Chemical Optimization of CBL0137 for Human African Trypanosomiasis Lead Drug Discovery.

The carbazole CBL0137 (1) is a lead for drug development against human African trypanosomiasis (HAT), a disease caused by Trypanosoma brucei. To advance 1 as a candidate drug, we synthesized new analogs that were evaluated for the physicochemical properties, antitrypanosome potency, selectivity against human cells, metabolism in microsomes or hepatocytes, and efflux ratios. Structure-activity/property analyses of analogs revealed eight new compounds with higher or equivalent selectivity indices (5j, 5t, 5v, 5w, 5y, 8d, 13i, and 22e). Based on the overall compound profiles, compounds 5v and 5w were selected for assessment in a mouse model of HAT; while 5v demonstrated a lead-like profile for HAT drug development, 5w showed a lack of efficacy. Lessons from these studies will inform further optimization of carbazoles for HAT and other indications.

Design, Synthesis, and the Effects of (E)-9-Oxooctadec-10-en-12-ynoic Acid Analogues to Promote Glucose Uptake.

(E)-9-Oxooctadec-10-en-12-ynoic acid is found to mediate its antidiabetic activity by increasing insulin-stimulated glucose uptake in L6 myotubes by activating the phosphoinositide 3-kinase (PI3K) pathway. A simultaneous study of site-specific modification followed by structure-activity relationship provides a tremendous scope for exploiting the bioactivity of the parent molecule. Therefore, in the present study, we focused on site-specific modification of (E)-9-oxooctadec-10-en-12-ynoic acid (1) to generate multiple derivatives and extensive structure-activity relationship (SAR) studies. We have done structural base design and synthesized a series of amides from acid compound 1. Compound 1 consists of an acid functionality, which is known for its metabolism-related liabilities. The SAR has been generated using scaffolds of different antidiabetic drugs such as biguanides, sulfonylureas, thiazolidinediones/glitazones, peroxisome proliferator-activated receptors, K + ATP, α-glucosidase inhibitors, and others. Furthermore, the study demonstrates and explains the promising derivatives and importance of SAR of the compound (E)-9-oxooctadec-10-en-12-ynoic acid. In order to gain mechanistic insights, a molecular docking study was performed against PI3K, which could identify the binding modes and thermodynamic interactions governing the binding affinity. According to our research, compounds 5, 6, 27, 28, 31, 32, and 33 are the best compounds from the series having EC50 values of 15.47, 8.89, 7.00, 13.99, 8.70, 12.27, and 16.14 µM, respectively.

Design, synthesis and biological evaluation of 2,3-dihydroimidazo[2,1-b]thiazoles as dual EGFR and IGF1R inhibitors.

Herein we describe the design, synthesis and anticancer evaluation of a series of 2,3-dihydroimidazo[2,1-b]thiazoles as dual kinase inhibitors of IGF1R and EGFR. A series of saturated dihydroimidazo[2,1-b] thiazoles were synthesized to understand the structure-activity relationship. Further, the key modifications were performed to improve drug like properties of the series. A 2-oxa-6-azaspiro [3.3] heptane moiety was incorporated as a bioisosteric replacement of morpholine on dihydroimidazo[2,1-b] thiazole scaffold.Subsequent structure-activity relationship (SAR) studies identified several compounds with nM range of activity. The compound 18a shows promising activity, IC50 = 52 nM against IGF1R and IC50 = 35.5 nM against EGFR with descent PK profile. The identified leadshows promising activity against both wild type and the T790M mutant forms of enzymes.

Chlorotrifluoroethylidenes: an efficient and convenient approach to their synthesis.

A convenient one step synthesis of chlorotrifluoroalkyl olefins starting from aldehydes was developed. The stable reagent 2-((1-chloro-2,2,2-trifluoroethyl)sulfonyl)benzothiazole was prepared from readily available benzothiazole-2-thiol and halothane. This method comprises using stable 2-((1-chloro-2,2,2-trifluoroethyl)sulfonyl)benzothiazole according to the Julia procedure and presents new opportunities for the synthesis of trifluoroalkylidene derivatives.

Design, synthesis and biological evaluation of (E)-5-styryl-1,2,4-oxadiazoles as anti-tubercular agents.

