Design,synthesis and biological evaluation of novel pyrrole derivatives as potential ClpP1P2 inhibitor against Mycobacterium tuberculosis

In an effort to discover novel inhibitors of M. tuberculosis Caseinolytic proteases (ClpP1P2), a combination strategy of virtual high-throughput screening and in vitro assay was employed and a new pyrrole compound, 1-(2-chloro-6-fluorobenzyl)-2, 5-dimethyl-4-((phenethylamino)methyl)-1H-pyrrole-3-carboxylate was found to display inhibitory effects against H₃₇Ra with an MIC value of 77 µM. In order for discovery of more potent anti-tubercular agents that inhibit ClpP1P2 peptidase in M. tuberculosis, a series of pyrrole derivatives were designed and synthesized based on this hit compound. The synthesized compounds were evaluated for in vitro studies against ClpP1P2 peptidase and anti-tubercular activities were also evaluated. The most promising compounds 2-(4-bromophenyl)-N-((1-(2-chloro-6-fluorophenyl)-2, 5-dimethyl-1H- pyrrolyl)methyl)ethan-1-aminehydrochloride 7d, ethyl 4-(((4-bromophenethyl) amino) methyl)-2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13i, ethyl 1-(4-chlorophenyl)-4-(((2-fluorophenethyl)amino)methyl)-2-methyl-5-phenyl-1H-pyrrole-3-carboxylate hydrochloride 13n exhibited favorable anti-mycobacterial activity with MIC value at 5 µM against Mtb H₃₇Ra, respectively.     

New hybrid trifluoromethylquinolines as antiplasmodium agents

Malaria remains a major public health problem worldwide, and it is responsible for high rates of morbidity and mortality. Resistance to current antimalarial drugs has been identified, and new drugs are urgently needed. In this study, we designed and synthesized seventeen novel quinolines based on the structures of mefloquine ((2,8-bis(trifluoromethyl)quinolin-4-yl)(piperidin-2-yl)methanol) and amodiaquine (4-((7-chloroquinolin-4-yl)amino)-2-((diethylamino)methyl)phenol) using ring bioisosteric replacement and molecular hybridization of the functional groups. The compounds were evaluated in vitro against Plasmodium falciparum and in vivo in mice infected with P. berghei. All derivatives presented anti-P. falciparum activity with IC₅₀ values ranging from 0.083 to 33.0?µM. The compound with the best anti-P. falciparum activity was N-(5-methyl-4H-1,2,4-triazol-3-yl)-2,8-bis(trifluoromethyl)quinolin-4-amine (12) which showed an IC₅₀ of 0.083?µM. The three most active compounds were selected for antimalarial activity tests against P. berghei-infected mice. Compound 12 was the most active on the 5th day after infection, reducing parasitemia by 66%, which is consistent with its in vitro activity. This is an important result as 12, a simpler molecule than mefloquine, does not contain the stereogenic center, and consequently, its synthesis in the laboratory is easier and less expensive. This system proved promising for the design of potential antimalarial compounds.     

Design,synthesis, and biological evaluation of selective and potent Carbazole-based butyrylcholinesterase inhibitors

Alzheimer’s disease (AD) is the most common form of dementia. Inhibition of BChE might be a useful therapeutic target for AD. A new series of Carbazole-Benzyl Pyridine derivatives were designed synthesized and evaluated as butyrylcholinesterase (BChE) inhibitors. In vitro assay revealed that all of the derivatives had selective and potent anti- BChE activities. 3-((9H-Carbazol-9-yl)methyl)-1-(4-chlorobenzyl)pyridin-1-ium chloride (compound 8f) had the most potent anti-BChE activity (IC₅₀ value?=?0.073?μM), the highest BChE selectivity and mixed-type inhibition. Docking study revealed that 8f interacted with the peripheral site, the choline binding site, catalytic site and the acyl pocket of BChE. Physicochemical properties were accurate to Lipinski's rule. In addition, compound 8f demonstrated neuroprotective activity at 10?µM. This compound could also inhibit AChE-induced and self-induced Aβ peptide aggregation at concentration of 100?µM and 10?µM respectively. The in-vivo study showed that compound 8f in 10?mg/kg increased the time spent in target quadrant in the probe day and decreased mean training period scape latency in rats. All results suggest that new sets of potent selective inhibitors of BChE have a therapeutic potential for the treatment of AD.     

