:MFCD00878458 MF:C8H11Cl2N3O MW:236.0984
LAZABEMIDE Catalog No.:AA008SQE CAS No.:103878-84-8 MDL No.:MFCD20488051 MF:C8H10ClN3O MW:199.6375	3,5-Dichloro-4-fluorobenzonitrile Catalog No.:AA00389T CAS No.:103879-31-8 MDL No.:MFCD09835204 MF:C7H2Cl2FN MW:190.0019
5-Methyl-1,3-oxazole-4-carboxylic acid Catalog No.:AA003MTM CAS No.:103879-58-9 MDL No.:MFCD01543374 MF:C5H5NO3 MW:127.0981	3-Iodobenzamide Catalog No.:AA00856G CAS No.:10388-19-9 MDL No.:MFCD00143169 MF:C7H6INO MW:247.0331
2-((TERT-BUTOXYCARBONYL)AMINO)-2-(3-CHLORO-4-FLUOROPHENYL)ACETIC ACID Catalog No.:AA01EKB1 CAS No.:1038817-56-9 MDL No.:MFCD07186276 MF:C13H15ClFNO4 MW:303.7139	Boc-p-iodo-dl-phe-oh Catalog No.:AA008Y3U CAS No.:103882-09-3 MDL No.:MFCD00176869 MF:C14H18INO4 MW:391.2015
gemcitabine Catalog No.:AA009OSV CAS No.:103882-84-4 MDL No.:MFCD00869720 MF:C9H11F2N3O4 MW:263.1981	MONOHYDRIDE TERMINATED POLYDIMETHYLSILOXANE, asyMMetric, 100 cSt Catalog No.:AA008ZJB CAS No.:1038821-58-7 MDL No.:MFCD00054788 MF:C7H21O2Si3 MW:221.4969
{5H,6H,7H,8H-imidazo[1,2-a]pyridin-2-yl}methanol Catalog No.:AA01B2J5 CAS No.:1038827-92-7 MDL No.:MFCD21336203 MF:C8H12N2O MW:152.1937	5-Fluoro-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol Catalog No.:AA00HA4Q CAS No.:1038828-32-8 MDL No.:MFCD16994248 MF:C12H16BFO3 MW:238.0630
5,6,7,8-Tetrahydroimidazo[1,2-a]pyridine-2-carboxylic acid hydrochloride Catalog No.:AA007FA0 CAS No.:1038828-34-0 MDL No.:MFCD21604043 MF:C8H11ClN2O2 MW:202.6381	3-(2,5-Dimethylphenyl)-1h-pyrazole-5-carboxylic acid Catalog No.:AA00HA4R CAS No.:1038829-40-1 MDL No.:MFCD04325788 MF:C12H12N2O2 MW:216.2359
Procyanidin A1 Catalog No.:AA008RXL CAS No.:103883-03-0 MDL No.:MFCD04039846 MF:C30H24O12 MW:576.5044	(4-OXOAZETIDIN-2-YL)METHYL METHANESULFONATE Catalog No.:AA01DX4X CAS No.:103883-23-4 MDL No.:MFCD24550418 MF:C5H9NO4S MW:179.1943
9-(2-Deoxy-2-fluoroarabinofuranosyl)guanine Catalog No.:AA008Z4P CAS No.:103884-98-6 MDL No.:MFCD01694134 MF:C10H12FN5O4 MW:285.2318	Spiro[piperidine-4,4'-pyrido[2,3-d][1,3]oxazin]-2'(1'h)-one hydrochloride Catalog No.:AA0095TU CAS No.:1038866-44-2 MDL No.:MFCD21608029 MF:C11H14ClN3O2 MW:255.7008
2-Chloro-6-fluorobenzotrifluoride Catalog No.:AA0039WF CAS No.:103889-37-8 MDL No.:MFCD03412198 MF:C7H3ClF4 MW:198.5453	(R)-2-Amino-2-(2-methoxyphenyl)acetic acid Catalog No.:AA007WW7 CAS No.:103889-84-5 MDL No.:MFCD07371750 MF:C9H11NO3 MW:181.1885
(S)-Amino-(2-methoxy-phenyl)-acetic acid Catalog No.:AA008RR7 CAS No.:103889-86-7 MDL No.:MFCD06858445 MF:C9H11NO3 MW:181.1885	L-Aspartic acid,calcium salt (1:1) Catalog No.:AA00856B CAS No.:10389-09-0 MDL No.:MFCD22422871 MF:C4H5CaNO4 MW:171.1648
4-(4-Nitrophenyl)morpholine Catalog No.:AA0033QA CAS No.:10389-51-2 MDL No.:MFCD00023317 MF:C10H12N2O3 MW:208.2139	(Boc-Cys-OH)2 Catalog No.:AA00HA4Z CAS No.:10389-65-8 MDL No.:MFCD00038250 MF:C16H28N2O8S2 MW:440.5321
2-methylcyclohexyl methanesulfonate Catalog No.:AA01BXL5 CAS No.:103890-73-9 MDL No.:MFCD26961251 MF:C8H16O3S MW:192.2758	Lacidipine Catalog No.:AA00HA50 CAS No.:103890-78-4 MDL No.:MFCD00865936 MF:C26H33NO6 MW:455.5433