Cinnamic acid and its derivatives are known for anti-tubercular activity. The present study reports the synthesis of cinnamic acid derivatives via bioisosteric replacement of terminal carboxylic acid with "oxadiazole". A series of cinnamic acid derivatives (styryl oxadiazoles) were designed and synthesized in good yields by reaction of substituted cinnamic acids (2, 15a-15s) with amidoximes. The synthesized styryl oxadiazoles were evaluated in vitro for anti-tubercular activity against Mycobacterium tuberculosis (Mtb) H37Ra strain. The structure-activity relationship (SAR) study has identified several compounds with mixed anti-tubercular profiles. The compound 32 displayed potent anti-tubercular activity (IC50 = 0.045 µg/mL). Molecular docking studies on mycobacterial enoyl-ACP reductase enzyme corroborated well with the experimental findings providing a platform for structure based hit-to-lead development.

Design, synthesis and biological evaluation of novel azaspiro analogs of linezolid as antibacterial and antitubercular agents.

The design, synthesis and antimicrobial evaluation of a novel series of azaspiro analogues of linezolid (1) have been described. Linezolid comprises of a morpholine ring which is known for its metabolism-related liabilities. Therefore, the key modification made in the linezolid structure was the replacement of morpholine moiety with its bioisostere, 2-oxa-6-azaspiro[3.3]heptane. Furthermore, the replacement of N-acetyl terminal of 1 with various aromatic or aliphatic functionalities was carried out. The title compounds were evaluated against a panel of Gram-positive and Gram-negative bacteria and Mycobacterium tuberculosis. Subsequent structure-activity relationship (SAR) studies identified several compounds with mixed antibacterial and antitubercular profiles. Compound 22 (IC50 0.72, 0.51, 0.88, 0.49 µg/mL for Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, Bacillus subtilis, respectively) exhibited similar antibacterial profile as 1. The N-acetyl derivative 18 was similar to 1 in antitubercular profile. Thus, the present study successfully demonstrated the use of azaspiro substructure in the medicinal chemistry of antibacterial and antitubercular agents.

Synthesis and biological activity of novel MIF antagonists.

Two series of novel furan and indole compounds were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds from both series inhibited the enzymatic activity of MIF at levels equal to or significantly better than ISO-1 (an early MIF inhibitor). The majority of the compounds that robustly inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells were from the furan series (compounds 5, 9, 13, 15, and 16). In contrast, compounds that markedly inhibited the MIF-induced production of pro-inflammatory cytokines were predominantly from the indole series (compounds 26, 29, and 32).

Novel derivatives of ISO-1 as potent inhibitors of MIF biological function.

A series of novel 1,2,4-oxadiazole, phthalimide, amide and other derivatives of ISO-1 were synthesized and probed for inhibition of macrophage migration inhibitory factor (MIF) activity. Several compounds inhibited MIF enzymatic activity at levels better than ISO-1. Of note, compounds 7, 22, 23, 24, 25 and 27 inhibited the spontaneous secretion/release/recognition of MIF from freshly isolated human peripheral blood mononuclear cells and, more importantly, inhibited the MIF-induced production of interleukin-6 (IL-6) and/or interleukin-1beta (IL-1beta) significantly better than ISO-1.

A fluorinated analog of ISO-1 blocks the recognition and biological function of MIF and is orally efficacious in a murine model of colitis.

A promising therapeutic approach to diminish pathological inflammation is to inhibit the synthesis and/or biological activity of macrophage migration inhibitory factor (MIF). Prior studies have shown that intraperitoneal administration of small-molecule inhibitors targeting the catalytic pocket of MIF (e.g., ISO-1) elicits a therapeutic effect in mouse inflammation models. However, it remains to be elucidated whether these tautomerase activity inhibitors block the synthesis and/or biological activity of MIF. In this study, we investigated and compared the activity of representative MIF inhibitors from isoxazole series (fluorinated analog of ISO-1; ISO-F) and substituted quinoline series (compound 7E; 7E). Our results demonstrate that ISO-F is a more potent MIF inhibitor than 7E. Both ISO-F and 7E do not inhibit MIF synthesis but "bind-onto" MIF thereby blocking its recognition. However, in contrast to 7E, ISO-F docks well in the active site of MIF and also has a stronger binding affinity towards MIF. In line with these observations, ISO-F, but not 7E, robustly inhibits the biological function of MIF. Most importantly, ISO-F, when administered orally in a therapeutic regimen, significantly suppresses dextran sulphate sodium (DSS)-induced murine colitis. This study, which provides mechanistic insights into the anti-inflammatory efficacy of ISO-F, is the first documented report of in vivo anti-inflammatory efficacy of a MIF inhibitor upon oral administration. Moreover, the findings from this study reinforce the potential of catalytic site of MIF as a target for eliciting therapeutic effect in inflammatory disorders. Compounds (e.g., ISO-F) that block not only the recognition but also the biological function of MIF are potentially attractive for reducing pathological inflammation.