Synthesis,biological evaluation and molecular modeling of aloe-emodin derivatives as new acetylcholinesterase inhibitors

A series of aloe-emodin derivatives were designed, synthesized and evaluated as acetylcholinesterase inhibitors. Most of the new prepared compounds showed remarkable acetylcholinesterase inhibitory activities. Among them, the compound 1-((4,5-dihydroxy-9,10-dioxo-9,10-dihydroanthracen-2-yl) methyl) pyridin-1-ium chloride (C3) which has a pyridinium substituent possessed the best inhibitory activity of acetylcholinesterase (IC₅₀ = 0.09 μM). The docking study performed with AUTODOCK demonstrated that C3 could interact with the catalytic active site (CAS) and the peripheral anionic site (PAS) of acetylcholinesterase.     

Potent ACE inhibitors from 5-hydroxy indanone derivatives

A novel triazole derivatives(±)-2-(hydroxymethyl)-7,8-dihydro-1H-indeno[5,4-b]furan-6(2H)-one (12a–j) were designed and synthesized by the reaction between racemic azide and terminal acetylenes under click chemistry reaction conditions followed by biological evaluation as angiotensin converting enzyme (ACE) inhibitors. β-Amino alcohol derivatives of 1-indanone (15a–l) were synthesized from 5-hydroxy indanone, it was reacted with epichlorohydrin and followed by oxirane ring opening with various piperazine derivatives. Among the newly synthesized compounds 12b (IC₅₀: 1.388024 µM), 12g (IC₅₀: 1.220696 µM), 12j (IC₅₀: 1.312428 µM) and 15k (IC₅₀: 1.349671 µM) and 15l (IC₅₀: 1.330764 µM) emerged as most active non-carboxylic acid ACE inhibitors with minimal toxicity comparable to clinical drug Lisinopril.     

In vitro cytotoxicity screening to identify novel anti-osteosarcoma therapeutics targeting pyruvate dehydrogenase kinase 2

Pyruvate dehydrogenase kinases (PDKs) act as negative modulator of mitochondrial pyruvate dehydrogenase complex (PDC) and play a crucial role in the regulation of oxidative glycolysis, which recently have been considered as a potential drug target for varying types of cancer and diabetes. Herein, we describe the discovery and biological validation of novel anti-osteosarcoma therapeutics targeting PDK2. We identified 14 anti-osteosarcoma compounds from an in-house small molecule library, which were then evaluated in a PDK2 kinase inhibition assay. We found that compounds with 2-((4-oxo-6-((4-phenylpiperazin-1-yl)methyl)-4H-pyran-3-yl)oxy)acetamide moiety showed promising inhibitory potencies to PDK2. Especial for 12, which bound to PDK2 with a K_d value of 2.3 µM, and inhibited PDK2 activity with an EC₅₀ value of 1.1 µM. In addition, 12 selectively inhibited PDK2, the selectivity indexes are 10.6, 22.0, and 60.9 for PDK2 as compared to PDK1, 2 and 4, respectively. The MTT assay suggested that 12 reduced MG-63 cancer cell proliferation with an IC₅₀ value of 4.7 µM. All these observations indicated that 12 was a novel anti-osteosarcoma therapeutic, which deserved for further investigation.     

Design,synthesis, docking study, α-glucosidase inhibition,and cytotoxic activities of acridine linked to thioacetamides as novel agents in treatment of type 2 diabetes

A novel series of acridine linked to thioacetamides 9a–o were synthesized and evaluated for their α-glucosidase inhibitory and cytotoxic activities. All the synthesized compounds exhibited excellent α-glucosidase inhibitory activity in the range of IC₅₀ = 80.0 ± 2.0–383.1 ± 2.0 µM against yeast α-glucosidase, when compared to the standard drug acarbose (IC₅₀ = 750.0 ± 1.5 µM). Among the synthesized compounds, 2-((6-chloro-2-methoxyacridin-9-yl)thio)-N-(p-tolyl) acetamide 9b displayed the highest α-glucosidase inhibitory activity (IC₅₀ = 80.0 ± 2.0 μM). The in vitro cytotoxic assay of compounds 9a–o against MCF-7 cell line revealed that only the compounds 9d, 9c, and 9n exhibited cytotoxic activity. Cytotoxic compounds 9d, 9c, and 9n did not show cytotoxic activity against the normal human cell lines HDF. Kinetic study revealed that the most potent compound 9b is a competitive inhibitor with a K_i of 85 μM. Furthermore, the interaction modes of the most potent compounds 9b and 9f with α-glucosidase were evaluated through the molecular docking studies.     

