AU2021105099A4 - In silico screening, physicochemical and pharmacokinetic analysis of novel sulfonamides as potential antimicrobial drugs docked with protein targets: PDB: 2VF5, 1KZN and 1JIJ - Google Patents
In silico screening, physicochemical and pharmacokinetic analysis of novel sulfonamides as potential antimicrobial drugs docked with protein targets: PDB: 2VF5, 1KZN and 1JIJ Download PDFInfo
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- 229940124530 sulfonamide Drugs 0.000 title claims abstract description 44
- 150000003456 sulfonamides Chemical class 0.000 title claims abstract description 44
- 229940079593 drug Drugs 0.000 title claims abstract description 30
- 239000003814 drug Substances 0.000 title claims abstract description 30
- 230000000845 anti-microbial effect Effects 0.000 title claims abstract description 27
- 238000000126 in silico method Methods 0.000 title claims abstract description 11
- 238000012216 screening Methods 0.000 title claims abstract description 6
- 102000004169 proteins and genes Human genes 0.000 title abstract description 16
- 108090000623 proteins and genes Proteins 0.000 title abstract description 16
- 238000004458 analytical method Methods 0.000 title description 3
- 230000003993 interaction Effects 0.000 claims abstract description 27
- BRNULMACUQOKMR-UHFFFAOYSA-N thiomorpholine Chemical compound C1CSCCN1 BRNULMACUQOKMR-UHFFFAOYSA-N 0.000 claims abstract description 22
- 238000003032 molecular docking Methods 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims abstract description 12
- 229960004125 ketoconazole Drugs 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- UCSJYZPVAKXKNQ-HZYVHMACSA-N streptomycin Chemical compound CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](NC(N)=N)[C@H](O)[C@@H](NC(N)=N)[C@H](O)[C@H]1O UCSJYZPVAKXKNQ-HZYVHMACSA-N 0.000 claims abstract description 12
- XMAYWYJOQHXEEK-OZXSUGGESA-N (2R,4S)-ketoconazole Chemical compound C1CN(C(=O)C)CCN1C(C=C1)=CC=C1OC[C@@H]1O[C@@](CN2C=NC=C2)(C=2C(=CC(Cl)=CC=2)Cl)OC1 XMAYWYJOQHXEEK-OZXSUGGESA-N 0.000 claims abstract description 11
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- 108010065556 Drug Receptors Proteins 0.000 claims abstract description 8
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- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
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- 238000006243 chemical reaction Methods 0.000 description 4
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- DXCWDJMBQYTBMF-UHFFFAOYSA-N 4-(4-methoxyphenyl)sulfonylthiomorpholine Chemical compound C1=CC(OC)=CC=C1S(=O)(=O)N1CCSCC1 DXCWDJMBQYTBMF-UHFFFAOYSA-N 0.000 description 3
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- APONFTUEZGUYGS-UHFFFAOYSA-N 4-(2,4-dichlorophenyl)sulfonylthiomorpholine Chemical compound ClC1=CC(Cl)=CC=C1S(=O)(=O)N1CCSCC1 APONFTUEZGUYGS-UHFFFAOYSA-N 0.000 description 2
- KEXFXUABNZIWLC-UHFFFAOYSA-N 4-(3-fluorophenyl)sulfonylthiomorpholine Chemical compound FC1=CC=CC(S(=O)(=O)N2CCSCC2)=C1 KEXFXUABNZIWLC-UHFFFAOYSA-N 0.000 description 2
- XNWPLDHVPQAVPC-UHFFFAOYSA-N 4-(4-chlorophenyl)sulfonylthiomorpholine Chemical compound C1=CC(Cl)=CC=C1S(=O)(=O)N1CCSCC1 XNWPLDHVPQAVPC-UHFFFAOYSA-N 0.000 description 2
- 206010020772 Hypertension Diseases 0.000 description 2
- ZDUWLNNGKSABGP-UHFFFAOYSA-N O=S(C(C=C1)=CC(Br)=C1F)(N1CCSCC1)=O Chemical compound O=S(C(C=C1)=CC(Br)=C1F)(N1CCSCC1)=O ZDUWLNNGKSABGP-UHFFFAOYSA-N 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 229940035676 analgesics Drugs 0.000 description 2
- 229940035674 anesthetics Drugs 0.000 description 2
- 239000000730 antalgic agent Substances 0.000 description 2
- 239000003242 anti bacterial agent Substances 0.000 description 2
- 230000001093 anti-cancer Effects 0.000 description 2
- 230000001430 anti-depressive effect Effects 0.000 description 2
- 230000001355 anti-mycobacterial effect Effects 0.000 description 2
- 230000000259 anti-tumor effect Effects 0.000 description 2
- 229940088710 antibiotic agent Drugs 0.000 description 2
- 239000000935 antidepressant agent Substances 0.000 description 2
- 239000003926 antimycobacterial agent Substances 0.000 description 2
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- 238000013459 approach Methods 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 229940127089 cytotoxic agent Drugs 0.000 description 2
- 229910052731 fluorine Inorganic materials 0.000 description 2
- 239000003193 general anesthetic agent Substances 0.000 description 2
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- 239000000203 mixture Substances 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 125000000565 sulfonamide group Chemical group 0.000 description 2
