- Probing phenylcarbamoylazinane-1,2,4-triazole amides derivatives as lipoxygenase inhibitors along with cytotoxic, ADME and molecular docking studies
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Hunting small molecules as anti-inflammatory agents/drugs is an expanding and successful approach to treat several inflammatory diseases such as cancer, asthma, arthritis, and psoriasis. Besides other methods, inflammatory diseases can be treated by lipoxygenase inhibitors, which have a profound influence on the development and progression of inflammation. In the present study, a series of new N-alkyl/aralky/aryl derivatives (7a-o) of 2-(4-phenyl-5-(1-phenylcarbamoyl)piperidine-4H-1,2,4-triazol-3-ylthio)acetamide was synthesized and screened for their inhibitory potential against the enzyme 15-lipoxygenase. The simple precursor ethyl piperidine-4-carboxylate (a) was successively converted into phenylcarbamoyl derivative (1), hydrazide (2), semicarbazide (3) and N-phenylated 5-(1-phenylcarbamoyl)piperidine-1,2,4-triazole (4), then in combination with electrophiles (6a-o) through further multistep synthesis, final products (7a-o) were generated. All the synthesized compounds were characterized by FTIR, 1H, 13C NMR spectroscopy, EIMS, and HREIMS spectrometry. Almost all the synthesized compounds showed excellent inhibitory potential against the tested enzyme. Compounds 7c, 7f, 7d, and 7g displayed potent inhibitory potential (IC50 9.25 ± 0.26 to 21.82 ± 0.35 μM), followed by the compounds 7n, 7h, 7e, 7a, 7b, 7l, and 7o with IC50 values in the range of 24.56 ± 0.45 to 46.91 ± 0.57 μM. Compounds 7c, 7f, 7d exhibited 71.5 to 83.5% cellular viability by MTT assay compared with standard curcumin (76.9%) when assayed at 0.125 mM concentration. In silico ADME studies supported the drug-likeness of most of the molecules. In vitro inhibition studies were substantiated by molecular docking wherein the phenyl group attached to the triazole ring was making a π-δ interaction with Leu607. This work reveals the possibility of a synthetic approach of compounds in relation to lipoxygenase inhibition as potential lead compounds in drug discovery.
- Muzaffar, Saima,Shahid, Wardah,Riaz, Naheed,Saleem, Muhammad,Ashraf, Muhammad,Aziz-ur-Rehman,Bashir, Bushra,Kaleem, Ayesha,al-Rashida, Mariya,Baral, Bikash,Bhattarai, Keshab,Gross, Harald
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- Synthesis and Antifungal Activity of New N-Aryl-2-(2-hydroxyphenylamino)ethylenediamine Derivatives
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Abstract: In this study, a series of new N-aryl-2-(2-hydroxyphenylamino)ethylenediamine derivatives has beendesigned, synthesized and evaluated for antifungal activity against six selectedspecies of phytopathogenic fungi. Among the products, the most potent compoundhave demonstrated 97.7% inhibitory activity against S.sclerotiorum at the concentration of 50 μg/mL, which is higherthan that of the positive control chlorothalonil.
- Gao, Han,Wan, Yichao,Tan, Yuhuan,Luo, Xi,Li, Lin
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p. 122 - 127
(2021/02/21)
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- Structural basis of binding and justification for the urease inhibitory activity of acetamide hybrids of N-substituted 1,3,4-oxadiazoles and piperidines
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In present, we have performed the Michaelis–Menten kinetics studies of urease inhibitors (6a–o), having basic skeleton of acetamide hybrids of N-substituted 1,3,4-oxadiazoles and piperidines. From the Lineweaver-Burk plot, Dixon plot and their secondary replots, it has been confirmed that all the compounds have inhibited the enzyme competitively with Ki values of in range from 3.11 ± 0.2 to 5.20 ± 0.7 μM. Compound 6a was found to have lowest Ki among the series, while compounds 6d, 6e, 6gand 6i were found subsequently the excellent Ki values after 6a. Molecular docking has supported their types of inhibitions and structure activity-relationship. Most frequently, the nitro group oxygen atoms were found in contact with nickel ions of the active site. Moreover, all the compounds were subjected to toxicity tests and were found nontoxic against human neutrophils and plants, respectively.