Synthesis and anticancer activity of bis-benzo[d][1,3]dioxol-5-yl thiourea derivatives with molecular docking study

New thiourea derivatives incorporating two benzo[d][1,3]dioxol-5-yl moieties have been synthesized through the reaction of two molecules of benzo[d][1,3]dioxol-5-yl isothiocyanate with one molecule of various diamino derivatives. The synthesized compounds were examined for their cytotoxic effects using SRB assay on three cancer cell lines HepG2, HCT116 and MCF-7. Most of compounds showed significant antitumor activity and some compounds showed strong results greater than the reference drug. As example, IC₅₀ values of 1,1′-(1,4-phenylene)bis(3-(benzo[d][1,3]dioxol-5-yl)thiourea) 5 were 2.38 µM for HepG2, 1.54 µM for HCT116 and 4.52 µM for MCF7, while the IC₅₀ values of standard drug doxorubicin were 7.46, 8.29 and 4.56 µM, respectively. Interestingly, these compounds were non cytotoxic toward the tested normal cell line (IC₅₀ value > 150 µM). The anticancer mechanisms were studied via EGFR inhibition assessment, annexin V-FITC apoptosis assessment, cell cycle analysis and study the effect on mitochondrial apoptosis pathway proteins Bax and Bcl-2 as well as molecular docking studies.     

Discovery of N-ethylpyridine-2-carboxamide derivatives as a novel scaffold for orally active γ-secretase modulators

Gamma-secretase modulators (GSMs) are promising disease-modifying drugs for Alzheimer’s disease because they can selectively decrease pathogenic amyloid-β42 (Aβ42) levels. Here we report the discovery of orally active N-ethylpyridine-2-carboxamide derivatives as GSMs. The isoindolinone moiety of 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethyl-2,3-dihydro-1H-isoindol-1-one hydrogen chloride (1a) was replaced with a picolinamide moiety. Optimization of the benzyl group significantly improved GSM activity and mouse microsomal stability. 5-{8-[([1,1′-Biphenyl]-4-yl)methoxy]-2-methylimidazo[1,2-a]pyridin-3-yl}-N-ethylpyridine-2-carboxamide hydrogen chloride (1v) potently reduced Aβ42 levels with an IC₅₀ value of 0.091 µM in cultured cells without inhibiting CYP3A4. Moreover, 1v demonstrated a sustained pharmacokinetic profile and significantly reduced brain Aβ42 levels in mice.     

Sulfonate and sulfamate derivatives possessing benzofuran or benzothiophene nucleus as potent carbonic anhydrase II/IX/XII inhibitors

In the current work, we report the discovery of new sulfonate and sulfamate derivatives of benzofuran- and benzothiophene as potent inhibitors of human carbonic anhydrases (hCAs) II, IX and XII. A set of derivatives, 1a–t, having different substituents on the fused benzofuran and benzothiophene rings (R = alkyl, cyclohexyl, aryl, NH₂, NHMe, or NMe₂) was designed and synthesized. Most of the derivatives exhibited higher potency than acetazolamide as inhibitors of the purified hCAII, IX and XII isoforms. The most potent inhibitors for hCAII, hCAIX and hCAXII were 1g, 1b and 1d with an IC₅₀ ± SEM values of 0.14 ± 0.03, 0.13 ± 0.03 and 0.17 ± 0.06 µM, respectively. In addition, compounds 1d and 1n exerted preferential inhibitory effect against hCAXII isozyme with good potencies. Some selected compounds were docked within the active pocket of these isozymes and binding of the molecules revealed that sulfonate and sulfamate rings were located towards the active cavity and compounds coordinated to zinc ions.     

