Molecular-level strategic goals and repressors in Leishmaniasis - Integrated data to accelerate target-based heterocyclic scaffolds.

Leishmaniasis is a complex of neglected tropical diseases caused by various species of leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, these drugs have many drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Among several identified potential molecular targets, enzymes involved in the purine salvage pathway include polyamine biosynthetic process, such as arginase, ornithine decarboxylase, S-adenosylmethionine decarboxylase, spermidine synthase, trypanothione reductase as well as enzymes in the DNA cell cycle, such as DNA topoisomerases I and II plays vital role in the life cycle survival of leishmanial parasite. This review mainly focuses on various heterocyclic scaffolds, and their specific inhibitory targets against leishmaniasis, particularly those from the polyamine biosynthesis pathway and DNA topoisomerases with estimated activity studies of various heterocyclic analogs in terms of their IC50 or EC50 value, reported molecular docking analysis from available published literatures.

Inspection of in-house designed novel thiochromone amino-acid conjugate derivatives as Lm-NMT inhibitor - An in-silico analysis.

Leishmaniasis is a complex neglected tropical disease caused by various leishmanial parasites that primarily affect the world's poorest people. A limited number of standard medications are available for this disease that has been used for several decades, which have drawbacks such as resistance, higher cost, and patient compliance, making it difficult to reach the poor. The search for novel chemical entities to treat leishmaniasis has led to target-based scaffold research. Thiochromone moieties in conjugation with aromatic amino acids have been considered for the study, along with possible substitutions of the electron-withdrawing and electron-donating groups. N-myristoyl transferase (NMT) has been selected as the molecular target for the study responsible for protein-protein interaction and ribosylation of proteins necessary for the growth inside the human body of the parasite. The designed novel thiochromone analogs were docked against the selected leishmanial NMT using thein-silico methods, physicochemical and toxicity properties were predicted, and Structure-Activity Relationship was also established in-silico. Finally, a molecular dynamics simulation study for 100 ns gave an idea about the stability of the protein-ligand complex. A time frame analysis of each 10 ns confirmation was also studied to understand better the putative binding pattern designed analogs.

Design, synthesis and biological evaluation of benzo-[d]-imidazo-[2,1-b]-thiazole and imidazo-[2,1-b]-thiazole carboxamide triazole derivatives as antimycobacterial agents.

In the search for new anti-mycobacterial agents, we revealed the importance of imidazo-[2,1-b]-thiazole and benzo-[d]-imidazo-[2,1-b]-thiazole carboxamide derivatives. We designed, in silico ADMET predicted and synthesized four series of novel imidazo-[2,1-b]-thiazole and benzo-[d]-imidazo-[2,1-b]-thiazole carboxamide analogues in combination with piperazine and various 1,2,3 triazoles. All the synthesized derivatives were characterized by 1H NMR, 13C NMR, HPLC and MS spectral analysis and evaluated for in vitro antitubercular activity. The most active benzo-[d]-imidazo-[2,1-b]-thiazole derivative IT10, carrying a 4-nitro phenyl moiety, displayed IC90 of 7.05 µM and IC50 of 2.32 µM against Mycobacterium tuberculosis (Mtb) H37Ra, while no acute cellular toxicity was observed (>128 µM) towards the MRC-5 lung fibroblast cell line. Another benzo-[d]-imidazo-[2,1-b]-thiazole compound, IT06, which possesses a 2,4-dichloro phenyl moiety, also showed significant activity with IC50 2.03 µM and IC90 15.22 µM against the tested strain of Mtb. Furthermore, the selected hits showed no activity towards a panel of non-tuberculous mycobacteria (NTM), thus suggesting a selective inhibition of Mtb by the tested imidazo-[2,1-b]-thiazole derivatives over the selected panel of NTM. Molecular docking and dynamics studies were also carried out for the most active compounds IT06 and IT10 in order to understand the putative binding pattern, as well as stability of the protein-ligand complex, against the selected target Pantothenate synthetase of Mtb.

Correction: Seeking potent anti-tubercular agents: design and synthesis of substituted-N-(6-(4-(pyrazine-2-carbonyl)piperazine/homopiperazine-1-yl)pyridin-3-yl)benzamide derivatives as anti-tubercular agents.

[This corrects the article DOI: 10.1039/D0RA01348J.].

Inhibitors of pantothenate synthetase of Mycobacterium tuberculosis - a medicinal chemist perspective.