- Abbasi, Muhammad Athar,Afridi, Sahib Gul,Khan, Ajmal,Khan, Asifullah,Khan, Farman Ali,Lodhi, Muhammad Arif,Rehman, Aziz Ur
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- Identification of phenylcarbamoylazinane-1,3,4-oxadiazole amides as lipoxygenase inhibitors with expression analysis and in silico studies
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In search for new anti-inflammatory agents that inhibit the enzymes of arachidonic acid pathway as the drug targets, the present article describes the screening of 1,3,4-oxadiazole analogues against lipoxygenase (LOX) enzyme. The work is based on the synthesis of new N-alkyl/aralky/aryl derivatives (6a-o) of 2-(4-phenyl-5-(1-phenylcarbamoylpiperidine)-4H-1,3,4-oxadiazol-3-ylthio)acetamide which were obtained by the reaction of 1,3,4-oxadiazole (3) with various electrophiles (5a-o), in KOH. The synthesized analogues showed potent to moderate inhibitory activity against the soybean 15-LOX enzyme; especially 6g, 6b, 6a and 6l displayed the potent inhibitory potential with IC50 values 7.15 ± 0.26, 9.32 ± 0.42, 15.83 ± 0.45 & 18.37 ± 0.53 μM, respectively, while excellent to moderate inhibitory profiles with IC50 values in the range of 26.13–98.21 μM were observed from the compounds 6k, 6m, 6j, 6o, 6h, 6f, 6n and 6c. Most of the active compounds exhibited considerable cell viability against blood mononuclear cells (MNCs) at 0.25 mM by MTT assay except 6f, 6h, 6k and 6m which showed around 50% cell viability. Flow cytometry studies of the selected compounds 6a, 6j and 6n revealed that these caused 79.5–88.51% early apoptotic changes in MNCs compared with 4.26% for control quercetin at their respective IC50 values. The relative expression of 5-LOX gene was monitored in MNCs after treatment with these three molecules and all down-regulated the enzyme activity. In silico ADME and molecular docking studies further supported these studies of oxadiazole derivatives and considered it as potential ‘lead’ compounds in drug discovery and development.
- Amjad, Hira,Ashraf, Muhammad,Aziz-ur-Rehman,Bashir, Bushra,Bhattarai, Keshab,Imran, Muhammad,Muzaffar, Saima,Riaz, Naheed,Saleem, Muhammad,Shahid, Wardah
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- A novel method for the synthesis of 1,2,4-triazole-derived heterocyclic compounds: enzyme inhibition and molecular docking studies
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Two series of new N-aryl/aralkyl derivatives (9a–q) of 2-(4-ethyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide and N-aryl/aralkyl derivatives (10a–q) of 2-(4-phenyl-5-(thiophen-2-ylmethyl)-4H-1,2,4-triazol-3-ylthio)acetamide were synthesized. The methods included successive conversions of thiophen-2-acetic acid (a) into its respective ester, hydrazide and N-aryl/aralkyl 1,3,4-triazole. The target compounds (9a–q; 10a–q) were obtained by the reaction of N-aryl/aralkyl 1,3,4-triazole (5, 6) with various electrophiles, (8a–q), in N,N-dimethyl formamide (DMF) and sodium hydroxide at room temperature. The characterization of these compounds was done by FTIR, 1H-, 13C-NMR, EI-MS and HR-EI-MS spectral data. All compounds were evaluated for their enzyme inhibitory potentials against electric eel acetylcholinesterase, AChE (10f, 10d; IC50 values 32.26 ± 0.12, 45.72 ± 0.11?μM, respectively), equine butyrylcholinesterase, BChE (9d, 9l, 9b, 10d, 10h; IC50 values 12.52 ± 0.19, 12.52 ± 0.19, 21.72 ± 0.18, 23.62 ± 0.22, 24.52 ± 0.21?μM, respectively), jack bean urease (10i, 10n, 9e; IC50 values 7.27 ± 0.05, 7.35 ± 0.04, 8.79 ± 0.05?μM, respectively) and yeast α-glucosidase enzymes (9o, 10i; IC50 values 62.94 ± 0.19, and 69.46 ± 0.15?μM, respectively). The molecular docking studies supported these findings. This study provides cheaper bioactive triazole amides as promising future lead molecules.
