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Tuberculosis (TB) transmitted by Mycobacterium tuberculosis (Mtb) is one of the top 10 causes of death globally. Currently, the widespread occurrence of resistance toward Mtb strains is becoming a significant concern to public health. This scenario exaggerated the need for the discovery of novel targets and their inhibitors. Targeting the “Mtb cell wall peptidoglycan synthesis” is an attractive strategy to overcome drug resistance. Mur enzymes (MurA-MurF) play essential roles in the peptidoglycan synthesis by catalyzing the ligation of key amino acid residues to the stem peptide. These enzymes are unique and confined to the eubacteria and are absent in humans, representing potential targets for anti-tubercular drug discovery. Mtb Mur ligases with the same catalytic mechanism share conserved amino acid regions and structural features that can conceivably exploit for the designing of the inhibitors, which can simultaneously target more than one isoforms (MurC-MurF) of the enzyme. In light of these findings in the current review, we have discussed the recent advances in medicinal chemistry of Mtb Mur enzymes (MurA-MurF) and their inhibitors, offering attractive multi-targeted strategies to combat the problem of drug-resistant in M. tuberculosis.

EGFR T790M mutation leads to resistance to most of clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation have been in active clinical development, which includes osimertinib, rociletinib, HM61713, ASP8273, EGF816, and PF-06747775. On the other hand recently EGFR C797S mutation was reported to be a leading mechanism of resistance to the third-generation inhibitors. The C797S mutation appears to be an ideal target for overcoming the acquired resistance to the third generation inhibitors. This review summarizes the third generation inhibitors, synthesis, their mechanism of resistance and latest development on the discovery of a fourth-generation EGFR TKIs and U to Y allosteric strategies to combat the C797S EGFR resistance problem.

We herein report the synthesis and in vitro antimicrobial evaluation of twenty five novel hybrid derivatives of imidazo [2,1- b ]-1,3,4-thiadiazole containing chalcones ( 5a – o ) and Schiff bases ( 6a – j ) against three fungal strains ( Candida albicans , Cryptococcus neoformans and Aspergillus niger ). Most of the tested compounds displayed substantial anti-fungal activity with MICs ranging between 1.56 and 100 μg/mL. Compounds 5a , 5b and 5n exhibited promising activity against C. neoformans at a MIC 1.56 μg/mL. In addition, compound 5n also demonstrated significant antifungal activity against the clinical isolates of C. neoformans at MIC 3.125 μg/mL. However, moderate activity was observed for these compounds against four bacterial strains ( Staphylococcus aureus , Bacillus subtilis , Escherichia coli and Pseudomonas aeruginosa ) and Mycobacterium tuberculosis (H 37 Rv).

A series of new sulphonamido-quinoxaline derivatives 3 ( a – p ) have been prepared which are structurally similar to the High Throughput Screening (HTS) hit identified by Porter and collaborator. The newly synthesized compounds 3b , 3c , 3f , 3i , 3j , 3l , 3n and 3o were further evaluated in the National Cancer Institute for in vitro cytotoxicity assay among them compound 3l showed highest activity against Leukemia RPMI-8226 cell lines (GI 50 : 1.11 μM) as compared to other tested compounds. It is to be noted that compound 3l shows significant activity (GI 50 : 1.11 μM) compared to the High Throughput Screening (HTS) hit identified by Porter and collaborator (IC 50 = 1.3 μM). Further docking study confirms the c-Met kinase inhibitory mechanism of the synthesized compounds.

A novel series of 2,5,6-trisubstituted imidazo[2,1- b ][1,3,4]thiadiazoles 4 ( a – d ) and 7 ( a – i ) were rationally designed through QSAR based pharmacophore approach and synthesized from 5-(1,3-benzodioxol-5-yl)-[1,3,4]thiadiazol-2-amine ( 1 ). The structures of these compounds were established by IR, 1 H NMR, 13 C NMR, HRMS technique. All the compounds were evaluated for their in vitro antihyperlipidemic activity using trition induced hyperlipidemic model. The newly synthesized title compound 7d , 7e and 7h showed a significant decrease in the serum, TCH, TG LDL and VLDL values along with an increase in serum HDL levels as compared to standard drug Fenofibrate. The treated groups also showed significant decrease in the atherogenic index, LDL:HDL risk ratios and the level of SGOT, SGPT and ALP activities compared to cholesterol induced hyperlipidemic control group.

New classes of drugs are needed to treat tuberculosis (TB) in order to combat the emergence of resistance (MDR and XDR) to existing agents and shorten the duration of therapy. Mycobacterial DNA gyrase B subunit has been identified to be one of the potentially under exploited drug targets in the field of antitubercular drug discovery. In the present review, we discussed the synthesis, structural optimization and docking study of effective potent DNA gyrase inhibitor against M. tuberculosis, with improved properties such as enhanced activity against MDR strains, reduced toxicity. Based on this progress, if we can successfully leverage the opportunities in this target, there is hope that we will be able to raise novel gyrase inhibitor in earnest in the long.