- 150000003461 sulfonyl halides Chemical class 0.000 description 2
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- 230000002195 synergetic effect Effects 0.000 description 2
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- 241000588724 Escherichia coli Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 102000004894 Glutamine-fructose-6-phosphate transaminase (isomerizing) Human genes 0.000 description 1
- 108090001031 Glutamine-fructose-6-phosphate transaminase (isomerizing) Proteins 0.000 description 1
- 101000632319 Homo sapiens Septin-7 Proteins 0.000 description 1
- 101710146427 Probable tyrosine-tRNA ligase, cytoplasmic Proteins 0.000 description 1
- 230000010799 Receptor Interactions Effects 0.000 description 1
- 102100027981 Septin-7 Human genes 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 102100025336 Tyrosine-tRNA ligase, mitochondrial Human genes 0.000 description 1
- 101710107268 Tyrosine-tRNA ligase, mitochondrial Proteins 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 125000001246 bromo group Chemical group Br* 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
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- 125000006575 electron-withdrawing group Chemical group 0.000 description 1
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- 239000011737 fluorine Substances 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- XHMJOUIAFHJHBW-VFUOTHLCSA-N glucosamine 6-phosphate Chemical compound N[C@H]1[C@H](O)O[C@H](COP(O)(O)=O)[C@H](O)[C@@H]1O XHMJOUIAFHJHBW-VFUOTHLCSA-N 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
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- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003334 potential effect Effects 0.000 description 1
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- 239000002904 solvent Substances 0.000 description 1
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- 238000003756 stirring Methods 0.000 description 1
- YBBRCQOCSYXUOC-UHFFFAOYSA-N sulfuryl dichloride Chemical class ClS(Cl)(=O)=O YBBRCQOCSYXUOC-UHFFFAOYSA-N 0.000 description 1
- 210000000971 yellow yolk Anatomy 0.000 description 1
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/10—Antimycotics
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
- C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
- C07D295/26—Sulfur atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
For the first time, sulfonamides bearing thiomorpholine were synthesized by a facile single-step
process in good to excellent yields (82-94%). All the compounds were screened for in vitro
antimicrobial activities. Results demonstrated that 3a, 3c and 3d promising antimicrobial activities
against the screened bacterial and fungal strains when compared with the standard drugs
streptomycin and ketoconazole at 12.5, 25, 50 and 100 pg/mL concentrations. This synthetic
protocol provides a simple work-up procedure, excellent yields, shorter reaction times, low cost of
starting substrates, and pharmacologically important new antimicrobial drugs. These drugs might
be a promising drug candidate for further investigation. In silico molecular screening of these
compounds gave an insight of drug-receptor interaction of synthesized novel six sulfonamides
bearing thiomorpholine. These derivatives were analyzed for antimicrobial activity via in silico
and in vitro studies. Physicochemical studies and BOILED- egg model ((the Brain Or IntestinaL
EstimateD permeation method) were evaluated. All derivatives fall under RO5 rule (Lipinski rule
of five). They showed zero violations whereas, marketed drugs showed three violations
(streptomycin) and one violation (ketoconazole). They all showed good oral drug bioavailability,
good drug likeness and very low toxicity. Molecular docking results have been focused on high
full fitness score, deltaG and binding energies against antimicrobial targets (PDB: 2VF5, 1KZN
and 1JIJ) which gave an insight of drug-receptor interaction of synthesized novel six sulfonamide
derivatives. They have been systematically docked with three antimicrobial protein targets
(PDB:2VF5, 1JIJ and 1KZN). As full fitness score, hydrogen binding interactions, binding energy
modes and DeltaG value are the main parameters for evaluating the molecular docking studies and
evaluation of drug target interactions. All screened derivatives exhibited strong interactions with
the respective protein targets, they showed maximum full fitness score, binding energy modes and
DeltaG values. The modified scaffolds exhibited higher efficacy over sulfonamides. These drugs
might be a promising drug candidate for further investigation.