- Riaz, Naheed,Iftikhar, Muhammad,Saleem, Muhammad,Aziz-ur-Rehman,Ahmed, Ishtiaq,Ashraf, Muhammad,Shahnawaz,Rehman, Jameel,al-Rashida, Mariya
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p. 1183 - 1200
(2020/01/31)
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- Convergent synthesis, free radical scavenging, Lineweaver-Burk plot exploration, hemolysis and in silico study of novel indole-phenyltriazole hybrid bearing acetamides as potent urease inhibitors
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In the current paper, through a convergent multi-step approach, a library of novel indole-phenyltriazole hybrids containing an amide moiety (9a-k) was synthesized. The structural verification of all synthesized molecules was accomplished by CHN and spectral analyses data. These synthesized bi-heterocyclic derivatives (9a-k) were evaluated for their anti-ulcer potential by inhibitory action against Jack bean urease enzyme and subsequently their structure-activity relationship was perceived. Moreover, these compounds were inspected for cytotoxic profile by hemolytic activity and it was professed that nearly all the synthesized compounds showed low cytotoxicity. In addition, free radical scavenging activity and kinetic analysis were also carried out for these compounds to understand their mode of inhibition. So, it was summated that these derivatives might lead to further research gateways for obtaining better and safe anti-ulcer agents.
- Abbasi, Muhammad A.,Ali Shah, Syed A.,Hassan, Mubashir,Khan, Wajiha,Nazir, Majid,Raza, Hussain,Rehman, Aziz-ur,Seo, Sung Y.,Shahid, Muhammad,Siddiqui, Sabahat Z.
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- Amide-Based Cinchona Alkaloids as Phase-Transfer Catalysts: Synthesis and Potential Application
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Herein we present a library of simple amide derivatives of Cinchona alkaloids in the form of quaternary ammonium salts. The obtained derivatives can be generated very easily and efficiently from inexpensive and commercially available substrates. We tested this class of alkaloids in the alkylation of glycine derivative, carried out under phase-transfer catalyst conditions. The presented hybrid catalysts offer both high reaction yields (up to 97%) and high enantioselectivities of the obtained product (up to 94% ee).
- Majdecki, Maciej,Niedbala, Patryk,Jurczak, Janusz
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supporting information
p. 8085 - 8090
(2019/10/14)
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- Synthesis and structure-activity relationship of tyrosinase inhibiting novel bi-heterocyclic acetamides: Mechanistic insights through enzyme inhibition, kinetics and computational studies
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The present research was designed for the selective synthesis of novel bi-heterocyclic acetamides, 9a-n, and their tyrosinase inhibition to overwhelm the problem of melanogenesis. The structures of newly synthesized compounds were confirmed by spectral techniques such as 1H NMR, 13C NMR, and EI-MS along with elemental analysis. The inhibitory effects of these bi-heterocyclic acetamides (9a-n) were evaluated against tyrosinase and all these molecules were recognized as potent inhibitors relative to the standard used. The Kinetics mechanism was analyzed by Lineweaver-Burk plots which explored that compound, 9h, inhibited tyrosinase competitively by forming an enzyme-inhibitor complex. The inhibition constants Ki calculated from Dixon plots for this compound was 0.0027 μM. The computational study was coherent with the experimental records and these ligands exhibited good binding energy values (kcal/mol). The hemolytic analysis revealed their mild cytotoxicity towards red blood cell membranes and hence, these molecules can be pondered as nontoxic medicinal scaffolds for skin pigmentation and related disorders.
