Pd/Cu-catalyzed access to novel 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinone derivatives: their in silico/in vitro evaluation as inhibitors of chorismate mutase (CM).

In view of the reported chorismate mutase (CM or MtbCM) inhibitory activities of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives the structurally similar 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinones were designed and evaluated in silico against CM. The docking of target molecules was performed at the interface site of MtbCM (PDB: 2FP2). All the best ranked molecules participated in a strong H-bonding with the ILE67 of the B chain at the backbone position in addition to several hydrophobic/van der Waals interactions with the hydrophobic residues. Based on encouraging docking results, the one-pot synthesis of newly designed benzofuran derivatives was carried out using tandem Pd/Cu-catalyzed Sonogashira cross-coupling followed by intramolecular cyclization of 2-iodophenols with appropriate terminal alkynes. A range of novel 3-(benzofuran-2-ylmethyl) substituted (pyrazolo/benzo)triazinone derivatives were prepared in high (>80%) yields. Three molecules i.e.3h, 3i and 3m that participated in good interaction with CM in silico showed encouraging (64-65%) inhibition at 30 µM in vitro. An SAR within this class of molecules suggested that the benzotriazinone series in general was better than the pyrazolotriazinone series. Based on molecular docking in silico, CM inhibition in vitro and computational ADME prediction the benzofuran derivatives 3i and 3m seemed to be of further medicinal interest in the context of discovery and development of new anti-tubercular agents.

Ultrasound assisted one-pot synthesis of rosuvastatin based novel azaindole derivatives via coupling-cyclization strategy under Pd/Cu-catalysis: Their evaluation as potential cytotoxic agents.

Addressing the increasing incidences of cancer worldwide along with the multifaceted problem of drug resistance via development of new anticancer agents has become an essential goal. Due to the known cytotoxic effects and reported Akt inhibitory potential of azaindoles we designed a new framework incorporating the structural features of rosuvastatin and 5- or 7-azaindole. The framework was used to construct a library of small molecules for further pharmacological evaluation. The design was supported by the docking studies of two representative molecules in silico. A one-pot sonochemical approach was established for the synthesis of these rosuvastatin based azaindoles that involved the coupling-cyclization of a rosuvastatin derived terminal alkyne with appropriate 3-iodopyridine derivatives under Pd/Cu-catalysis. When tested using an MTT assay, some of the synthesized compounds showed desirable cytotoxic effects against three cancer cell lines e.g. HCT 116, Hep G2 and PA-1 but no significant effects against the non-cancerous HEK cell line. According to the SAR the 5-azaindole ring appeared to be marginally better than the 7-azaindole whereas the activity was varied with the variation of sulfonamide moiety attached to the N-1 atom of the azaindole ring. Among all the groups present in the sulfonamide moiety the p-MeC6H4 group appeared to be most effective in terms of activity. While 3b and 5b were identified as initial hit molecules the compound 5b (in addition to 3b) also showed significant inhibition of Akt1 in vitro that was reflected by its strong interaction with Akt1 in silico (with the docking score -11.7 kcal/mol) involving two H-bonding interactions with Ser7 and Asp439 residues. Further, a reasonable ADME was predicted for 5bin silico. Being a potent inhibitor (MIA Paca-2 IC50 = 18.79 ± 0.17 nM) and with NOAEL (No Observed Adverse Effect Level) > 100 µM in Zebrafish, 5b emerged as a promising compound.

Fe(III)-catalyzed regioselective and faster synthesis of isocoumarins with 3-oxoalkyl moiety at C-4: Identification of new inhibitors of PDE4.