Description
EDITORIAL NOTE 2021105099
There are 8 pages of description only.
In silico screening, physicochemical and pharmacokinetic analysis of novel sulfonamides as potential antimicrobial drugs docked with protein targets: PDB: 2VF5, 1KZN and 1JIJ
The main purpose is to evaluate the potential antimicrobial activity, efficacy, drug likeness, molecular docking, physicochemical and pharmacokinetic studies of six new synthesized sulfonamide scaffolds 3(a-f). Molecular docking results have been focused on high full fitness score, deltaG and binding energies against antimicrobial targets (PDB: 2VF5, 1KZN and 1JIJ) which gave an insight of drug-receptor interaction of synthesized novel six sulfonamides bearing thiomorpholine. Six new sulfonamides were synthesized via green synthesis. Out of six derivatives, three derivatives, i.e., 3a, 3c and 3d exhibited anti-bacterial activity and anti-fungal activity. It was observed that incorporation of various substituted sulfonyl chlorides containing electron-withdrawing groups such as two chlorine atoms in 3a compound, fluorine and bromine atoms in 3c compound, and fluorine atom in 3d compound in the basic sulfonamide scaffold bearing thiomorpholine enhanced the activity of these compounds. These have been compared with the standard drugs streptomycin and ketoconazole at 12.5, 25, 50 and 100 pg/mL concentrations.
Owing to wide spectrum of biological activities of sulfonamides bearing thiomorpholine and also keeping in view of earlier literature reports of these scaffolds, we explored the in silico screening and potential antimicrobial drugs of novel sulfonamides bearing thiomorpholine docked with protein targets: PDB: 2VF5, 1KZN and 1JIJ.
Antimicrobial Targets: 3
[1] 2VF5 (Glucosamine-6-phosphate synthase in complex with glucosamine-6-phosphate)
[2] 1JIJ (S. aureus TyrRS in complex with SB-239629) and
[3] 1KZN (E.coli 24kDa Domain in Complex with Clorobioci)
All sulfonamides derivatives were compared with commercially available marketed drugs, i.e., streptomycin and ketoconazole drugs. All six compounds proved as active drugs via physicochemical and pharmacokinetic properties.
Background and prior art:
Antimicrobial diseases by drug resistance have increased for the treatment of variety of infections. This encouraged to develop new antimicrobial drugs with enhanced physicochemical and pharmacokinetic properties with less side effects. In such search, thiomorpholine scaffolds are considered as effective pharmacophores and have received significant attention owing to their wide range of pharmacological activities such as, antimycobacterial, anti-cancer, antioxidant, hypertensive, antimicrobial, anti-inflammatory, dipeptidyl peptidase IV (DPP-IV) inhibitors, anesthetics, and analgesics. Sulfonamides are the most broadly used antibiotics and acts as effective chemotherapeutic agents. Sulfonamides also called as sulfa drugs have prominent applications as anti-depressant, antimicrobial, anti-tumor, anti-inflammatory, HIV protease inhibitors, herbicides and veterinary practice. The synergistic action of sulfonamides with thiomorpholine has brought about a large usage of sulfonamides. The most commonly employed method for the synthesis of sulfonamides is by one-pot, two component reaction of by sulfonylation of amines with sulfonyl halides in the presence of a base. Molecular docking studies was performed with protein targets: PDB: 2VF5, 1KZN and JJIJ of the six novel sulfonamide derivatives to get an insight of drug-receptor interaction via in silico approach.