- Butt, Abdul Rehman Sadiq,Abbasi, Muhammad Athar,Aziz-ur-Rehman,Siddiqui, Sabahat Zahra,Raza, Hussain,Hassan, Mubashir,Shah, Syed Adnan Ali,Shahid, Muhammad,Seo, Sung-Yum
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p. 459 - 472
(2019/02/19)
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- Design, synthesis, fungicidal activity and molecular docking studies of novel 2-((2-hydroxyphenyl)methylamino)acetamide derivatives
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A series of novel 2-hydroxyphenyl substituted aminoacetamides was designed by molecular hybridization of the aminoacetamide scaffold and 2-hydroxyphenyl motif. The target compounds were synthesized and their fungicidal activities were evaluated. Some of the target compounds showed excellent antifungal activities against S. sclerotiorum and P. capsici. Significantly, compounds 5e displayed the most potent activity against S. sclerotiorum with EC50 = 2.89 μg/mL, which was lower than that of commercial chlorothalonil. The systematic studies provided strong confidence that the hydroxyl group and the carbonyl group are crucial for the fungicidal activity. Molecular docking studies suggest that SDH enzyme could be one of the potential action targets of our compounds.
- Tang, Zilong,Li, Xinxing,Yao, Yuan,Qi, Yongcun,Wang, Ming,Dai, Ningning,Wen, Yuhao,Wan, Yichao,Peng, Lifen
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p. 2572 - 2578
(2019/03/26)
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- S-substituted derivatives of 1,2,4-triazol-3-thiol as new drug candidates for type II diabetes
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The therapeutic applications of 1,2,4-triazoles motivated us to synthesize some new derivatives. Two series of S -substituted derivatives (8a–8j, 12a–12i) of 5- (1-[(4-chlorophenyl)sulfonyl]-3-piperidinyl )-4-phenyl-4 H -1,2,4-triazol-3-thiol (6) have been synthesized and evaluated for their biological potential. Using 4-chlorobenzene sulfonyl chloride (1) and ethyl piperidine-3-carboxylate (2), ethyl 1-[(4-chlorophenyl)sulfonyl]piperidine-3-carboxylate (3) was synthesized and converted into 3,4,5-trisubstituted 1,2,4-triazole (6) through formation of the corresponding carbohydrazide (4) and hydrazinecarbothioamide (5). Compound 6 was transformed into 8a–8j by alkyl halides (7a–7j) and into 12a–12i by N -aralkyl/aryl-2-bromoacetamides (11a–11i) in an aprotic solvent. The electrophiles, 11a–11i, were synthesized by gearing up N -substituted aralkyl/aryl amines (10a–10i) with 2-bromoacetyl bromide (9) under dynamic pH control by aqueous sodium carbonate. Structures were elucidated through the spectral techniques of IR, EIMS, 1 H NMR, and 13 C NMR. Most of the synthesized derivatives were found to be potent inhibitors of α -glucosidase enzyme and even better than acarbose. Acarbose is a reference standard and is a commercially available α -glucosidase inhibitor to treat patients with type II diabetes. The low hemolytic activity also emphasized the potential of the synthesized compounds as new drug candidates.
- Ur-Rehman, Aziz,Nafeesa, Khadija,Athar Abbasi, Muhammad,Zahra Siddiqui, Sabahat,Rasool, Shahid,Adnan Ali Shah, Syed,Ashraf, Muhammad,Lodhi, Muhammad Arif,Khan, Farman Ali,Jahan, Bakhat
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p. 652 - 671
(2018/06/07)
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- Synthesis, biological evaluation, and in silico study of some unique multifunctional 1,2,4-triazole acetamides
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The imperative demand for antibacterial agents and enzyme inhibitors prompted us to synthesize some new compounds, 6a–6k, bearing multifunctional moieties. The target acetamides were derived from 4-phenyl-5-(1-tosylpiperidin-4-yl)-4H-1,2,4-triazole-3-thiol (3). The structural analysis was carried out using modern spectroscopic techniques including IR, NMR, and EIMS spectral analysis. The antibacterial activity was screened against five bacterial strains including three gram-negative and two gram-positive ones. Enzyme inhibition was carried out against lipoxygenase enzyme and results were supported by in silico study. The synthesized compounds were proved to be potent antibacterial agents and enzyme inhibitors.