Tuberculosis (TB), one of the most prevalent infections, is on the rise today. Although there are drugs available in the market to combat this lethal disorder, there are several shortcomings with the current drug regimen, such as prolonged treatment period, drug resistance, high cost, etc. Hence, it is inevitable for the current researchers across the globe to embark on new strategies for TB drug discovery, which will yield highly active low cost drugs with a shorter treatment period. To achieve this, novel strategies need to be adopted to discover new drugs. Pantothenate Synthetase (PS) is one such striking drug target in Mycobacterium tuberculosis (MTB). It was observed that the pantothenate biosynthetic pathway is crucial for the pathogenicity of MTB. Pantothenate is absent in mammals and needs to be obtained from dietary sources. Hence, the pantothenate biosynthesis pathway is an impending target for emerging new therapeutics to treat TB. Worldwide, several approaches have been implemented by researchers in the quest for these inhibitors such as high-throughput screening, simulating the reaction intermediate pantoyl adenylate, use of vibrant combinatorial chemistry, hybridization approach, virtual screening of databases, inhibitors based on the crystal structure of MTB PS, etc. The present review recapitulates current developments in PS inhibitors, important analogues of numerous metabolic intermediates, and newly established inhibitors with innumerable chemical structures.

Synthesis and activity of benzopiperidine, benzopyridine and phenyl piperazine based compounds against Leishmania infantum.

In the present study, anti-leishmanial evaluation of twenty four structurally diverse compounds based on benzopiperidine, benzopyridine and phenylpiperazine nucleuses against Leishmania infantum has been reported. Cytotoxicity studies of all the compounds were performed on murine non-infected splenocytes. Tested compounds exhibited weak to potent activity against promastigote (IC50 3.21 ±â€¯1.40 to >100 µM) as well as amastigote (IC50 6.84 ±â€¯2.5 to 92.47 ±â€¯17.61 µM) forms of tested strains. Moreover, two compounds F13 and F15 exhibited potent activity (IC50 < 10 µM) against both forms of the parasite with selectivity index ranges from 11.40 to 22.10. Overall, the current study afforded few hits with novel anti-leishmanial activity in low micromolar concentration, further hit optimization studies can be performed to get more potent candidates against the selected species of parasite.

Novel amide and sulphonamide derivatives of 6-(piperazin-1-yl)phenanthridine as potent Mycobacterium tuberculosis H37Rv inhibitors.

A series of thirty three novel 6-(piperazin-1-yl)phenanthridine amide and sulphonamide analogues were synthesized, characterized and screened for their in vitro antimycobacterial activity against Mycobacterium tuberculosis (MTB) H37Rv strain. These compounds exhibited minimum inhibitory concentration (MIC) between 1.56 and ≥50 µg/mL. Out of these derivatives, few compounds 6l, 6r, 7b, 7f, 7g and 7k exhibited moderate activity (MIC = 6.25 µg/mL) and compounds 6b, 6e, 6k, 6n, 7h, 7i and 7n displayed good activity (MIC = 3.13 µg/mL), whereas compounds 6m, 6s and 7d exhibited excellent anti-tubercular activity (MIC = 1.56 µg/mL). In addition, MTT assay was accomplished on the active analogues of the series against mouse macrophage (RAW 264.7) cells to evaluate the toxicity profile of the newly synthesized compounds and selectivity index of the compounds was determined. Additionally, compounds 6b and 7d were docked to the ATPase domain of M. tuberculosis GyrB protein to know the interaction profile and structures of compounds 6b and 7d were further substantiated through single crystal XRD.

Design, synthesis, and preliminary in vitro and in vivo pharmacological evaluation of 2-{4-[4-(2,5-disubstituted thiazol-4-yl)phenylethyl]piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles as atypical antipsychotic agents.

A series of 2-{4-[4-(2,5-disubstituted thiazolyl)phenylethyl] piperazin-1-yl}-1,8-naphthyridine-3-carbonitriles were synthesized in an effort to prepare novel atypical antipsychotic agents. The compounds were synthesized either by microwave irradiation technique or by conventional synthesis and were characterized by spectral data (IR, (1)H NMR, and MS) and the purity was ascertained by microanalysis. The D(2) and 5-HT(2A) affinity of the synthesized compounds was screened in vitro by radioligand displacement assays on membrane homogenates isolated from rat striatum and rat cortex, respectively. Furthermore, all the synthesized compounds were screened for their in vivo pharmacological activity in Swiss albino mice. The D(2) antagonism studies were performed using climbing mouse assay model and 5-HT(2A) antagonism studies were performed using quipazine-induced head twitches in mice. It was observed that none of the new chemical entities exhibited catalepsy and 10f is the most active among the synthesized compounds with 5-HT(2A)/D(2) ratio of 1.1286 although the standard drug risperidone exhibited 5-HT(2A)/D(2) ratio of 1.0989.