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Item Structural modification of zolpidem led to potent antimicrobial activity in imidazo[1,2-: A] pyridine/pyrimidine-1,2,3-triazoles(Royal Society of Chemistry, 2019) Reddyrajula, R.; Udayakumar, U.Ambien (zolpidem), an imidazo[1,2-a]pyridine derivative, is a commercial drug to treat insomnia which also possesses antitubercular activity against Mycobacterium tuberculosis H37Rv. In this paper, we describe the synthesis of three diverse lead series of imidazo[1,2-a]pyridine/pyrimidine-1,2,3-triazoles (IPTs) which are designed by specific structural modifications of zolpidem. Most of the IPTs exhibited remarkable in vitro antitubercular activity with an MIC of 1.56 ?g mL-1, which is two-fold higher than the MIC of zolpidem. Further, the synthesized IPTs displayed moderate inhibitory activity against several bacterial and fungal strains as well, and also showed an acceptable safety profile as verified through in vitro cytotoxicity assessment against Vero cells. In addition, the potent IPTs exhibited promising binding interactions within the active site of the InhA enzyme. An interesting correlation between the in vitro inhibitory activity and the binding mode was observed: most of the potent molecules (MIC = 1.56 ?g mL-1) interact through a H-bond with the Tyr 158 residue of the target enzyme. These efforts toward the structural modification of zolpidem could be helpful for further optimization of the IPT core to develop new anti-TB drugs. This journal is © 2019 The Royal Society of Chemistry and the Centre National de la Recherche Scientifique.Item Quinoline–1,2,3-triazole Hybrids: Design and Synthesis through Click Reaction, Evaluation of Anti-Tubercular Activity, Molecular Docking and In Silico ADME Studies(Wiley-Blackwell info@wiley.com, 2019) Reddyrajula, R.; Udayakumar, U.A new series of quinoline-1,2,3-triazole derivatives (6a-j and 10a-j) were designed based on the molecular hybridization concept and the molecules were synthesized by employing a click chemistry approach. The pharmacophoric units (quinoline and 1,2,3-triazole) are linked through either an ether or an amide functionality; such a simple structural modification of the linker group significantly enhanced the anti-tubercular activity of the molecules and all the amide derivatives showed better inhibition activity as compared to their ether analogs. However, these compounds did not inhibit significantly the growth of tested bacterial strains: the activity profile is similar to that observed for standard anti-TB drugs indicating the specificity of these compounds towards the M.tuberculosis strain. The molecular docking studies of the active compounds with two target enzymes (Inh A and CYP121) of M.tuberculosis revealed the strong binding interactions, mainly through hydrogen bonding, between the molecules and the target receptors. Furthermore, prediction of in silico-ADME (A: absorption, D: distribution, M: metabolism and E: excretion) parameters indicated that these compounds have an excellent oral bioavailability. The results suggest that these quinoline-1,2,3-triazole hybrids are a promising class of molecular entities for the development of new anti-tubercular leads. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, WeinheimItem Molecular hybridization approach for phenothiazine incorporated 1,2,3-triazole hybrids as promising antimicrobial agents: Design, synthesis, molecular docking and in silico ADME studies(Elsevier Masson SAS 62 rue Camille Desmoulins Issy les Moulineaux Cedex 92442, 2019) Reddyrajula, R.; Udayakumar, U.; Madan Kumar, S.The objective of the current study is to synthesize a library consisting of four sets of phenothiazine incorporated 1,2,3-triazole compounds using molecular hybridization approach. In total, 36 new hybrid molecules were synthesized and screened for in vitro growth inhibition activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Among the tested compounds, nineteen compounds exhibited significant activity with MIC value 1.6 ?g/mL, which is twofold higher than the MIC value of standard first-line TB drug Pyrazinamide. In addition, all these compounds are proved to be non-toxic (with selective index > 40) against VERO cell lines. However, these compounds