- Sattar, Almas,Ur Rehman, Aziz,Abbasi, Muhammad Athar,Siddiqui, Sabahat Zahra,Rasool, Shahid,Khalid, Hira,Lodhi, Muhammad Arif,Khan, Farman Ali
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p. 401 - 417
(2018/06/11)
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- 3-position functionalized N (O,S)-heteroindene derivatives and application thereof in resistance of respiratory syncytial virus
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The invention discloses 3-position functionalized N (O,S)-heteroindene derivatives and application thereof in resistance of respiratory syncytial virus. The structures of the derivatives are describedin the description, wherein n is 0 or 1; X represents a
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Paragraph 0043; 0046; 0047
(2018/07/30)
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- New indole based hybrid oxadiazole scaffolds with N-substituted acetamides: As potent anti-diabetic agents
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Current study is based on the sequential conversion of indolyl butanoic acid (1) into ethyl indolyl butanoate (2), indolyl butanohydrazide (3), and 1,3,4-oxadiazole-2-thiol analogs (4) by adopting chemical transformations. In a parallel series of reaction
- Nazir, Majid,Abbasi, Muhammad Athar,Aziz-ur-Rehman,Siddiqui, Sabahat Zahra,Khan, Khalid Mohammed,Kanwal,Salar, Uzma,Shahid, Muhammad,Ashraf, Muhammad,Arif Lodhi, Muhammad,Ali Khan, Farman
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p. 253 - 263
(2018/09/05)
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- 2-(Quinolin-4-yloxy)acetamides Are Active against Drug-Susceptible and Drug-Resistant Mycobacterium tuberculosis Strains
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2-(Quinolin-4-yloxy)acetamides have been described as potent in vitro inhibitors of Mycobacterium tuberculosis growth. Herein, additional chemical modifications of lead compounds were carried out, yielding highly potent antitubercular agents with minimum inhibitory concentration (MIC) values as low as 0.05 μM. Further, the synthesized compounds were active against drug-resistant strains and were devoid of apparent toxicity to Vero and HaCat cells (IC50s ≥ 20 μM). In addition, the 2-(quinolin-4-yloxy)acetamides showed intracellular activity against the bacilli in infected macrophages with action similar to rifampin, low risk of drug-drug interactions, and no sign of cardiac toxicity in zebrafish (Danio rerio) at 1 and 5 μM. Therefore, these data indicate that this class of compounds may furnish candidates for future development to, hopefully, provide drug alternatives for tuberculosis treatment.
- Pissinate, Kenia,Villela, Anne Drumond,Rodrigues, Valnês,Giacobbo, Bruno Couto,Grams, Estêv?o Silveira,Abbadi, Bruno Lopes,Trindade, Rogério Valim,Roesler Nery, Laura,Bonan, Carla Denise,Back, Davi Fernando,Campos, Maria Martha,Basso, Luiz Augusto,Santos, Diógenes Santiago,Machado, Pablo
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supporting information
p. 235 - 239
(2016/03/22)
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- Synthesis and cytotoxicity of thieno[2,3-b]quinoline-2-carboxamide and cycloalkyl[b]thieno[3,2-e]pyridine-2-carboxamide derivatives
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Seventy nine derivatives of thieno[2,3-b]quinolines, tetrahydrothieno[2,3-b]quinoline, dihydrocyclopenta[b]thieno[3,2-e]pyridine, cyclohepta[b]thieno[3,2-e]pyridine and hexahydrocycloocta[b]thieno[3,2-e]pyridine were either synthesized or obtained commercially and tested for their antiproliferative activity against HCT116, MDA-MB-468 and MDA-MB-231 human cancer cell lines. The most potent eight compounds were active against all cell lines with IC50 values in the 80–250 nM range. In general hexahydrocycloocta[b]thieno[3,2-e]pyridines were most active with increasing activity observed as larger cycloalkyl rings were fused to the pyridine ring.
