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The design, synthesis and anti-mycobacterial activities of 23 conformationally-constrained indeno[2,1-c]quinolines against Mycobacterium tuberculosis H37Rv is reported. Based on a structural comparison with the anti-TB TMC207 we have devised a synthetic methodology for making new conformationally-constrained indeno[2,1-c]quinoline analogs (Fig. 1), by retaining the biologically significant quinoline and the phenyl rings in the SW and NW hemispheres, respectively. This new class of conformationally-constrained compounds has been designed such that their conformational flexibility across C4-C2¢ is diminished to nil by covalently locking the C4 center of the quinoline moiety in the SW hemisphere with the C2¢ center of the phenyl ring in the NW hemisphere, thereby decreasing the entropic penalty for their complex formation within the target protein, which will in turn give improved free-energy of stabilization of the complex. The efficacies of these anti-TB compounds were evaluated in vitro for 8/9 consecutive days using the BACTEC radiometric assay upon administration of a single-dose on day one. Compounds 11, 13, 16, 24, 30, 32 and 34 showed 85-99% growth inhibition of Mycobacterium tuberculosis. Compounds 13 and 34 however have inhibited the mycobacterial growth more effectively than others in the series, with minimum inhibitory concentrations (MIC) of 0.39 mg mL-1 (1 mM) and 0.78 mg mL-1 (2 mM) respectively.

A synthetic sequence to the benzo[j]fluoranthene nucleus is described. Crucial steps of the procedure include a Suzuki coupling between appropriately substituted 2-bromo-acenaphthylene-1-carbaldehydes and 2-formylbenzeneboronates followed by McMurry ring closure. The synthesis represents a new approach to the benzo[j]fluoranthene ring system and specifically provides a method for the rapid preparation of differently substituted derivatives. Following this strategy, the first total synthesis of the recently isolated natural product benzo[j]fluoranthene-4,9-diol was carried out.

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A practical and convenient synthesis of naturally occurring farinomaleins C-E was achieved starting from readily available ethyl 3-methyl-2-oxobutyrate and triethyl phosphonoacetate. The key steps of the sequence included a Horner-Wadsworth-Emmons condensation to obtain the precursor farinomalein A and coupling with suitable alcohols to install the chain. The synthesis of farinomalein D has been achieved starting from (R)-isopropylideneglycerol on the basis of which the S configuration was assigned to the natural compound. The antifungal activity of the synthesized compounds was evaluated against Cladosporium cladosporioides. .

The development of miniaturized flow platforms would enable efficient and selective synthesis of drug and lead molecules by rapidly exploring synthetic methodologies and screening for optimal conditions, progress in which could be transformative for the field. In spite of tremendous advances made in continuous flow technology, these reported flow platforms are not devised to conduct many different reactions simultaneously. Herein, we report a metal-based flow parallel synthesizer that enables multiplex synthesis of libraries of compounds and efficient screening of parameters. This miniaturized synthesizer, equipped with a unique built-in flow distributor and n number of microreactors, can execute multiple types of reactions in parallel under diverse conditions, including photochemistry. Diazonium-based reactions are explored as a test case by distributing the reagent to 16 (n = 16) capillaries to which various building blocks are supplied for the chemistry library synthesis at the optimal conditions obtained by multiplex screening of 96 different reaction variables in reaction time, concentration, and product type. The proficiency of the flow parallel synthesizer is showcased by multiplex formation of various C–C, C–N, C–X, and C–S bonds, leading to optimization of 24 different aryl diazonium chemistries.

Continuous-flow microreactors enable ultrafast chemistry; however, their small capacity restricts industrial-level productivity of pharmaceutical compounds. In this work, scale-up subsecond synthesis of drug scaffolds was achieved via a 16 numbered-up printed metal microreactor (16N-PMR) assembly to render high productivity up to 20 g for 10 min operation. Initially, ultrafast synthetic chemistry of unstable lithiated intermediates in the halogen–lithium exchange reactions of three aryl halides and subsequent reactions with diverse electrophiles were carried out using a single microreactor (SMR). Larger production of the ultrafast synthesis was achieved by devising a monolithic module of 4 numbered-up 3D-printed metal microreactor (4N-PMR) that was integrated by laminating four SMRs and four bifurcation flow distributors in a compact manner. Eventually, the 16N-PMR system for the scalable subsecond synthesis of three drug scaffolds was assembled by stacking four monolithic modules of 4N-PMRs.

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