Objectives of the invention
1. Screening of antimicrobial activity of six novel sulfonamide derivatives by analyzing physicochemical and pharmacokinetic properties 2. BOILED-egg model(the Brain Or IntestinaL EstimateD permeation method) is carried out for analyzing gastrointestinal absorption and brain penetration effect 3. Molecular docking studies with protein targets: PDB: 2VF5, 1KZN and JJIJ of the six novel sulfonamide derivatives to get an insight of drug-receptor interaction via in silico approach 4. Design and synthesis of novel six sulfonamides bearing thiomorpholine 5. Develop a simple and effective method for the green synthesis of target/designed molecules based on the pharmacological importance
Statement of invention:
In our current invention, we have synthesized six novel derivatives by incorporating various functional groups on the basic scaffold of sulfonamides via green strategy. Their structures and IUPAC names are listed in Table 1. These derivatives were analysed for antimicrobial activities and in silico studies were carried out using protein targets: PDB: 2VF5, 1KZN and 1JIJ. Physicochemical studies and BOILED-egg model (the Brain Or IntestinaL EstimateD permeation method) were evaluated with the help of swissADME online server tool, whereas, pkCSM server was used for evaluating the pharmacokinetic properties (Tables 2 & 3). All derivatives fall under RO5 rule (Lipinski rule of five). They showed zero violations whereas, marketed drugs showed 3 violations (streptomycin) and 1 violation (ketoconazole). On the basis of in silico properties, it was found that all six derivatives showed good oral drug bioavailability, good drug likeness and very low toxicity. All six derivatives come under good gastrointestinal absorption and brain penetration region, which has been predicted by BOILED- egg model. Five screened derivatives 3a, 3b, 3c, 3d and 3f come under yellow yolk region of egg which indicated good brain penetration of these derivatives whereas one derivative (3e) comes under white region which indicates good gastrointestinal absorption (Figure 1). Their potential activities were analysed via in vitro method (Tables 4 and 5). They have been systematically docked with three antimicrobial protein targets (PDB:2VF5, JIJ and 1KZN) through online server tool, swissDock. All data of molecular docking is listed in Table 6 and images are listed in (Figure 2-4). As full fitness score, hydrogen binding interactions, binding energy modes and DeltaG value were the main parameters for evaluating the molecular docking studies for evaluation of drug target interactions. All screened derivatives exhibited strong interactions with the respective protein targets, they showed maximum full fitness score, binding energy modes and DeltaG values. Out of six derivatives docked with PDB: 2VF5, derivative 3b showed maximum fullfitness score (-1696.50) and DeltaG (-7.32) having binding interactions with THR 1.783,A.
In case of PDB: 1JIJ, again 3b is the most effective in terms of fulfitness score (-1989.45) and DeltaG (-6.60) with PHE 4.2701 xWhen all derivatives docked with PDB: 1KZN, 3b showed maximum fullfitness score (-1150.97) and DeltaG (-7.28). So out of all six derivatives, 3b is the most effective drug. The modified scaffolds exhibited higher efficacy over sulfonamides. These drugs might be a promising drug candidate for further investigation.
