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[Display omitted] • Rosuvastatin based azaindole framework was designed to identify cytotoxic agents. • Sonochemical synthesis of target compounds involved coupling–cyclization strategy. • Several compounds showed significant cytotoxic effects on three cancer cell lines. • 5b inhibited Akt1 in vitro that was supported by its strong interaction with Akt1 in silico. • 5b is a potent inhibitor (MIA Paca-2 IC50 ∼ 19 nM) with NOAEL > 100 μM in Zebrafish. 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 -MeC 6 H 4 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 5b in silico. Being a potent inhibitor (MIA Paca-2 IC 50 = 18.79 ± 0.17 nM) and with NOAEL (No Observed Adverse Effect Level) > 100 µM in Zebrafish, 5b emerged as a promising compound. [ABSTRACT FROM AUTHOR]

The construction of N -unsubstituted vs N -sulfonyl indole ring was studied using propargylamine as the terminal alkyne in the presence of Pd/Cu catalysts under environmentally friendly conditions. [Display omitted] • Construction of N -unsubstituted vs N -sulfonyl indole ring was studied. • Propargylamines were explored as the terminal alkyne reactants. • The Pd/Cu-catalyzed reactions proceeded under environmentally friendly conditions. • A library of small molecules of potential biological interest was accessed. The Pd/Cu-catalyzed tandem coupling–cyclization- N -deprotection in a single pot (Method a) vs sequential coupling–cyclization under similar conditions (Method b) has been studied using propargylamine as a terminal alkyne under environmentally friendly conditions. The first sequence (Method a) was followed to afford the N -unsubstituted indoles when 2,2,2-trifluoro- N -(2-iodophenyl)acetamides were employed as halides whereas N -sulfonyl indoles were obtained following the second path (Method b) when 2-iodo sulfanilides were used as halides. A number of compounds based on either the framework indolo[2,3– b ]quinoxaline-indole or a similar framework possessing a sulfonyl group at the indole nitrogen were obtained in good yield employing the Method a or b, respectively. While the study was carried out with the goal of accessing a library of indolo[2,3– b ]quinoxaline-indole based small molecules of potential biological interest (especially as anti-tubercular agents) the generality/scope of Method a was expanded further via the synthesis of simpler indole derivatives using various other propargylamines as terminal alkynes. [ABSTRACT FROM AUTHOR]

An improved and rapid synthesis of mefenamic acid based indole derivatives has been achieved via the ligand free Cu-catalyzed coupling-cyclization method under ultrasound irradiation. This simple, straightforward and inexpensive one-pot method involved the reaction of a terminal alkyne derived from mefenamic acid with 2-iodosulfanilides in the presence of CuI and K 2 CO 3 in PEG-400. The reaction proceeded via an initial C C bond formation (the coupling step) followed by C N bond formation (the intramolecular cyclization) to afford the mefenamic acid based indole derivatives in good to acceptable yields. Several of these compounds showed inhibition of PDE4 in vitro and the SAR (Structure Activity Relationship) within the series is discussed. The compound 3d has been identified as a promising and selective inhibitor of PDE4B (IC 50 = 1.34 ± 0.46 µM) that showed TNF-α inhibition in vitro (IC 50 = 5.81 ± 0.24 µM) and acceptable stability in the rat liver microsomes. [ABSTRACT FROM AUTHOR]