did not inhibit significantly the growth of Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains: the activity profile is similar to that observed for standard anti-TB drugs (isoniazid and pyrazinamide), indicating the specificity of these compounds towards the Mycobacterium tuberculosis strain. Also, we report the molecular docking studies against two target enzymes (Inh A and CYP121) to further validate the antitubercular potency of these molecules. Furthermore, prediction of in silico-ADME and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. The results suggest that these phenothiazine incorporated 1,2,3-triazole compounds are a promising class of molecular entities for the development of new antitubercular leads. © 2019 Elsevier Masson SASItem Design, synthesis, in-vitro evaluation and molecular docking studies of novel indole derivatives as inhibitors of SIRT1 and SIRT2(Academic Press Inc. apjcs@harcourt.com, 2019) Manjula, R.; Gokhale, N.; Unni, S.; Deshmukh, P.; Reddyrajula, R.; Srinivas-Bharath, M.M.; Udayakumar, U.; Padmanabhan, B.Sirtuins (SIRTs), class III HDAC (Histone deacetylase) family proteins, are associated with cancer, diabetes, and other age-related disorders. SIRT1 and SIRT2 are established therapeutic drug targets by regulating its function either by activators or inhibitors. Compounds containing indole moiety are potential lead molecules inhibiting SIRT1 and SIRT2 activity. In the current study, we have successfully synthesized 22 indole derivatives in association with an additional triazole moiety that provide better anchoring of the ligands in the binding cavity of SIRT1 and SIRT2. In-vitro binding and deacetylation assays were carried out to characterize their inhibitory effects against SIRT1 and SIRT2. We found four derivatives, 6l, 6m, 6n, and 6o to be specific for SIRT1 inhibition; three derivatives, 6a, 6d and 6k, specific for SIRT2 inhibition; and two derivatives, 6s and 6t, which inhibit both SIRT1 and SIRT2. In-silico validation for the selected compounds was carried out to study the nature of binding of the ligands with the neighboring residues in the binding site of SIRT1. These derivatives open up newer avenues to explore specific inhibitors of SIRT1 and SIRT2 with therapeutic implications for human diseases. © 2019 Elsevier Inc.Item The bioisosteric modification of pyrazinamide derivatives led to potent antitubercular agents: Synthesis via click approach and molecular docking of pyrazine-1,2,3-triazoles(Elsevier Ltd, 2020) Reddyrajula, R.; Udayakumar, U.Tuberculosis remains as a major public health risk which causes the highest mortality rate globally and an improved regimen is required to treat the drug-resistant strains. Pyrazinamide is a first-line antitubercular drug used in combination therapy with other anti-TB drugs. Herein, we describe the modification of pyrazinamide structure using bioisosterism and rational approaches by incorporating the 1,2,3-triazole moiety. Three sets of pyrazine-1,2,3-triazoles (3a-o, 5a-o and 9a-l) are designed, synthesized and evaluated for their in vitro inhibitory potency against mycobacterium tuberculosis H37Rv. The pyrazine-1,2,3-triazoles synthesized through the bioisosteric modification displayed improved activity as compared to rationally modified pyrazine-1,2,3-triazoles. Among 42 title compounds, seven derivatives demonstrated significant anti-tubercular activity with the MIC of 1.56 ?g/mL, which are two-fold more potent than the parent compound pyrazinamide. Further, the synthesized pyrazinamide analogs demonstrated moderate inhibition activity against several bacterial strains and possessed an acceptable in vitro cytotoxicity profile as well. Additionally, the activity profile of pyrazine-1,2,3-triazoles was validated by performing the molecular docking studies against the Inh A enzyme. Furthermore, in silico ADME prediction revealed good oral bioavailability for the potent molecules. © 2019 Elsevier LtdItem Discovery of 1,2,3-triazole incorporated indole-piperazines as potent antitubercular agents: Design, synthesis, in vitro biological evaluation, molecular docking and ADME studies(Elsevier Ltd, 2024) Reddyrajula, R.; Etikyala, U.; Vijjulatha, V.; Udayakumar, U.In this report, a library consisting of three sets of