Detailed description of the invention
Following scheme is used for manifestation of the current invention: All derivatives are novel and carried out by green synthesis. In vitro antimicrobial activities have been done and compared with marketed drugs. All screened derivatives have been selected on the basis of physicochemical and pharmacokinetic analysis. "SMILES" have been generated for analyzing of in silico properties. Their structures were made using ChemDraw Pro, version 12.0 software. 3D structures have been generated with the help of molinspiration, online server. Ligands/derivatives and proteins have been prepared before docking. All ligand structures were cleaned with the help of MarvinSketch software. They were cleaned in "CLEAN 2D & CLEAN 3D" and saved in Mol2 format. UCSF Chimera software has been used for analyzing the binding interactions of drug/ligand/derivative and protein.
Molecular docking and targets
Molecular docking is just like "lock & key" hypothesis, where protein targets act as lock and ligand/derivative acts as key. This model is "best-fit" orientation method. There are different mutual confirmations for the drug/derivative inside the protein. There are active sites are present inside the protein target where ligand/derivative have to bind for making possible confirmation. Their confirmation/binding are depending on different factors, i.e., full fitness score, hydrogen binding interactions, deltagligsolvolpol, DeltaG, binding energy modes etc. In this model drug receptor interactions have been studied. These drug-receptor interactions help in identifying the effectiveness, activity and affinity of the drug with their respective protein targets.
In the light of above, thiomorpholine frameworks are considered as best pharmacophores and have received significant attention owing to their wide range of pharmacological activities such as anti-cancer, antimycobacterial, hypertensive, antioxidant, antimicrobial, anti-inflammatory, dipeptidyl peptidase IV (DPP-IV) inhibitors, anesthetics, and analgesics. Sulfonamides are the most extensively used antibiotics and acts as effective chemotherapeutic agents. Sulfonamides widely named as sulfa drugs have prominent applications as antimicrobial, anti-depressant activity, anti-tumor, anti-inflammatory, HIV protease inhibitors, herbicides and veterinary practice. The synergistic action of sulfonamides with thiomorpholine has brought about an enormous usage of sulfonamides. The most commonly employed method for the synthesis of sulfonamides is by one-pot, two-component reaction of by sulfonylation of amines with sulfonyl halides in the presence of a base.
In the pursuit of research efforts in the development of efficient synthesis and new medicinally important compounds, we herein disclose for the first time on the synthesis of sulfonamides bearing thiomorpholine with their efficacy, drug likeness, molecular docking, physicochemical and pharmacokinetic studies.
KN 0 PEG-400 C) + R-S-CI 001S N 0 rt,3h sN
R 1 2a-f 3a-f
Yield Compound R (M) Product
CI CI 0 _
3a CI 89 S N- CI CI \/ 11 0 CI CI 0 _
3b 93 S N
0 BrBr
3c F 86 S N \-_N - S F 0 FF 3d 82 S N- 0
3e H 3CO 94 S N- OCH 3
0
0 _
3f CI 90 S N-S- CI 0
Scheme 1. Synthesis of new sulfonamides
General procedure for the synthesis of new sulfonamides
To a 50 mL round-bottom flask, thiomorpholine (0.001 mol) (1) was reacted with various
aromatic sulfonyl chlorides (0.001 mol) 2(a-f) in the presence of PEG-400 as a solvent and the
mixture was continued stirring for 3 h. The progress of the reaction was monitored by thin-layer
chromatography (TLC) (hexane:ethyl acetate, 7:3). After completion of the reaction, the crude
mixture was worked up in ice-cold water. The product, that separated out, was filtered and the
filtrate was evaporated to remove water, leaving PEG behind. The product was further purified by column chromatography on silica gel (60-120 mesh) using hexane: ethyl acetate (7:3) as an eluent to yield sulfonamide derivatives 3(a-f) (Scheme 1) in good to excellent yields (82-94%).
4-(2,4-dichlorophenylsulfonyl)thiomorpholine (3a) White solid, Yield: 89 %, mp 161-163 °C; 1H NMR (400 MHz, CDCl 3) : 7.82 (s, 1H), 7.68 (d, 13C J= 7.8 Hz, 3H), 6.75 (d, J= 7.6 Hz, 1H), 3.03 (t, J= 8.0 Hz, 2H), 2.17 (t, J= 8.0 Hz, 2H); NMR (100 MHz, CDCl 3) 6: 139.20, 135.10, 132.70, 129.64, 126.94, 122.58, 55.07, 24.58; HRMS of [CioHuNO2S2Cl2+ H]+ (m/z): 311.1158; Calcd: 311.1160.