Discovery of novel scaffolds for γ-secretase modulators without an arylimidazole moiety

Gamma-secretase modulators (GSMs) selectively inhibit the production of amyloid-β 42 (Aβ42) and may therefore be useful in the management of Alzheimer’s disease. Most heterocyclic GSMs that are not derived from nonsteroidal anti-inflammatory drugs contain an arylimidazole moiety that potentially inhibits cytochrome P450 (CYP) activity. Here, we discovered imidazopyridine derivatives that represent a new class of scaffold for GSMs, which do not have a strongly basic end group such as arylimidazole. High-throughput screening identified 2-methyl-8-[(2-methylbenzyl)oxy]-3-(pyridin-4-yl)imidazo[1,2-a]pyridine (3a), which inhibited the cellular production of Aβ42 (IC₅₀?=?7.1?µM) without changing total production of Aβ. Structural optimization of this series of compounds identified 5-[8-(benzyloxy)-2-methylimidazo[1,2-a]pyridin-3-yl]-2-ethylisoindolin-1-one (3m) as a potent inhibitor of Aβ42 (IC₅₀?=?0.39?µM) but not CYP3A4. Further, 3m demonstrated a sustained pharmacokinetic profile in mice and sufficiently penetrated the brain.     

Novel pyridazinone derivatives as butyrylcholinesterase inhibitors

In the current study, forty-four new [3-(2/3/4-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl carbamate derivatives were synthesized and evaluated for their ability to inhibit electric eel acetylcholinesterase (EeAChE) and equine butyrylcholinesterase (eqBuChE) enzymes. According to the inhibitory activity results, [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl heptylcarbamate (16c, eqBuChE, IC₅₀ = 12.8 μM; EeAChE, no inhibition at 100 μM) was the most potent eqBuChE inhibitor among the synthesized compounds and was found to be a moderate inhibitor compared to donepezil (eqBuChE, IC₅₀ = 3.25 μM; EeAChE, IC₅₀ = 0.11 μM). Kinetic and molecular docking studies indicated that compounds 16c and 14c (hexylcarbamate derivative, eqBuChE, IC₅₀ = 35 μM; EeAChE, no inhibition at 100 μM) were mixed-type inhibitors which accommodated within the catalytic active site (CAS) and peripheral anionic site (PAS) of hBuChE through stable hydrogen bonding and π-π stacking. Furthermore, it was determined that [3-(2-methoxyphenyl)-6-oxopyridazin-1(6H)-yl]methyl (4-methylphenyl)carbamate 7c (eqBuChE, IC₅₀ = 34.5 μM; EeAChE, 38.9% inhibition at 100 μM) was the most active derivative against EeAChE and a competitive inhibitor binding to the CAS of hBuChE. As a result, 6-(2-methoxyphenyl)pyridazin-3(2H)-one scaffold is important for the inhibitory activity and compounds 7c, 14c and 16c might be considered as promising lead candidates for the design and development of selective BuChE inhibitors for Alzheimer’s disease treatment.     

The first radiosynthesis of [11C]AZD8931 as a new potential PET agent for imaging of EGFR,HER2 and HER3 signaling

The reference standard AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-methylacetamide} (11a) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-chloro-N-methylacetamide in 11 steps with 2–5% overall chemical yield. The precursor N-desmethyl-AZD8931{2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)acetamide} (11b) was synthesized from methyl 4,5-dimethoxy-2-nitrobenzoate or ethyl 4,5-dimethoxy-2-nitrobenzoate and 2-bromoacetamide in 11 steps with 2–4% overall chemical yield. The target tracer [¹¹C]AZD8931 {2-(4-((4-((3-chloro-2-fluorophenyl)amino)-7-methoxyquinazolin-6-yl)oxy)piperidin-1-yl)-N-[¹¹C]methylacetamide} ([¹¹C]11a) was prepared from N-desmethyl-AZD8931 (11b) with [¹¹C]CH₃OTf under basic condition (NaH) through N-[¹¹C]methylation and isolated by HPLC combined with solid-phase extraction (SPE) in 40–50% radiochemical yield based on [¹¹C]CO₂ and decay corrected to end of bombardment (EOB) with 370–1110 GBq/μmol specific activity at EOB.     

Design,synthesis and biological evaluation of some tetrazole acetamide derivatives as novel non-carboxylic PTP1B inhibitors

A series of ten N-(3-(1H-tetrazole-5-yl)phenyl)acetamide derivatives (NM-07 to NM-16) designed from a lead molecule identified previously in our laboratory were synthesized and evaluated for protein tyrosine phosphatase 1B (PTP1B) inhibitory activity. Among the synthesized molecules, NM-14, a 5-Cl substituted benzothiazole analogue elicited significant PTP1B inhibition with an IC₅₀ of 1.88 µM against reference standard suramin (IC₅₀ ≥ 10 µM). Furthermore, this molecule also showed good in vivo antidiabetic activity which was comparable to that of standard antidiabetic drugs metformin and glimepiride. Overall, the results of the study clearly reveal that the reported tetrazole derivatives especially NM-14 are valuable prototypes for the development of novel non-carboxylic inhibitors of PTP1B with antidiabetic potential.     

