Synthesis, antimicrobial, anti-biofilm evaluation, and molecular modelling study of new chalcone linked amines derivatives

<p>A series of amide chalcones conjugated with different secondary amines were synthesised and characterised by different spectroscopic techniques ¹H NMR, ¹³C NMR, and ESI-MS. They were screened for <i>in vitro</i> antibacterial activity. Compounds <b>36</b>, <b>37</b>, <b>38</b>, <b>42</b>, and <b>44</b> are the most active among the synthesised series exhibiting MIC value of 2.0–10.0 µg/ml against different bacterial strains. Compound <b>36</b> was equipotent to the standard drug Ampicillin displaying MBC value of 2.0 µg/ml against the bacterial strain <i>Staphylococcus aureus.</i> The products were screened for anti-biofilm activity. Compounds <b>36</b>, <b>37</b>, and <b>38</b> exhibited promising anti-biofilm activity with IC₅₀ value ranges from 2.4 to 8.6 µg. Molecular modelling was performed suggesting parameters of signalling anti-biofilm mechanism. AspB327 HisB340 (arene–arene interaction) and IleB328 amino acid residues seemed of higher importance to inhibit c-di-GMP. Hydrophobicity may be crucial for activity. ADME calculations suggested that compounds <b>36</b>, <b>37</b>, and <b>38</b> could be used as good orally absorbed anti-biofilm agents.</p

Nonclassical antifolates, part 5. Benzodiazepine analogs as a new class of DHFR inhibitors: Synthesis, antitumor testing and molecular modeling study

A new series of tetrahydro-quinazoline and tetrahydro-1H-dibenzo[b,e][1,4]diazepine analogs were synthesized and tested for their DHFR inhibition and in vitro antitumor activity. Compound 35 showed a remarkable DHFR inhibitory potency (IC50, 0.004 mM) which is twenty fold more active than metho- trexate (MTX). Compounds 17 and 23 proved to be fifteen fold more active than the known antitumor 5- FU, with MG-MID GI50, TGI, and LC50 values of 1.5, 46.8, 93.3 and 1.4, 17.4, 93.3 mM, respectively. Com- puter modeling studies allowed the identification that methoxy and methyl substituents, the p-system of the chalcone core, the nitrogen atoms, on the dibenzodiazepine ring as pharmacophoric features essential for activity. These mark points could be used as template model for further future optimization

Bioorganic & Medicinal Chemistry Letters

A new series of 2,3,6-substituted-quinazolin-4-ones was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, and antitumor activities. Compounds 28 and 61 proved to be active DHFR inhibitors with IC50 0.02 and 0.01 µM, respectively. Molecular modeling studies concluded that recognition with the key amino acid Phe34 is essential for binding and hence DHFR inhibition. Compounds 34, 56 and 66 showed broad spectrum antimicrobial activity comparable to Gentamicin and Ciprofloxacin. Compounds 40 and 64 showed broad spectrum antitumor activity toward several tumor cell lines and proved to be 10 fold more active than 5-FU, with GI50 MG-MID values of 2.2 and 2.4 µM, respectively

Synthesis, biological evaluation and molecular modeling study of some new thiazolodiazepine analogs as CNS active agents

New derivatives of ethyl 8-oxo-5,6,7,8-tetrahydro-thiazolo[3,2-a][1,3]diazepin-3-carboxylate (HIE-124, 3), were synthesized as continuation to our previous patented efforts. Compounds 15 and 20 showed marginal hypnotic potency compared to 3. Compounds 15 (0.78 mmol/kg) and 20 (0.39 mmol/kg) showed remarkable 100% protection against PTZ induced convulsions with two and four fold increase in activity than sodium valproate (1.38 mmol/kg), respectively. Molecular modeling studies showed hydrogen bonding interaction between 15 and Thr56 residues at the binding site of GABA . Superposition, flexible alignment and surface mapping of 15, 20 and diazepam supports their biological resemblance where ADMET study suggested that those compounds could be used as oral anticonvulsants

Nonclassical antifolates, part 4. 5-(2-Aminothiazol-4-yl)-4-phenyl-4H1,2,4-triazole-3-thiols as a new class of DHFR inhibitors: Synthesis, biological evaluation and molecular modeling study

A new series of compounds possessing 5-(2-aminothiazol-4-yl)-4-phenyl-4H-1,2,4-triazole-3-thiol skeleton was designed, synthesized, and evaluated for their in vitro DHFR inhibition, antimicrobial, antitumor and schistosomicidal activities. Four active compounds were allocated, the antibacterial 22 (comparable to gentamicin and ciprofloxacin), the schistosomicidal 29 (comparable to praziquantel), the DHFR inhibitor 34 (IC 0.03 mM, 2.7 fold more active than MTX), and the antitumor 36 (comparable to doxorubicin). Molecular modeling studies concluded that recognition with key amino acid Leu4 and Val1 is essential for DHFR binding. Flexible alignment and surface mapping revealed that the obtained model could be useful for the development of new class of DHFR inhibitors