4-(2-chloro-3-methylphenylsulfonyl)thiomorpholine (3b) White solid, Yield: 93 %, mp 177-179 °C; 1H NMR (400 MHz, CDCl3 ) : 7.63 (d, J= 8.4 Hz, 1H), 7.33 (d, J= 8.2 Hz, 1H), 6.75 (d, J= 6.3 Hz, 1H), 3.05 (t, J= 8.1 Hz, 2H), 2.51 (s, 3H, CH 3), 2.06 (t, J= 7.9 Hz, 2H); 13C NMR (100 MHz, CDC 3 ) 6:137.25,135.08,129.64,126.91, 122.48, 121.10, 54.99, 25.36, 24.57; HRMS of [CI H 14 NO 2 S 2 Cl + H]+ (m/z): 292.1079; Calcd: 292.1090.
4-(3-bromo-4-fluorophenylsulfonyl)thiomorpholine (3c) White solid, Yield: 86 %, mp 154-156 °C; 1H NMR (400 MHz, CDCl 3) : 8.05 (s, 1H), 7.72 (d, 13C J= 8.8 Hz, 2H), 7.53 (d, J= 8.8 Hz, 2H), 3.09 (t, J= 8.1 Hz, 2H), 2.11 (t, J= 8.0 Hz, 2H); NMR (100 MHz, CDCl 3 ) 6: 141.96, 141.38, 139.98, 139.42, 135.14, 129.72, 129.69, 126.96, 122.41, 54.93, 24.58; HRMS of [CioHNO2S2FBr + H]+ (m/z): 339.0454; Calcd: 339.0456.
4-(3-fluorophenylsulfonyl)thiomorpholine (3d) White solid, Yield: 82 %, mp 166-169 °C; 1H NMR (400 MHz, CDCl3 ) : 8.09 (d, J= 6.4 Hz, 1H), 7.62 (dd, J= 8.4, 1.9 Hz, 1H), 7.32 (d, J= 8.2 Hz, 1H), 6.69 (d, J= 2.2 Hz, 19H), 3.18 (t, J= 7.9 Hz, 2H), 1.94 (t, J= 8.0 Hz, 2H); 13C NMR (100 MHz, CDC 3 ) :132.35,131.75,130.59, 129.92, 128.86, 128.78, 126.25, 126.02, 56.45, 25.47; HRMS of [CioH12NO2S2F + H]+ (m/z): 262.0183; Calcd: 262.0174.
4-(4-methoxyphenylsulfonyl)thiomorpholine (3e)
White solid, Yield: 94 %, mp 181-183 °C; 1H NMR (400 MHz, CDC3) : 7.65 (d, J= 9.0 Hz, 2H), 7.04 (d, J= 8.9 Hz, 2H), 3.88 (s, 3H, OCH3), 3.02 (t, J= 5.5 Hz, 2H), 2.11 (t, J= 5.8 Hz, 2H); 13C NMR (100 MHz, CDCl 3 ) 6: 132.15, 129.70, 126.92, 125.34, 65.37, 54.98, 24.58; HRMS of [C 1 iHs5NO 3 S 2 + H]+ (m/z): 274.1046; Calcd: 274.1051.
4-(4-chlorophenylsulfonyl)thiomorpholine (3f) White solid, Yield: 90 %, mp 175-177 °C; 1H NMR (400 MHz, CDCl3 ) : 8.45 (d, J= 9.0 Hz, 2H), 8.01 (d, J= 9.0 Hz, 2H), 3.01 (t, J= 8.2 Hz, 2H), 2.09 (t, J= 8.0 Hz, 2H); 13 C NMR (100 MHz, CDCl 3 ) 6: 129.21, 126.88, 123.86, 122.90, 54.72, 24.46; HRMS of [CioH1 2N0 2 S 2 Cl
+ H]+ (m/z): 277.0850; Calcd: 277.0854.