Synthesis and urease inhibitory potential of benzophenone sulfonamide hybrid in vitro and in silico

This study deals with the synthesis of benzophenone sulfonamides hybrids (1–31) and screening against urease enzyme in vitro. Studies showed that several synthetic compounds were found to have good urease enzyme inhibitory activity. Compounds 1 (N′-((4′-hydroxyphenyl)(phenyl)methylene)-4′′-nitrobenzenesulfonohydrazide), 2 (N′-((4′-hydroxyphenyl)(phenyl)methylene)-3′′-nitrobenzenesulfonohydrazide), 3 (N′-((4′-hydroxyphenyl)(phenyl)methylene)-4′′-methoxybenzenesulfonohydrazide), 4 (3′′,5′′-dichloro-2′′-hydroxy-N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide), 6 (2′′,4′′-dichloro-N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide), 8 (5-(dimethylamino)-N′-((4-hydroxyphenyl)(phenyl)methylene)naphthalene-1-sulfono hydrazide), 10 (2′′-chloro-N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide), 12 (N′-((4′-hydroxyphenyl)(phenyl)methylene)benzenesulfonohydrazide) have found to be potently active having an IC₅₀ value in the range of 3.90–17.99?µM. These compounds showed superior activity than standard acetohydroxamic acid (IC₅₀?=?29.20?±?1.01?µM). Moreover, in silico studies on most active compounds were also performed to understand the binding interaction of most active compounds with active sites of urease enzyme. Structures of all the synthetic compounds were elucidated by ¹H NMR, ¹³C NMR, EI-MS and FAB-MS spectroscopic techniques.     

Synthesis,evaluation and docking of novel pyrazolo pyrimidines as potent p38α MAP kinase inhibitors with improved anti-inflammatory,ulcerogenic and TNF-α inhibitory properties

A series of nine new N-substituted-4-((1-phenyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)amino)benzamides (6a-i) derivatives was synthesized. All the compounds were screened in-vitro for BSA anti-denaturation property, antioxidant assay and p38α MAP kinase inhibition. The in vitro anti-inflammatory assay results revealed that the compounds (6f-i) showed better activity than the compounds 6a-e. Compound 6f bearing the 4-chlorophenyl group showed in vitro anti-inflammatory activity (82.35 ± 4.04) comparable to standard drug diclofenac sodium (84.13 ± 1.63) and better p38α MAP kinase inhibitory activity (IC₅₀ = 0.032 ± 1.63 µM) than the prototypic inhibitor SB203580 (IC₅₀ = 0.041 ± 1.75 µM). The selected active compounds (6f-i) were further studied in animal models for anti-inflammatory activity, ulcerogenic liability, lipid peroxidation and TNF-α inhibition potential. Compound 6f showed promising anti-inflammatory potential with a percentage inhibition of 83.73% when compared to the standard, diclofenac sodium (78.05%). Compound 6f was also found to show reduced ulcerogenic liability and lipid peroxidation in comparison to the standard. This compound also potently inhibited the lipopolysaccharide (LPS)-induced TNF-α production in mice model (ID₅₀ = 8.23 mg/kg) in comparison to SB 203580 (ID₅₀ = 26.38 mg/kg). The molecular docking of compounds 6a-i against p38α MAP kinase receptor was also performed to understand ligand receptor interaction. Amongst all synthesized molecules compound 6f displayed highest docking score of −9.824. It showed hydrogen bonding interactions with Asn115 and pi-cation interaction with Lys53.     