indole-piperazine derivatives was designed through the molecular hybridization approach. In total, fifty new hybrid compounds (T1-T50) were synthesized and screened for antitubercular activity against Mycobacterium tuberculosis H37Rv strain (ATCC-27294). Five (T36, T43, T44, T48 and T49) among fifty compounds exhibited significant inhibitory potency with the MIC of 1.6 µg/mL, which is twofold more potent than the standard first-line TB drug Pyrazinamide and equipotent with Isoniazid. N-1,2,3-triazolyl indole-piperazine derivatives displayed improved inhibition activity as compared to the simple and N-benzyl indole-piperazine derivatives. In addition, the observed activity profile of indole-piperazines was similar to standard anti-TB drugs (isoniazid and pyrazinamide) against Staphylococcus aureus, Escherichia coli, and Pseudomonas aeruginosa strains, demonstrating the compounds’ selectivity towards the Mycobacterium tuberculosis H37Rv strain. All the active anti-TB compounds are proved to be non-toxic (with IC50 > 300 μg/mL) as verified through the toxicity evaluation against VERO cell lines. Additionally, molecular docking studies against two target enzymes (Inh A and CYP121) were performed to validate the activity profile of indole-piperazine derivatives. Further, in silico-ADME prediction and pharmacokinetic parameters indicated that these compounds have good oral bioavailability. © 2023 Elsevier LtdItem Design, synthesis and molecular docking of 5-fluoro indole derivatives as inhibitors of PI3K/Akt signalling pathway in cervical cancer(Elsevier B.V., 2024) Etikyala, U.; Reddyrajula, R.; Pasha, A.; Udayakumar, U.; Pawar, S.C.; Vijjulatha, V.The PI3K/Akt signalling pathway promotes variety of cellular processes and the inhibition of PI3K/Akt signalling pathway could lead to decrease in tumour growth effectively in cancer cells. AD412, an indole derivative, is a potent immunosuppressive agent which also reported as an anticancer agent through significant inhibition of PI3K/Akt signalling pathway. In this current work, we designed and synthesized the two diverse lead series of 5-fluoro indole derivatives (6a-l and 11a-l) by specific structural modifications of AD412. In total, 24 new derivatives were evaluated for their antiproliferative activity against two cervical cancer cell lines (HeLa and SiHa) and a normal cell line (HEK 293). Among them, 6e exhibited excellent antiproliferative activity against HeLa and SiHa cells with IC50 values of 9.366 and 8.475 µM respectively, as well displayed a low toxicity profile. Further, 6e inhibited the migration and invasion of HeLa cells in a dose-dependent manner by affecting the synthesis of DNA. Moreover, the Western blot analysis revealed that 6e could inhibit cervical cancer progression by downregulating the PI3K-p85 and phosphorylation of Akt in Hela cells. In vitro mechanism studies demonstrated that 6e could significantly increase apoptosis in HeLa cells by upregulating the expression of proapoptosis related protein Bax. The binding mechanism and the activity profile of 5-fluoro indole derivatives were validated by employing molecular docking studies against the active sites of Akt and PI3K enzymes. In addition, in silico ADME and pharmacokinetic parameters prediction of compound 6e resulted in good oral bioavailability. Therefore, compound 6e could be a lead compound for further development of PI3K/Akt inhibitors and anticancer agents. © 2024Item N-Acyl phenothiazines as mycobacterial ATP synthase inhibitors: Rational design, synthesis and in vitro evaluation against drug sensitive, RR and MDR-TB(Academic Press Inc., 2024) Reddyrajula, R.; Perveen, S.; Negi, A.; Etikyala, U.; Vijjulatha, V.; Sharma, R.; Udayakumar, D.The mycobacterial F-ATP synthase is responsible for the optimal growth, metabolism and viability of Mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the discovery of an N-acyl phenothiazine derivative, termed PT6, targeting the mycobacterial F-ATP synthase. PT6 is bactericidal and active against the drug sensitive, Rifampicin-resistant as well as Multidrug-resistant tuberculosis strains. Compound PT6 showed noteworthy inhibition of F-ATP synthesis, exhibiting an IC50 of 0.788 µM in M. smegmatis IMVs and was observed that it could deplete intracellular ATP