EDITORIAL NOTE 2021105099
There is 1 page of claims only.
Claims (3)
- We Claim: 1. The invention describes six new sulfonamides bearing thiomorpholine via green synthesis 2. Three new compounds 3a, 3c and 3d proved to be most promising anti-bacterial drugs against the screened bacterial strains S. aureus, B. subtilis, P. aeruginosaand K. pneumoniae and anti-fungal activity against the screened fungal strains A. niger and P. chrysogenum when compared with the standard drugs streptomycin and ketoconazole at concentrations of 12.5, 25, 50 and 100 pg/mL 3. This is the first report for the synthesis of sulfonamides bearing thiomorpholine with their efficacy, drug likeness, molecular docking, physicochemical and pharmacokinetic studies 4. Screened derivatives exhibited antimicrobial activities and shown promising results than commercially available marketed drugs in terms of full fitness score, binding energy mode and DeltaG 5. In silico molecular screening of these compounds gave an insight of drug-receptor interaction of synthesized novel six sulfonamides bearing thiomorpholine 6. Sulfonamides displayed good oral bioavailability, drug likeness, lower toxicity and high biocompatibility 7. Sulfonamides shown high gastrointestinal absorption and brain penetration effect based on BOILED-egg model (the Brain Or IntestinaL EstimateD permeation method) 8. On the basis of full fitness score, 3b was the most effective derivative against antimicrobial targetsTablesTable-1 IUPAC name and structures of the potentially active sulfonamide derivatives 3(a−f)Derivatives Derivative IUPAC name Structures 20211050994-((3,4- 3a dichlorophenyl)sulfonyl)thiomorpholine4-((2-chloro-3- 3b methylphenyl)sulfonyl)thiomorpholine4-((3-bromo-4- 3c fluorophenyl)sulfonyl)thiomorpholine4-((3- 3d fluorophenyl)sulfonyl)thiomorpholine4-((4- 3e methoxyphenyl)sulfonyl)thiomorpholine4-((4- 3f chlorophenyl)sulfonyl)thiomorpholine1-(4-(4-(((2R,4S)-2-((1H-imidazol-1- yl)methyl)-2-(2,4-dichlorophenyl)-1,3- Ketoconazole dioxolan-4-yl)methoxy)phenyl)piperazin- 1-yl)ethenoneTable-2 Computed physicochemical properties of screened sulfonamide derivatives 3(a−f)No. of Der.* MW nRot HBA HBD TPSA MR violations 3a 312.24 2 3 0 71.06 0 76.06 20211050993b 291.82 2 3 0 71.06 0 76.22 3c 340.23 2 4 0 71.06 0 73.90 3d 261.34 2 4 0 71.06 0 66.20 3e 273.37 3 4 0 80.29 0 72.84 3f 277.79 2 3 0 71.06 0 71.25 Ketoconazole 531.43 8 5 0 69.06 1 144.44Table-3 Computed pharmacokinetic properties of screened sulfonamide derivatives 3(a−f)Oral Rat Oral Rat Renal AMES hERG I Acute Chronic Hepato- Skin Der. OCT2 toxicity inhibitor Toxicity Toxicity toxicity Sensitization substrate (LD50) (LOAE) 3a No No No 2.89 1.748 Yes No 3b No No No 2.55 1.841 Yes No 3c No No No 2.69 1.807 Yes No 3d No No No 2.44 1.897 No No 3e No No No 2.59 1.953 No No 3f No No No 2.65 1.829 Yes No Ketoconazole Yes No No 3.19 0.687 Yes NoTable-4 Molecular docking results of screened sulfonamide derivatives 3(a−f)Target: PDB: 2VF5Der. deltaG Fullfitness Energy Hydrogen-Binding Interactions (kcal/mol) 20211050993a -6.91 -1670.21 -15.63 [1]. #0 THR 302 HN-#1.40 LIG 1 O1 1.851 Å.