Synthesis of (Z)-3-(arylamino)-1-(3-phenylimidazo[1,5-a]pyridin-1-yl)prop-2-en-1-ones as potential cytotoxic agents

The new derivatives based on (Z)-3-(arylamino)-1-(3-phenylimidazo[1,5-a]pyridin-1-yl)prop-2-en-1-one scaffold was synthesized and evaluated for their in vitro cytotoxic potential against a panel of cancer cell lines, viz., A549 (human lung cancer), HCT-116 (human colorectal cancer), B16F10 (murine melanoma cancer), BT-474 (human breast cancer), and MDA-MB-231 (human triple-negative breast cancer). Among them, many of the synthesized compounds exhibited promising cytotoxic potential against the panel of tested cancer cell lines with IC₅₀ <30 µM. Based on the preliminary screening results, the structure-activity relationship (SAR) of the compounds was established. Among the synthesized compounds, 15i displayed a potential anti-proliferative activity against HCT-116 cancer cell line with an IC₅₀ value of 1.21 ± 0.14 µM. Flow cytometric analysis revealed that compound 15i arrested the G0/G1 phase of the cell cycle. Moreover, increased reactive oxygen species (ROS) generation, clonogenic assay, acridine orange staining, DAPI nuclear staining, measurement of mitochondrial membrane potential (ΔΨm), and annexin V-FITC assays revealed that compound 15i promoted cell death through apoptosis.     

Synthesis,biological evaluation and docking study of N-(2-(3,4,5-trimethoxybenzyl)benzoxazole-5-yl) benzamide derivatives as selective COX-2 inhibitor and anti-inflammatory agents

A series of N-(2-(3,4,5-trimethoxybenzyl)-benzoxazole-5-yl)benzamide derivatives (3a–3n) was synthesized and evaluated for its in vitro inhibitory activity against COX-1 and COX-2. The compounds with considerable in vitro activity (IC₅₀ < 1 µM), were evaluated in vivo for their anti-inflammatory and ulcerogenic potential. Out of the fourteen newly synthesized compounds; 3b, 3d, 3e, 3h, 3l and 3m were found to be most potent COX-2 inhibitors in in vitro enzymatic assay with IC₅₀ in the range of 0.14–0.69 µM. In vivo anti-inflammatory activity of these six compounds (3b, 3d, 3e, 3h, 3l and 3m) was assessed by carrageenan induced rat paw edema method. The compound 3b (79.54%), 3l (75.00%), 3m (72.72%) and 3d (68.18%) exhibited significant anti-inflammatory activity than standard drug ibuprofen (65.90%). Ulcerogenic activity with histopathological studies was performed, and the screened compounds demonstrated significant gastric tolerance than ibuprofen. Molecular Docking study was also performed with resolved crystal structure of COX-2 to understand the interacting mechanisms of newly synthesized inhibitors with the active site of COX-2 enzyme and the results were found to be in line with the biological evaluation studies of the compounds.     

Synthesis, in vitro and in silico studies of novel potent urease inhibitors: N-[4-({5-[(3-Un/substituted-anilino-3-oxopropyl)sulfanyl]-1,3,4-oxadiazol-2-yl}methyl)-1,3-thiazol-2-yl]benzamides

The present article describes the synthesis, in vitro urease inhibition and in silico molecular docking studies of a novel series of bi-heterocyclic bi-amides. The synthesis of title compounds was initiated by benzoylation, with benzoyl chloride (1), of the key starter ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (2) in weak basic aqueous medium followed by hydrazide formation, 4, and cyclization with CS₂ to reach the parent bi-heterocyclic nucleophile, N-{4-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-thiazol-2-yl}benzamide (5). Various electrophiles, 8a–l, were synthesized by a two-step process and these were finally coupled with 5 to yield the targeted bi-heterocyclic bi-amide molecules, 9a–l. The structures of the newly synthesized products were corroborated by IR, ¹H NMR, ¹³C NMR, EI-MS and elemental analysis. The in vitro screening of these molecules against urease explored that most of the compounds exhibit potent inhibitory potential against this enzyme. The compound 9j, with IC₅₀ value of 2.58?±?0.02?µM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC₅₀ value of 21.11?±?0.12?µM. In silico studies fully augmented the experimental enzyme inhibition results. Chemo-informatics analysis showed that synthesized compounds (9a–l) mostly obeyed the Lipinski's rule. Molecular docking study suggested that ligand 9j exhibited good binding energy value (?7.10?kcal/mol) and binds within the active region of target protein. So, on the basis of present investigation, it was inferred that 9j may serve as a novel scaffold for designing more potent urease inhibitors.     

N-aryl 2-aryloxyacetamides as a new class of fatty acid amide hydrolase (FAAH) inhibitors

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4g, with an IC₅₀ of 2.6?µM as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-phenylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4i, with an IC₅₀ of 0.35?µM.