levels, exhibiting an IC50 of 30 µM. PT6 displayed a high selectivity towards mycobacterial ATP synthase compared to mitochondrial ATP synthase. Compound PT6 showed a minor synergistic effect in combination with Rifampicin and Isoniazid. PT6 demonstrated null cytotoxicity as confirmed by assessing its toxicity against VERO cell lines. Further, the binding mechanism and the activity profile of PT6 were validated by employing in silico techniques such as molecular docking, Prime MM/GBSA, DFT and ADMET analysis. These results suggest that PT6 presents an attractive lead for the discovery of a novel class of mycobacterial F-ATP synthase inhibitors. © 2024 Elsevier Inc.Item Ionic liquid promoted facile one-pot synthesis of phenothiazine-thiazolidin-4-ones as potent antitubercular agents via mycobacterial ATP synthase inhibition(Elsevier B.V., 2025) Reddyrajula, R.; Etikyala, U.; Mahapathra, H.C.; Udaybhan, R.A.; Vijjulatha, V.; Udayakumar, U.The mycobacterial ATP synthase is responsible for the optimal growth, metabolism and viability of mycobacteria, establishing it as a validated target for the development of anti-TB therapeutics. Herein, we report the facile and efficient one-pot three component synthesis of 2-(10H-phenothiazin-3-yl)-3-substituted thiazolidin-4-one derivatives by using ionic liquid, 1?butyl?3-methylimidazolium bromide [Bmim]Br and their inhibitory potency against mycobacterium tuberculosis H37Rv strain (ATCC-27,294). Compound T27 exhibited the highest inhibition activity with an MIC of 0.78 ?g/mL, which is twofold and fourfold superior (in terms of the MIC values) to the standard first-line TB drugs isoniazid (MIC: 1.56 ?g/mL) and pyrazinamide (MIC: 3.12 ?g/mL) respectively. Two other compounds (T25 and T30) are equipotent as the isoniazid. The SAR studies revealed that insertion of 1,2,3-traizole and thiozolidine-2-one rings enhance the anti-TB activity in most of the tested compounds. Also, compound T27 was screened for mycobacterial ATP synthase inhibition activity and it exhibited an IC50 of 0.735 µM in M. smegmatis IMVs. Further, toxicity evaluation against VERO cell lines confirmed null cytotoxicity (selectivity index > 70) of the potent analogues. The title compounds are highly specific towards to the M. tb strain, i.e., most of the compounds exhibited moderate inhibitory potency against the tested bacterial strains (MIC ? 6.25 ?g/mL). In addition, molecular docking was employed against the active site of the ATP synthase enzyme to validate the binding mechanism and in vitro activity profile of the phenothiazine derivatives. Furthermore, in silico ADME and pharmacokinetic parameters’ prediction indicated good oral bioavailability. © 2024 Elsevier B.V.Item An in silico approach to identify novel and potential Akt1 (protein kinase B-alpha) inhibitors as anticancer drugs(Springer Nature, 2025) Etikyala, U.; Reddyrajula, R.; Vani, T.; Kuchana, V.; Udayakumar, U.; Vijjulatha, V.Akt1 (protein kinase B) has become a major focus of attention due to its significant functionality in a variety of cellular processes and the inhibition of Akt1 could lead to a decrease in tumour growth effectively in cancer cells. In the present work, we discovered a set of novel Akt1 inhibitors by using multiple computational techniques, i.e. pharmacophore-based virtual screening, molecular docking, binding free energy calculations, and ADME properties. A five-point pharmacophore hypothesis was implemented and validated with AADRR38. The obtained R2 and Q2 values are in the acceptable region with the values of 0.90 and 0.64, respectively. The generated pharmacophore model was employed for virtual screening to find out the potential Akt1 inhibitors. Further, the selected hits were subjected to molecular docking, binding free energy analysis, and refined using ADME properties. Also, we designed a series of 6-methoxybenzo[b]oxazole analogues by comprising the structural characteristics of the hits acquired from the database. Molecules D1–D10 were found to have strong binding interactions and higher binding free energy values. In addition, Molecular dynamic simulation was performed to understand the conformational changes of protein–ligand complex. © The Author(s), under exclusive licence to Springer Nature Switzerland AG 2024.