In search of potent and new anti-inflammatory agents, we explored a new class of isocoumarin derivatives possessing the 3-oxoalkyl moiety at C-4 position. These compounds were synthesized via the FeCl3 catalyzed construction of isocoumarin ring. The methodology involved coupling of 2-alkynyl benzamides with alkyl vinyl ketone and proceeded via a regioselective cyclization to give the desired compound as a result of formation of CO and CC bonds. A large number of isocoumarins were synthesized and assessed against PDE4B in vitro. While isocoumarins containing an aminosulfonyl moiety attached to the C-3 aryl ring showed encouraging inhibition of PDE4B, some of the derivatives devoid of aminosulfonyl moiety also showed considerable inhibition. According to the SAR analysis the C6H4NHSO2R2-m moiety at C-3 position of the isocoumarin ring was favorable when the R2 was chosen as an aryl or 2-thienyl group whereas the presence of F or OMe substituent at C-7 of the isocoumarin ring was found to be beneficial. The compound 5f with IC50 values 0.125 ± 0.032 and 0.43 ± 0.013 µM against PDE4B and 4D, respectively was identified as an initial hit. It showed in silico interaction with the PHE678 residue in the CR3 region of PDE4B and relatively less number of interactions with PDE4D. Besides showing the PDE4 selectivity over other PDEs and TNF-α inhibition in vitro the compound 5f at an intraperitoneal dose of 30 mg/kg demonstrated the protective effects against the development of arthritis and potent immunomodulatory activity in adjuvant induced arthritic (AIA) rats. Furthermore, no significant adverse effects were observed for this compound when evaluated in a systematic toxicity (e.g. teratogenicity, hepatotoxicity and cardiotoxicity) studies in zebrafish at various concentrations. Collectively, being a new, potent, moderately selective and safe inhibitor of PDE4B the isocoumarin 5f can be progressed into further pharmacological studies.

Amberlyst-15 catalysed synthesis of novel indole derivatives under ultrasound irradiation: Their evaluation as serotonin 5-HT2C receptor agonists.

A series of indole based novel Schiff bases was designed as potential agonists of 5-HT2C receptor that was supported by docking studies in silico. These compounds were synthesized via Amberlyst-15 catalysed condensation of an appropriate pyrazole based primary amine with the corresponding indole-3-aldehyde under ultrasound irradiation at ambient temperature. A number of target Schiff bases were obtained in good yields (77-87%) under mild conditions within 1 h. Notably, the methodology afforded the corresponding pyrazolo[4,3-d]pyrimidin-7(4H)-one derivatives when the primary amine was replaced by a secondary amine. Several Schiff bases showed agonist activity when tested against human 5-HT2C using luciferase assay in HEK293T cells in vitro. The SAR (Structure-Activity-Relationship) studies suggested that the imine moiety was more favorable over its cyclic form i.e. the corresponding pyrazolopyrimidinone ring. The Schiff bases 3b (EC50 1.8 nM) and 3i (EC50 5.7 nM) were identified as the most active compounds and were comparable with Lorcaserin (EC50 8.5 nM). Also like Lorcaserin, none of these compounds were found to be PAM of 5-HT2C. With ∼24 and ∼150 fold selectivity towards 5-HT2C over 5-HT2A and 5-HT2B respectively the compound 3i that reduced locomotor activity in zebrafish (Danio rerio) larvae model emerged as a promising hit molecule for further study.

Pd-catalysed general access to 7-membered N/O-heterocyclic compounds as potential agents against inflammation.

A Pd-catalysed regioselective synthesis of 4,5-disubstituted 7-membered N/O-heterocycles was achieved via the 7-endo-dig cyclization followed by C-C bond formation of 2-(1-alkynyl)phenylacetamide. The ligand/additive free cascade reaction proceeded in the presence of PdCl2 in aqueous MeCN when the separate and individual use of methyl vinyl ketone and allyl bromide generally afforded an O- and N-heterocycle, respectively. The pharmacological assay was performed to identify the first example of a 1H-benzo[d]azepin-2(3H)-one based novel inhibitor of PDE4B.

PdCl2-catalyzed synthesis of a new class of isocoumarin derivatives containing aminosulfonyl / aminocarboxamide moiety: First identification of a isocoumarin based PDE4 inhibitor.