- [2]. #0 SER 401 HN-#1.40 LIG 1 O2 2.578 Å. 3b -7.32 -1696.50 -21.66 [1]. #0 THR 302 HN-#1.10 LIG 1 O2 1.783 Å. 3c -7.09 -1677.92 -24.32 [1]. #0 THR 302 HN-#1.30 LIG 1 O2 1.764 Å.[2]. #0 SER 401 HN-#1.30 LIG 1 O1 2.490 Å. 3d -6.70 -1681.12 -23.89 [1]. #0 THR 302 HN-#1.82 LIG 1 O2 1.778 Å. 3e -6.50 -1668.71 -10.26 [1]. #0 THR 302 HN-#1.30 LIG 1 O2 1.764 Å.[2]. #0 SER 401 HN-#1.30 LIG 1 O1 2.490 Å. 3f -6.79 -1679.47 -23.82 [1]. #0 THR 302 HN-#1.4 LIG 1 O2 1.809 Å. ketoconazole -8.72 -1632.24 21.69 NO INTERACTIONTarget: PDB: 1JIJDer. deltaG Fullfitness Energy Hydrogen-Binding Interactions (kcal/mol) 3a -6.08 -1958.42 -3.58 [1]. #0 SER 237 HN-#1.64 LIG 1 O1 2.433 Å. 3b -6.60 -1989.45 -11.36 [1]. #0 PHE 136 HN-#1.32 LIG 1 O1 4.270 Å. 3c -6.68 -1970.26 -14.44 [1]. #0 GLU 236 HN-#1.19 LIG 1 O2 3.936 Å.[2]. #0 GLU 236 HN-#1.19 LIG 1 N1 4.745 Å.
- [3]. #0 SER 237 HN-#1.19 LIG 1 O1 2.797 Å. 3d -6.17 -1965.02 -5.93 [1]. #0 SER 237 HN-#1.25 LIG 1 O1 2.544 Å. 3e -6.83 -1974.33 -11.92 [1]. #0 LEU 5 HN-#1.9 LIG 1 O3 2.313 Å. 3f -6.59 -1976.73 -13.95 NO INTERACTIONketoconazole -8.11 -1931.00 31.75 NO INTERACTION 2021105099Target: PDB: 1KZNDer. deltaG Energy Hydrogen-Binding Interactions Fullfitness (kcal/mol) 3a -6.80 -1123.33 -13.94 [1]. #0 GLY 77 HN-#1.6 LIG 1 O2 4.613 Å. 3b -7.28 -1150.97 -18.12 NO INTERACTION3c -7.18 -1127.95 -15.87 [1]. #0 GLY 77 HN-#1.34 LIG 1 O2 4.412 Å. 3d -6.97 -1135.84 -16.71 NO INTERACTION3e -7.51 -1135.94 -14.67 NO INTERACTION3f -7.19 -1134.73 -18.70 NO INTERACTIONketoconazole -8.82 -1087 28.10 NO INTERACTIONFigures 2021105099Figure-1 BOILED-egg model image of sixscreened out sulfonamide derivatives 3(a−f)Figure-2 Molecular docking structures of antimicrobial target (PDB: 2VF5) with screened out sulfonamide derivatives 3(a−f)Figure-3 Molecular docking structures of antimicrobial target (PDB: 1JIJ) with screened out sulfonamide derivatives 3(a−f)Figure-4 Molecular docking structures of antimicrobial target (PDB: 1KZN) with screened out sulfonamide derivatives 3(a−f)O 08 Aug 2021S PEG-400 S + R S Cl N O rt, 3 h N H O S O R 1 2a-f 3a-f 2021105099Yield Compound R (%) ProductCl Cl O 3a Cl 89 S N S Cl OCl Cl O 3b 93 S N S O Br Br O 3c 86 F S N S F O F F 3d O 82 S N S OO 3e H3 CO 94 S N S OCH 3 OO 3f Cl 90 S N S Cl OFigure-5 Synthesis of novel sulfonamides3 (a-f) via green methodology
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