- Leung, Euphemia,Pilkington, Lisa I.,van Rensburg, Michelle,Jeon, Chae Yeon,Song, Mirae,Arabshahi, Homayon J.,De Zoysa, Gayan Heruka,Sarojini, Vijayalekshmi,Denny, William A.,Reynisson, Jóhannes,Barker, David
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supporting information
p. 1142 - 1154
(2019/05/24)
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- Synthesis and evaluation of thiazolyl-1H-benzo[d]imidazole inhibitors of Mycobacterium tuberculosis inosine monophosphate dehydrogenase
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Using an orthologue-based design approach, we synthesized and assayed a series of thiazolyl-1H-benzo[d]imidazole derivatives as inhibitors of Mycobacterium tuberculosis inosine 5′-monophosphate dehydrogenase (MtIMPDH). From these experiments, a benzo[d] imidazole compound was described to inhibit the enzyme in the low micromolar range (KiIMP = 0.55 ± 0.02 μM), which places this compound among the most potent in vitro MtIMPDH inhibitors developed to date. In addition, steady-state kinetic measurements and docking simulations were employed to determine its inhibition and interaction modes. The results described herein may be useful for the design and development of novel alternative therapeutics for tuberculosis that target MtIMPDH, a predicted to be essential (for optimal in vitro bacillus growth), druggable and assayable molecular target.
- Pissinate, Kenia,Rostirolla, Diana Carolina,Pinheiro, Laura Miranda,Suryadevara, Priyanka,Yogeeswari, Perumal,Sriram, Dharmarajan,Basso, Luiz Augusto,Machado, Pablo,Santos, Diógenes Santiago
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p. 1357 - 1366
(2015/07/15)
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- Antibacterial and enzyme inhibition screening of some new acetamide and azomethine derivatives
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The synthesis of poly-functional moieties as one unit has been under consideration by the synthetic chemists to search out new potent molecules. 2-Chlorobenzoic acid (1) was converted to 5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-thiol (4) through a series of steps. This nucleophile was attached with different electrophiles, prepared by the reaction of aryl/alkyl amines with 2-bromoacetylbromide, in NaH/DMF to synthesize N-substituted-2-((5-(2-chlorophenyl)-1,3,4-Oxadiazol-2- yl)sulfanyl)acetamide, 7a-f. The molecule 4 was stepped to ethyl ester and carbohydrazide. The carbohydrazide was made to react with aryl carboxaldehydes in methanol to synthesize N'-substituted-2-(5-(2-chlorophenyl)-1,3,4-Oxadiazol-2-ylthio)acetohydrazide, 11a-i. The structures of all the molecules were corroborated through IR, 1H-NMR and EI-MS spectral data. Both the series were screened for antibacterial and enzyme inhibition activity.
- Rasool, Shahid,Rehman, Aziz-Ur,Abbasi, Muhammad Athar,Siddiqui, Sabahat Zahra,Shah, Syed Adnan Ali,Ahmad, Irshad,Afzal, Saira
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p. 2704 - 2710
(2016/03/08)
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- N-substituted derivatives of 5-(4-chlorophenyl)-1,3,4-oxadiazol-2-yl-2- sulfanyl acetamide as valuable bioactive compounds
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In the described research work, a new series of N-substituted derivatives of 5-(4- chlorophenyl)-1,3,4-Oxadiazol-2-yl-2-sulfanyl acetamide has been synthesized. The synthesis was carried out by converting 4-chlorobenzoic acid (1) into ethyl 4-chlorobenzoate (2), 4- chlorobenzohydrazide (3) and then 5-(4-chlorophenyl)-1,3,4-Oxadiazol-2-thiol (4) respectively. The target molecules 6a-o were synthesized by reacting compound 4 with different N-alkyl/aryl substituted 2-bromoacetamide (5a-o) in equimolar ratios of using DMF and sodium hydride (NaH). The structure of all the synthesized compounds was confirmed by spectral data like EI-MS, IR and 1H-NMR. The compounds were also analysed for antimicrobial & hemolytic activity and most of them were found active against the selected microbial species at variable extent relative to reference standards. But 6f and 6o were the active against the selected panel of microbes and former was most potent one. This series revealed less toxicity and may consider for further biological screening and application trial except 6g and 6j, exhibiting high cytotoxicity.