In this study, some novel 2,6-disubstituted imidazo[2,1- b ][1,3,4]thiadiazoles 4 ( a – i ), 7 ( a – p ) and 11 ( a – i ) were synthesized from 5-substituted-1,3,4-thiadiazol-2-amine. The newly synthesized compounds 4a , 4b , 4c , 4e , 4g , 7j , 7l , 11b and 11c were evaluated in the National Cancer Institute for single dose in vitro primary cytotoxicity assay. Among the tested nine compounds, compound 4b (107166/760239) and 4c (107168/760240) were passed the criteria for activity in this assay and scheduled automatically for evaluation against the full panel of 60 human tumor cell lines at a minimum of five concentrations at 10-fold dilutions. 3-(2-(4-methoxyphenyl)imidazo[2,1- b ][1,3,4]thiadiazol-6-yl)aniline ( 4c ) exhibited significant in vitro anticancer activity against Non Small Cell Lung Cancer HOP-92 cell line (GI 50 : 0.114 μM) and Renal Cancer CAKI-1 cell line (GI 50 : 0.743 μM).

A series of 2,5,6-trisubstituted imidazo[2,1- b ][1,3,4]-thiadiazole derivatives 4 ( a – k ) have been prepared by reaction of 2-amino-5-cyclopropyl-1,3,4-thiadiazole and an appropriate phenacyl bromide. Further 5-bromo 5 ( a – k ) and 5-thiocyanato 6 ( a – k ) derivatives were synthesized in order to study the effect of these substituents on antitumor activity. Structures of these compounds were established by IR, 1 H NMR, 13 C NMR and Mass spectroscopy. Seven compounds were granted NSC code at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10 −5 M) in full NCI 60 cell panel. Among the compounds tested, 5-bromo-6-(4-chlorophenyl)-2-cyclopropylimidazo[2,1- b ][1,3,4]thiadiazole 5b ( NSC D - 96022 / 1 ) was found to be the most active candidate of the series at five dose level screening with degree of selectivity toward Leukemic cancer cell line.

The synthesis of some 2-furano-4(3H)-quinazolinones, diamides (open ring quinazolines), quinoxalines and their biological evaluation as antitumor agents using National Cancer Institute (NCI) disease oriented antitumor screen protocol are investigated. Among the synthesize compounds, seventeen compounds were granted NSC code and screened at National Cancer Institute (NCI), USA for anticancer activity at a single high dose (10(-5) M) in full NCI 60 cell panel. Among the selected compounds, 3-(2-chloro benzylideneamine)-2-(furan-2-yl) quinazoline-4(3h)-one 21 was found to be the most active candidate of the series at five dose level screening against Ovarian OVCAR-4 and Non-small cell lung cancer NCI-H522 with GI50 1.82 & 2.14 μM respectively. Rational approach and QSAR techniques enabled the understanding of the pharmacophoric requirement for quinazoline, diamides and quinoxaline derivatives.

A new series of imidazo[2,1- b ][1,3,4]thiadiazoles 5 ( a – g ), 6 ( a – g ), 9 ( a – i ) and 12 ( a – h ) were synthesized as transforming growth factor-β (TGF-β) type I receptor (also known as activin receptor-like kinase 5 or ALK5) inhibitors. These compounds were evaluated for their ALK5 inhibitory activity in an enzyme assay and their TGF-β -induced Smad2/3 phosphorylation inhibitory activity in a cell-based assay. Compound 6d , 2-(5-((2-cyclopropyl-6-(4-fluorophenyl) imidazo [2,1-b][1,3,4]thiadiazol-5-yl)methylene)-4-oxo-2-thioxothiazolidin-3-yl) acetic acid, shows prominent ALK5 inhibition (IC 50 = 0.0012 μM) and elective inhibition (91%) against the P38αkinase at10 μM. The binding mode of compound 6d by XP docking studies shows that it fits well into the active site cavity of ALK5 by forming broad and tight interactions. Lipinski's rule and in silico ADME pharmacokinetic parameters are within the acceptable range defined for human use thereby indicating their potential as a drug-like molecules.

A series of 6-bromo-2-ethyl-3-(substitutedbenzo[ d ]thiazol-2-yl)quinazolin-4(3 H )-one 3 ( a – j ) were synthesized using appropriate synthetic route and evaluated experimentally by the Maximal Electro Shock (MES) and the PTZ-induced seizure methods. Among the tested compounds, 3-(benzo[ d ]thiazol-2-yl)-6-bromo-2-ethylquinazolin-4(3 H )-one ( 3a ) has shown significant activity against tonic seizure by the MES model and 6-bromo-2-ethyl-3-(6-methoxybenzo[ d ]thiazol-2-yl)quinazolin-4(3 H )-one ( 3h ) against clonic seizure by PTZ-induced seizure model. Not one of the selected compounds demonstrated any sign of neurotoxicity and hepatotoxicity.

Novel derivatives of 2-amino benzothiazoles 4(a-j) have been synthesized and tested for their antitumor activity using National Cancer Institute (NCI) disease oriented antitumor screen protocol against nine panel of cancer cell lines. Among the synthesized compounds, two compounds were granted NSC code and screened at National Cancer Institute (NCI)-USA for anticancer activity at a single high dose (10(-5) M) and five dose in full NCI 60 cell panel. Among the selected compounds, 7-chloro-N-(2,6-dichlorophenyl)benzo[d]thiazol-2-amine (4i) with GI(50) values of 7.18 × 10(-8) M against Non-Small Cell HOP-92 Lung Cancer cell line proved to be the most active members in this study. Virtual screening was carried out through docking the designed compounds into the ATP binding site of epidermal growth factor receptor (EGFR) to predict if these compounds have analogous binding mode to the EGFR inhibitors.