While anti-inflammatory properties of isocoumarins are known their PDE4 inhibitory potential was not explored previously. In our effort the non-PDE4 inhibitor isocoumarins were transformed into the promising inhibitors via introducing an aminosulfonyl/aminocarboxamide moiety to the C-3 benzene ring attached to the isocoumarin framework. This new class of isocoumarins were synthesized via a PdCl2-catalyzed construction of the 4-allyl substituted 3-aryl isocoumarin ring starting from the appropriate 2-alkynyl benzamide derivative. Several compounds showed good inhibition of PDE4B in vitro and the SAR indicated superiority of aminosulfonamide moiety over aminocarboxamide in terms of PDE4B inhibition. Two compounds 3q and 3u with PDE4B IC50 = 0.43 ± 0.11 and 0.54 ± 0.19 µM and ≥ 2-fold selectivity over PDE4D emerged as initial hits. The participation of aminosulfonamide moiety in PDE4B inhibition and the reason for selectivity though moderate shown by 3q and 3u was revealed by the in silico docking studies. In view of potential usefulness of moderately selective PDE4B inhibitors the compound 3u (that showed PDE4 selectivity over other PDEs) was further evaluated in adjuvant induced arthritic rats. At an intraperitoneal dose of 30 mg/kg the compound showed a significant reduction in paw swelling (in a dose dependent manner), inflammation and pannus formation (in the knee joints) as well as pro-inflammatory gene expression/mRNA levels and increase in body weight. Moreover, besides its TNF-α inhibition and no significant toxicity in an MTT assay the compound did not show any adverse effects in a thorough toxicity studies e.g. teratogenicity, hepatotoxicity, cardiotoxicity and apoptosis in zebrafish. Thus, the isocoumarin 3u emerged as a new, safe and moderately selective PDE4B inhibitor could be useful for inflammatory diseases possibly including COVID-19.

Indole Derivatives as Anti-Tubercular Agents: An Overview on their Synthesis and Biological Activities.

BACKGROUND: The indole framework is considered as one of the privileged structures in the area of medicinal chemistry and drug discovery because compounds containing this framework have shown to possess a remarkable ability to bind with many receptors or proteins with high affinity. It is therefore not surprising that the indole nucleus is a frequently found moiety in many bioactive agents or drugs. Indole derivatives have also been explored or studied for their anti-tubercular properties for a long time. The growth inhibition of Mycobacterium tuberculosis (MTB) in vitro and in vivo by the gut microbiota metabolite indole propionic acid (IPA) is one of the recent examples. Notably, tuberculosis (TB), an intractable disease and a major cause of death worldwide, has caused an alarming rise in the number of TB cases recently because of two main reasons, i.e., a several-fold rise among HIV-infected patients and increased drug resistance by some bacterial strains. Thus, the identification of new agents or potential drugs against TB is urgently needed. METHODS: While the specific pharmacological target or mechanism of action (MOA) for antitubercular activities has been reported for many indole derivatives, the MOA is not well defined or known for a number of indole derivatives though they were found to be active against MTB. In the current review article, we have focused on both types of indole derivatives that have shown activities against MTB. The indoles with known MOA are further segregated based on this pharmacological target reported or indicated whereas other indoles are classified based on the type of anti-TB properties shown by them. The literature for the last 20 years as well as related to up to date knowledge and information was searched on Pubmed, Google Scholar, MEDLINE, and various other databases until August 2020. RESULTS: A diverse range of functionalized indole derivatives, such as indole-based alkaloids, simple indoles, fused indoles, amide/peptide derivatives of indole, isatin derivatives, etc., have been reported to possess anti-tubercular activities. The anti-tubercular activities, in silico studies (if reported) and the chemical syntheses (in most of the cases) of representative indole derivatives are presented briefly in the current article. The papers referenced by this review allow a deep analysis of the status of the indole-based anti-tubercular agents explored over the past two decades. CONCLUSION: This review aims at stimulating renewed interest and effort in the discovery and development of new indole-based agents or potential drugs for the treatment of TB. The emergence of modern methods, especially those based on transition metal-catalyzed reactions, has opened up tremendous opportunities in the area of indole synthesis. The desired goal would be to have utilized these modern methodologies for the identification of potent and promising agents to fight against MTB.

Rosuvastatin based novel 3-substituted isocoumarins / 3-alkylidenephthalides: Ultrasound assisted synthesis and identification of new anticancer agents.