- Rehman, Aziz-Ur,Gul, Samreen,Abbasi, Muhammad Athar,Nafeesa, Khadija,Siddiqa, Asia,Khan, Khalid Mohammed,Shahid, Muhammad,Subhani, Zinayyera
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p. 503 - 511
(2014/08/05)
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- Synthesis, spectral analysis and biological evaluation of sulfonamides bearing piperidine nucleus
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In the current study, two new series of N-alkyl-N-(piperidin-1-yl) benzenesulfonamide (3a-f) and N-aryl substitued 2-[(phenylsulfonyl)- (piperidin-1-yl)amino]acetamide (5a-c) were synthesized and enzyme inhibiting activity was screened for all these chemi
- Khalid, Hira,Rehman, Aziz-Ur,Abbasi, Muhammad Athar,Malik, Abdul,Ashraf, Muhammad,Ahmad, Irshad,Ismail, Tayaba
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p. 9468 - 9472
(2014/01/06)
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- Structure-activity relationships in the binding of chemically derivatized CD4 to gp120 from human immunodeficiency virus
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The first step in HIV infection is the binding of the envelope glycoprotein gp120 to the host cell receptor CD4. An interfacial "Phe43 cavity" in gp120, adjacent to residue Phe43 of gp120-bound CD4, has been suggested as a potential target for therapeutic intervention. We designed a CD4 mutant (D1D2F43C) for site-specific coupling of compounds for screening against the cavity. Altogether, 81 cysteine-reactive compounds were designed, synthesized, and tested. Eight derivatives exceeded the affinity of native D1D2 for gp120. Structure-activity relationships (SAR) for derivatized CD4 binding to gp120 revealed significant plasticity of the Phe43 cavity and a narrow entrance. The primary contacts for compound recognition inside the cavity were found to be van der Waals interactions, whereas hydrophilic interactions were detected in the entrance. This first SAR on ligand binding to an interior cavity of gp120 may provide a starting point for structure-based assembly of small molecules targeting gp120-CD4 interaction.
- Xie, Hui,Ng, Danny,Savinov, Sergey N.,Dey, Barna,Kwong, Peter D.,Wyatt, Richard,Smith III, Amos B.,Hendrickson, Wayne A.
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p. 4898 - 4908
(2008/03/11)
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- Structure-activity relationship studies of novel benzophenones leading to the discovery of a potent, next generation HIV nonnucleoside reverse transcriptase inhibitor
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Despite the progress of the past two decades, there is still considerable need for safe, efficacious drugs that target human immunodeficiency virus (HIV). This is particularly true for the growing number of patients infected with virus resistant to currently approved HIV drugs. Our high throughput screening effort identified a benzophenone template as a potential nonnucleoside reverse transcriptase inhibitor (NNRTI). This manuscript describes our extensive exploration of the benzophenone structure-activity relationships, which culminated in the identification of several compounds with very potent inhibition of both wild type and clinically relevant NNRTI-resistant mutant strains of HIV. These potent inhibitors include 70h (GW678248), which has in vitro antiviral assay IC50 values of 0.5 nM against wild-type HIV, 1 nM against the K103N mutant associated with clinical resistance to efavirenz, and 0.7 nM against the Y181C mutant associated with clinical resistance to nevirapine. Compound 70h has also demonstrated relatively low clearance in intravenous pharmacokinetic studies in three species, and it is the active component of a drug candidate which has progressed to phase 2 clinical studies.
- Romines, Karen R.,Freeman, George A.,Schaller, Lee T.,Cowan, Jill R.,Gonzales, Steve S.,Tidwell, Jeffrey H.,Andrews III, Clarence W.,Stammers, David K.,Hazen, Richard J.,Ferris, Robert G.,Short, Steven A.,Chan, Joseph H.,Boone, Lawrence R.
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p. 727 - 739
(2007/10/03)
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- Synthesis and biological evaluations of sulfanyltriazoles as novel HIV-1 non-nucleoside reverse transcriptase inhibitors
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A novel sulfanyltriazole was discovered as an HIV-1 non-nucleoside reverse transcriptase inhibitor via HTS using a cell-based assay. Chemical modifications and molecular modeling studies were carried out to establish its SAR and understand its interactions with the enzyme. These modifications led to the identification of sulfanyltriazoles with low nanomolar potency for inhibiting HIV-1 replication and promising activities against selected NNRTI resistant mutants. These novel and potent sulfanyltriazoles could serve as advanced leads for further optimization.
- Wang, Zhiwei,Wu, Baogen,Kuhen, Kelli L.,Bursulaya, Badry,Nguyen, Truc N.,Nguyen, Deborah G.,He, Yun
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p. 4174 - 4177
(2007/10/03)
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