A new class of 3-substituted isocoumarin/3-alkylidenephthalide based novel small molecules derived from rosuvastatin were designed and synthesized via the ultrasound assisted Cu-mediated coupling-cyclization in a single pot with remarkable regioselectivity. The phthalides were generally obtained at lower temperature whereas the use of elevated temperature afforded isocoumarins. Two compounds e.g. 3n and 4d showed promising cytotoxic effects when tested against HCT 116, HepG2 and PA-1 cell lines at 10 µM. Indeed, 4d was found to be a potent cytotoxic agent (IC50 ∼ 0.76-4.51 µM). Both 3n and 4d were tested for their effects on PANC-1 cells. Considerable decrease in p-Akt substrates shown by 4d and 3n at 50 µM (western blot analysis) indicated their ability to inhibit p-Akt signal transduction pathway and arresting growth of PANC-1 cells in vitro. This was further supported by the cytotoxic effect of 4d on PANC-1 cells (MTT assay) that was better than rosuvastatin. While none of 3n and 4d showed any significant effect on non-cancerous HEK cell line (indicating their potential selectivity towards cancer cells) these compounds were further evaluated for their toxicities in Zebrafish embryo. The NOAEL (No Observed Adverse Effect Level) for teratogenicity, hepatotoxicity and cardiotoxicity was found to be 100 µM for both compound. Thus, 4d as a novel and potent but safer cytotoxic agent with potential to treat colorectal/ovarian and pancreatic cancer is of further medicinal interest.

Synthesis of 11,12-dihydro benzo[c]phenanthridines via a Pd-catalyzed unusual construction of isocoumarin ring/FeCl3-mediated intramolecular arene-allyl cyclization: First identification of a benzo[c]phenanthridine based PDE4 inhibitor.

In spite of their various pharmacological properties the anti-inflammatory potential of benzo[c]phenanthridines remained underexplored. Thus, for the first time PDE4 inhibitory potential of 11,12-dihydro benzo[c]phenanthridine/benzo[c]phenanthridine was assessed in vitro. Elegant synthesis of these compounds was performed via a multi-step sequence consisting of a Pd-catalyzed unusual construction of 4-allyl isocoumarin ring and FeCl3-mediated intramolecular regio- as well as site-selective arene-allyl cyclization as key steps. The overall strategy involved Sonogashira coupling followed by isocoumarin and isoquinolone synthesis, then chlorination and subsequent cyclization to afford a range of 11,12-dihydro derivatives. One of these dihydro compounds was converted to the corresponding benzo[c]phenanthridine that showed concentration dependent inhibition of PDE4B affording an initial hit molecule. The SAR study suggested that 11,12-dihydro analogs were less potent than the compound having unsaturation at the same part of the ring.

Synthesis of 3-indolylmethyl substituted (pyrazolo/benzo)triazinone derivatives under Pd/Cu-catalysis: Identification of potent inhibitors of chorismate mutase (CM).

The chorismate mutase (CM) is considered as an attractive target for the identification of potential antitubercular agents due to its absence in animals but not in bacteria. A series of 3-indolylmethyl substituted pyrazolotriazinone derivatives were designed and docked into CM in silico as potential inhibitors. These compounds were efficiently synthesized using the Pd/Cu-catalyzed coupling-cyclization in a single pot involving the construction of indole ring. The methodology was later extended to the preparation of corresponding benzo analogs of pyrazolotriazinones i.e. 3-indolylmethyl substituted benzotriazinone derivatives. Several of these novel compounds showed significant inhibition of CM when tested in vitro at 30 µM. The SAR (Structure-Activity-Relationship) studies suggested that benzotriazinone moiety was more favorable over the pyrazolotriazinone ring. The two best active compounds showed IC50 ∼ 0.4-0.9 µM (better than the reference/known compounds used) and no toxicity till 30 µM in vitro.

Novel isatin-indole derivatives as potential inhibitors of chorismate mutase (CM): their synthesis along with unexpected formation of 2-indolylmethylamino benzoate ester under Pd-Cu catalysis.

A series of novel isatin-indole derivatives has been designed as potential inhibitors of chorismate mutase (CM) that is known to be present in bacteria, fungi and higher plants but not in human. The design was supported by in silico docking studies that predicted strong interactions of these molecules with CM. The target compounds were synthesized via the one-pot coupling/cyclization method involving the reaction of an isatin based terminal alkyne with 2-iodosulfanilides under Pd-Cu catalysis. A number of isatin-indole derivatives were prepared using this method. A side product e.g. 2-indolylmethylamino benzoate ester derivative was obtained as a result of isatin ring opening (ethanolysis) of products in certain cases. Additionally, regioselective reduction of selected compounds afforded the corresponding C-3 hydroxy derivatives. All isatin-indole derivatives showed good to high inhibition of CM in vitro among which two compounds (3e and 3f) showed inhibition at nanomolar concentration.